EA040364B1 - BISPECIFIC ANTI-CD3 ANTIBODIES AND METHODS OF THEIR APPLICATION - Google Patents

Description

Technical field

The present invention relates to cassette of differentiation 3 (CD3) antibodies and methods for their use.

State of the art

Cell proliferative disorders such as cancer are characterized by the uncontrolled growth of cell populations. They are the leading cause of death in developed countries and the second leading cause of death in developing countries, with 12 million new cancer cases diagnosed each year and 7 million deaths. According to the National Cancer Institute, more than half a million Americans died of cancer in 2013, about one in four deaths in the country. As the older population has increased, so too has the incidence of cancer, as the chance of developing cancer after seventy more than doubles. Thus, cancer represents a significant and ever-increasing social burden.

Traditional approaches to cancer treatment include chemotherapy, radiation therapy, and surgery to remove solid tumors. Recently, immunotherapy based on bispecific antibodies has been developed. Such bispecific antibodies are capable of simultaneously binding cell surface antigens on cytotoxic cells and tumor cells so that the associated cytotoxic cell destroys the associated tumor cell. Existing bispecific antibodies currently in clinical trials are limited by short half-lives and/or variable potency. Therefore, there is an unmet need in the art for the development of effective bispecific antibodies for use in the treatment of cancer.

The essence of the invention

In one aspect, the invention provides a bispecific antibody that binds to HER2 and CD3, the bispecific antibody comprising an anti-CD3 arm comprising a first binding domain containing the following six hypervariable regions (HVRs):

(a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 1;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 2;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 3;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 4;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 5;

(f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 6; and an anti-HER2 arm containing a second binding domain containing the following six (HVRs):

(a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 169;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 170;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 171;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 172;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 173; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 174.

In one embodiment, the first binding domain comprises (a) a heavy chain variable domain (VH) comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 184;

(b) a light chain variable domain (VL) containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 185; or (c) a VH domain according to (a) and a VL domain according to (b).

In one embodiment, the VH domain contains the amino acid sequence of SEQ ID NO: 184 and/or the VL domain contains the amino acid sequence of SEQ ID NO: 185.

In one embodiment, the second binding domain comprises (a) a VH domain containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 270;

(b) a VL domain containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 271; or (c) a VH domain according to (a) and a VL domain according to (b).

In one embodiment, the second binding domain comprises (a) a VH domain containing the amino acid sequence of SEQ ID NO: 270 and/or (b) a VL domain containing the amino acid sequence of SEQ ID NO: 271.

In one embodiment, the bispecific antibody comprises an anti-CD3 arm comprising a first binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 184; And

- 1 040364 (b) VL domain containing the amino acid sequence of SEQ ID NO: 185; and aHTu-HER2 arm containing a second binding domain containing (a) a VH domain containing the amino acid sequence of SEQ ID NO: 270; and (b) a VL domain containing the amino acid sequence of SEQ ID NO: 271.

In one embodiment, the first binding domain binds to a human CD3 polypeptide or a cynomolgus monkey (cyno) CD3 polypeptide.

In one embodiment, (a) the human CD3 polypeptide is a human CD3ε polypeptide or a human CD3y polypeptide, or (b) the cynomolgus CD3 polypeptide is a cynomolgus CD3ε polypeptide or a cynomolgus CD3y polypeptide.

In one embodiment, the bispecific antibody contains a substitution mutation in the Fc region that reduces effector function.

In one embodiment, the substitution mutation occurs at amino acid residue N297, L234, L235 and/or D265 (EU numbering).

In one embodiment, the substitution mutation is selected from the group consisting of N297G, N297A, L234A, L235A, and D265A.

In one embodiment, the bispecific antibody is one or more of (i) a humanized antibody or a chimeric antibody; and (ii) IgG antibodies.

In one embodiment, the bispecific antibody comprises one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from a first CH1 domain (CH11), a first CH2 domain (CH21), a first CH3 domain (CH31), a second CH1 domain (CH1 ₂ ), a second CH2 domain (CH22), and a second CH3 domain (CH32).

In one embodiment, at least one of one or more heavy chain constant domains is conjugated to another heavy chain constant domain, wherein (i) each of the CH31 and CH32 domains contains a ridge or trough, with the trough or trough in the CH31 domain being compatible, respectively. with a depression or ledge in the CH32 domain; or (ii) each of the CH21 and CH22 domains contains a ridge or pit, with the ridge or pit in the CH21 domain being compatible with the pit or ridge in the CH22 domain, respectively.

In one embodiment, the anti-CD3 shoulder comprises a dimple and the anti-HER2 shoulder comprises a protrusion.

In another aspect, the invention relates to a set of nucleic acids encoding a bispecific antibody.

In another aspect, the invention relates to a set of expression vectors containing a set of isolated nucleic acids.

In another aspect, the invention relates to a set of host cells for expressing a set of nucleic acids, where the set of host cells contains a set of expression vectors.

In another aspect, the invention provides an isolated nucleic acid encoding a bispecific antibody.

In another aspect, the invention relates to an expression vector containing an isolated nucleic acid.

In another aspect, the invention relates to a host cell for expression of a nucleic acid containing an expression vector.

In another aspect, the invention relates to a method for producing a bispecific antibody, comprising culturing a host cell in a culture medium and isolating the bispecific antibody from the host cell or culture medium.

In another aspect, the invention relates to an immunoconjugate that binds HER2 and CD3, containing a bispecific antibody and a cytotoxic agent.

In another aspect, the invention provides a composition for treating or slowing the progression of a cell proliferative disorder, the composition comprising a bispecific antibody and a pharmaceutically acceptable carrier, adjuvant or diluent.

In one embodiment, the composition further comprises an antagonist that binds to a component of the PD-1 signaling pathway or an additional therapeutic agent.

In another aspect, the invention relates to the use of a bispecific antibody in the manufacture of a medicament for treating or slowing the progression of a cell proliferative disorder.

In another aspect, the invention relates to the use of a bispecific antibody in the manufacture of a medicament for enhancing immune function.

In one embodiment, the cell proliferative disorder is an HER2 positive cancer.

In one embodiment, the HER2 positive cancer is HER2 positive breast cancer or HER2 positive gastric cancer.

In another aspect, the invention relates to a method for treating or slowing the progression of a cell proliferative disorder in a subject in need thereof, comprising administering to the subject an effective amount of a bispecific antibody.

In another aspect, the invention relates to a method for enhancing immune function in a subject having a cell proliferative disorder, comprising administering to the subject a bispecific antibody.

In one embodiment, the cell proliferative disorder is an HER2 positive cancer.

In one embodiment, the HER2 positive cancer is HER2 positive breast cancer or HER2 positive gastric cancer.

In one embodiment, the bispecific antibody is administered to the subject at a dose of about 0.01 mg/kg to about 10 mg/kg, about 0.1 mg/kg to about 10 mg/kg, or about 1 mg/kg.

In one embodiment, the method further comprises administering to the subject an antagonist that binds to a component of the PD-1 signaling pathway and/or an additional therapeutic agent.

In one embodiment, the antagonist that binds to a component of the PD-1 signaling pathway is a PD-L1 binding antagonist.

In one embodiment, the PD-L1 binding antagonist is selected from the group consisting of MPDL3280A, MDX-1105 and MEDI4736.

In one embodiment, the antagonist that binds to a component of the PD-1 signaling pathway is a PD-1 binding antagonist.

In one embodiment, the PD-1 binding antagonist is selected from the group consisting of MDX-1106 (nivolumab), MK-3475 (lambrolizumab), and AMP-224.

In one embodiment, the antagonist that binds to a component of the PD-1 signaling pathway is a PD-L2 binding antagonist.

In one embodiment, the PD-L2 binding antagonist is an antibody or an immunoadhesin.

In one embodiment, the method further comprises administering a glucocorticoid or an antibody drug conjugate (ADC) to the subject.

In one embodiment, the method further comprises administering to the subject one or more therapeutic agents that target the HER pathway.

In one embodiment, one or more additional therapeutic agents that target the HER pathway are selected from trastuzumab, T-DM1, and pertuzumab.

In one embodiment, the additional therapeutic agent is trastuzumab.

In one embodiment, the bispecific antibody is administered subcutaneously, intravenously, intramuscularly, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally.

In one embodiment, the subject is a human.

In another aspect, the invention relates to a kit for treating or slowing the progression of a cell proliferative disorder in a subject, characterized in that it contains a composition and an insert containing instructions for administering the composition to a subject to treat or slow the progression of a cell proliferative disorder.

In one embodiment, the cell proliferative disorder is an HER2 positive cancer.

In one embodiment, the HER2 positive cancer is HER2 positive breast cancer or HER2 positive gastric cancer.

Brief description of graphic materials

In FIG. 1 shows the amino acid sequence of single chain human CD3εγ with a 26mer linker sequence used in CD3 epitope mapping experiments (SEQ ID NO: 282).

In FIG. 2A is a table summarizing the characteristics of selected hybridoma clones. The table summarizes the results of CD3 binding experiments performed by ELISA using human and cynomolgus CD3ε ¹ ' ²⁷ -Fc;

FACS binding experiments using human Jurkat T cells, human PBMCs, and cynomolgus monkey PBMCs;

T cell activation experiments using FACS analysis; and experiments to determine the isotype.

In FIG. 2B is a table summarizing the binding affinities (Kd values) of selected hybridoma clones for the commercial human CD3εγ antigen.

In FIG. 3A is a table summarizing the characteristics of selected hybridomas. The table summarizes the results of CD3 binding experiments performed by ELISA using human and cynomolgus CD3ε ¹ ' ²⁷ -Fc;

- 3,040,364 FACS binding experiments using human Jurkat T cells, human PBMCs, and cynomolgus monkey PBMCs;

T cell activation experiments using FACS analysis; and experiments to determine the isotype.

In FIG. 3B and 3C are tables summarizing the binding affinity (Kd values) of the selected hybridoma clones.

In FIG. 4A shows the amino acid sequences of the light chain variable domains of antu-CD3 antibodies. The HVR sequences for each of the antibodies are delimited and indicated by boxes.

In FIG. 4B shows the amino acid sequences of the light chain variable domains of antu-CD3 antibodies.

In FIG. 4C shows the amino acid sequences of the heavy chain variable domains of anti-CD3 antibodies.

In FIG. 5A shows the amino acid sequences of the light chain variable domains of anti-CD3 antibodies.

In FIG. 5B shows the amino acid sequences of the heavy chain variable domains of anti-CD3 antibodies.

In FIG. 6A shows the amino acid sequences of the light chain variable domains of the anti-CD3 antibodies 21A9 and Rab17.

In FIG. 6B shows the amino acid sequences of the heavy chain variable domains of the anti-CD3 antibodies 21A9 and Rab17.

In FIG. 7 shows sequence alignments of the light chain variable domain (top) and heavy chain variable domain (bottom) for the amino acid sequences of anti-CD3 antibodies, illustrating the 40G5c consensus sequence derived from related clonal antibodies.

In FIG. 8A shows sequence alignments of the light chain variable domain (top) and the heavy chain variable domain (bottom) for the amino acid sequences of the anti-CD3 antibody 13A3 and its humanized variant (hu13A3).

In FIG. 8B shows the sequence alignment of the light chain variable domain (top) and the heavy chain variable domain (bottom) for the amino acid sequences of the anti-CD3 antibody 30A1 and its humanized variant (hu30A1).

In FIG. 8C shows the sequence alignment of the light chain variable domain (top) and the heavy chain variable domain (bottom) for the amino acid sequences of the anti-CD3 antibody 41D9a and its humanized variant (hu41D9a).

In FIG. 8D shows the sequence alignment of the light chain variable domain (top) and the heavy chain variable domain (bottom) for the amino acid sequences of the anti-CD3 antibody SP34 and its humanized variant (huSP34).

In FIG. 8E shows sequence alignments of the light chain variable domain (top) and the heavy chain variable domain (bottom) for the amino acid sequences of the anti-CD3 antibody 38E4 and its humanized variant (hu38E4).

In FIG. 8F shows sequence alignments of the light chain variable domain (top) and the heavy chain variable domain (bottom) for the amino acid sequences of the anti-CD3 antibody 40G5 and its humanized variant (hu40G5).

In FIG. 9A is a table summarizing selected humanized variants of the 13A3 anti-CD3 antibody and their binding affinity as assessed by commercial CD3ε (Creative Biomart, Shirley, NY; catalog number CD3E-2194H).

In FIG. 9B is a table summarizing selected humanized 30A1 anti-CD3 antibody variants and their binding affinity as assessed by commercial CD3ε (Creative Biomart, Shirley, NY; catalog number CD3E-2194H).

In FIG. 9C is a table summarizing selected humanized variants of the 41D9a anti-CD3 antibody and their binding affinity as assessed by commercial CD3ε (Creative Biomart, Shirley, NY; catalog number CD3E-2194H).

In FIG. 9D is a table summarizing selected humanized variants of the SP34 anti-CD3 antibody and their binding affinity as assessed by commercial CD3ε (Creative Biomart, Shirley, NY; catalog number CD3E-2194H).

In FIG. 9E is a table summarizing selected humanized variants of the 38E4 anti-CD3 antibody and their binding affinity assessed using commercial CD3ε (Creative Biomart, Shirley, NY; catalog number CD3E-2194H).

In FIG. 9F is a table summarizing selected humanized variants of the 40G5c anti-CD3 antibody and their binding affinity as assessed by commercial CD3ε (Creative Biomart, Shirley, NY; catalog number CD3E-2194H).

- 4 040364

In FIG. 10 is a table summarizing the binding affinity of humanized aHTu-CD3 antibodies for various CD3ε antigens.

In FIG. 11 is a table summarizing the binding affinity data for humanized anti-CD3 antibodies 38E4v1 to 38E4v9 and 40G5c obtained by the Biacore method with human

CD3εγ on the chip and anti-CD3 antibodies in the flow fraction.

In FIG. 12A is a table summarizing the relative binding affinities for single alanine, serine, threonine, or glutamate mutants of the humanized anti-CD3 antibody 38E4v1 containing a single mutation in HVR-L3 or HVR-H3 compared to 38E4v1 generated by single-cycle or conventional multi-cycle kinetic analysis. Biacore analysis.

In FIG. 12B shows the amino acid sequences of HVR-L3 (top) and HVR-H3 (bottom) of the humanized anti-CD3 antibody 38E4v1.

In FIG. 13A are graphs illustrating the relative binding of said anti-CD3 antibody to alanine variants of CD3ε ¹ ' ²⁷ -Fc.

In FIG. 13B is a graph illustrating the relative abundance of alanine-scanned CD3εγ phagemid mutants bound to anti-CD3 antibodies 38E4.v1, 40G5c, and SP34.v52 compared to wild-type CD3εγ phage binding.

In FIG. 13C are graphs illustrating the relative binding of anti-CD3 antibodies 38E4.v1, 40G5c, and SP34.v52 to selected alanine-scanned CD3εγ phagemid mutants as a function of phage concentration.

In FIG. 13D are tables illustrating the relative binding affinity of anti-CD3 antibodies SP34.v52 and 38E4v1 to selected alanine-scanned CD3εγ phagemid mutants according to Biacore. HC - no detectable binding.

In FIG. 14A shows the sequence of the 16mer CD3ε polypeptide used in cocrystallization studies with 38E4.v1 Fab.

In FIG. 14B-14F are a series of crystal structure images illustrating the hu38E4.v1 Fab/CD3ε peptide complex from different angles.

In FIG. 14G shows sequence alignments of the light chain variable domain (top) and heavy chain variable domain (bottom) for the amino acid sequences of the hu40G5c and hu38E4.v1 anti-CD3 antibodies, with circled residues of each antibody that are important for CD3 binding (contact residues). The circled residues were found to occupy up to 5 A in the CD3 peptide according to crystallographic analysis.

Δ Indicates vernier positions (for reference see, for example, Foote, Winter, JMB, 224: 487, 1992);

* denotes FW-HVR interactions (for reference, see, for example, Padlan et al., Mol. Immunol., 31: 169, 1994); a • denotes VH-VL interactions (for reference, see, for example, Padlan et al., Mol. Immunol., 31: 169, 1994).

In FIG. 14H shows the crystal structure of the hu38E4.v1 Fab bound CD3ε polypeptide. All contact residues of the antigen are indicated in light gray. All contact residues are identical for hu38E4.v1 and hu40G5, except that in hu40G5 G96 (marked in dark grey) is S96.

In FIG. 14I and 14J are strip diagrams of the crystal structures of hu38E4.v1 Fab and SP34v52 Fab, respectively, in the same orientation, overlapping with a VL region with RMS=2.24.

In FIG. 14K shows a three-dimensional model of the hu38E4.v1 Fab in complex with the N-terminal CD3ε peptide bound in the recess between the heavy and light chains.

In FIG. 14L shows a 3D model of an SP34v52 Fab with the N-terminal CD3ε peptide superimposed in the same orientation as the CD3ε/hu38E4.v1 Fab complex shown in FIG. 14K. Residues R50 and R52 of HVR-H2 in SP34v52 Fab are important for CD3 binding. The exact contact points of the CD3 peptide with the SP34v52 Fab are indicated by arrows.

In FIG. 14M depicts the crystal structure of hu38E4.v1 in complex with the N-terminal peptide CD3εγ and illustrates key intermolecular interactions involving the first pyroglutamine residue and the sixth residue (E6) in CD3εγ. Putative hydrogen bonds are shown in dotted lines.

In FIG. 14N shows a spatial model of the hu38E4.v1 Fab in complex with the N-terminal CD3εγ peptide bound in the recess between the heavy and light chains. As illustrated, the fifth residue (E5) is directed away from the site of interaction, which contains the sixth residue (E6) of the complex of the N-terminal peptide CD3εγ and Fab.

In FIG. 15 shows a general scheme for the formation of a TDB antibody. The particular TDB shown is shown as a full length TDB in ridge-in-gap (BBB) format, which may contain any aglycosylation-associated mutation when produced by a eukaryotic cell (e.g.,

- 5 040364 CHO cell). In an alternative format, the protrusion may be on the aHTu-CD3 arm and the trough may be on the antitumor antigen arm. An aglycosylation-associated mutation may also be present in this format when produced by a eukaryotic cell (e.g., a cell

CHO).

In FIG. 16 are graphs illustrating the results of an in vitro FACS binding assay for various CD3/CD20 TDBs containing various combinations of anti-CD3 arms of the UCHT1 series and anti-CD20 arms of the 2H7 series. Bjab B tumor cell line binding (CD20 binding) is shown on the left. Jurkat cell binding (CD3 binding) is shown on the right.

In FIG. 17 is a group of tables summarizing monovalent (top) and bivalent (bottom) binding affinities as Kd values for various CD3/CD20 TDBs containing various combinations of UCHT1 series anti-CD3 arms and 2H7 series anti-CD20 arms.

In FIG. 18 is a graph illustrating the results of in vitro FACS analysis of Jurkat cell binding (CD3 binding) of various CD3/CD20 TDBs containing different combinations of anti-CD3 arms with an anti-CD20 arm from 2H7v16.

In FIG. 19 is a graph illustrating the results of in vitro FACS analysis of Jurkat cell binding (CD3 binding) of various CD3/CD20 TDBs containing various combinations of anti-CD3 arms with an anti-CD20 arm from 2H7v16.

In FIG. 20 is a graph illustrating the results of an in vitro FACS analysis of Bjab cell binding (CD20 binding) of various CD3/CD20 TDBs containing various combinations of anti-CD3 arms with an anti-CD20 arm from 2H7v16.

In FIG. 21A and 21B are graphs illustrating the results of in vitro FACS analysis of Jurkat cell binding (CD3 binding) of various CD3/CD20 TDBs containing various combinations of anti-CD3 arms with an anti-CD20 arm from 2H7v16.

In FIG. 21C is a table summarizing EC50 (µg/mL) for each CD3/CD20 TDB tested in FIG. 21A and 21B.

In FIG. 22A and 22B are graphs illustrating the results of an in vitro FACS analysis of Bjab cell binding (CD20 binding) of various CD3/CD20 TDBs containing various combinations of anti-CD3 arms with an anti-CD20 arm from 2H7v16.

In FIG. 23 is a graph illustrating the results of in vitro FACS analysis of Jurkat cell binding (CD3 binding) of various CD3/CD20 TDBs containing different combinations of anti-CD3 arms with an anti-CD20 arm from 2H7v16.

In FIG. 24 is a table summarizing the binding affinities for various CD3/CD20 TDBs and Fab obtained by the Biacore assay with human CD3εγ on chip and CD3/CD20 TDB or Fab in the flow fraction.

In FIG. 25A is a graph illustrating the percentage of T cell activation as measured by CD69 and CD25 surface expression after 24 hours of incubation of a specific CD3/CD20 TDB (2H7 lot) with 20,000 Bjab cells and 5x purified human CD8+ T cells.

In FIG. 25B is a graph illustrating the percentage kill of Bjab compared to an untreated TDB control after 24 hours of incubation of specific CD3/CD20 TDB (2H7 lot) with 20,000 Bjab cells and 5x purified human CD8+ T cells according to FACS analysis.

In FIG. 26A is a graph illustrating the percentage of T cell activation as measured by CD69 and CD25 surface expression after 24 hours of incubation of a specific CD3/CD20 TDB (2H7 lot) with 200,000 human PBMCs per well.

In FIG. 26B is a graph illustrating the percentage kill of endogenous (endo) B cells compared to an untreated TDB control after 24 hours of incubation with a specific CD3/CD20 TDB (2H7 lot) with 200,000 human PBMCs per well according to FACS analysis.

In FIG. 27A is a graph illustrating the percentage of T cell activation as measured by CD69 and CD25 surface expression after 24 hours of incubation of a specific CD3/CD20 TDB (UCHT1 series) with 20,000 Bjab cells and 5x purified human CD8+ T cells.

In FIG. 27B is a graph illustrating the percentage kill of Bjab compared to an untreated TDB control after 24 hours of incubation of specific CD3/CD20 TDB (UCHT1 series) with 20,000 Bjab cells and 5x purified human CD8+ T cells according to FACS analysis.

In FIG. 28A is a graph illustrating the percentage of T cell activation as measured by surface expression of CD69 and CD25 after 24 hours of incubation of a specific CD3/CD20 TDB (UCHT1 series) with 200,000 human PBMCs per well.

In FIG. 28B is a graph illustrating the percentage of B cell kill compared to an untreated TDB control after 24 hours of incubation with a specific CD3/CD20 TDB (UCHT1 series) with 200,000 human PBMCs per well according to FACS analysis.

In FIG. 29A is a graph illustrating the percentage killing of endo-B cells compared to an untreated TDB control after 24 h incubation of various CD3/CD20 TDBs containing different combinations of anti-CD3 arms with an anti-CD20 arm from 2H7v16, from 200,000 human

- 6 040364

PBMCs (isolated from donor #3) per well as determined by FACS analysis.

In FIG. 29B is a graph illustrating the percentage of T cell activation according to CD69 and CD25 surface expression data after 24 h incubation of various CD3/CD20 TDBs containing different combinations of anti-CD3 arms with an anti-CD20 arm from 2H7v16, from 200,000 human

PBMCs (isolated from donor #3) per well as determined by FACS analysis.

In FIG. 30A is a graph illustrating the percentage of endo-B cell kill compared to an untreated TDB control after 24 h incubation of various CD3/CD20 TDBs containing various combinations of anti-CD3 arms with an anti-CD20 arm from 2H7v16, from 200,000 human PBMCs (isolated from donor #4) per well according to FACS analysis.

In FIG. 30B is a graph illustrating the percentage of T cell activation according to CD69 and CD25 surface expression data after 24 h incubation of various CD3/CD20 TDBs containing different combinations of anti-CD3 arms with an anti-CD20 arm from 2H7v16, from 200,000 human PBMCs (isolated from donor #4) per well according to FACS analysis.

In FIG. 31A is a graph illustrating the percentage of endo-B cell kill compared to an untreated TDB control after 24 h incubation of various CD3/CD20 TDBs containing various combinations of anti-CD3 arms with an anti-CD20 arm from 2H7v16, with 200,000 cynomolgus monkey PBMCs ( isolated from donor #2) per well according to FACS analysis.

In FIG. 31B is a graph illustrating the percentage of T cell activation according to CD69 and CD25 surface expression data after 24 h incubation of various CD3/CD20 TDBs containing different combinations of anti-CD3 arms with an anti-CD20 arm from 2H7v16, with 200,000 cynomolgus monkey PBMCs ( isolated from donor #2) per well according to FACS analysis.

In FIG. 32A is a graph illustrating the percentage of endo-B cell kill compared to an untreated TDB control after 24 h incubation of various CD3/CD20 TDBs containing various combinations of anti-CD3 arms with an anti-CD20 arm from 2H7v16, with 200,000 cynomolgus monkey PBMCs ( isolated from donor #3) per well according to FACS analysis.

In FIG. 32B is a graph illustrating the percentage of T cell activation according to CD69 and CD25 surface expression data after 24 h incubation of various CD3/CD20 TDBs containing different combinations of anti-CD3 arms with an anti-CD20 arm from 2H7v16, with 200,000 cynomolgus monkey PBMCs ( isolated from donor #3) per well according to FACS analysis.

In FIG. 33A is a graph illustrating the percentage kill of Bjab cells compared to an untreated TDB control after 24 hours of incubation of various CD3/CD20 TDBs containing different combinations of anti-CD3 arms with an anti-CD20 arm from 2H7v16, with 200,000 cynomolgus monkey PBMC per well according to the data. FACS analysis.

In FIG. 33B is a graph illustrating the percentage of T cell activation as measured by CD69 and CD25 surface expression after 24 h incubation of various CD3/CD20 TDBs containing different combinations of anti-CD3 arms with an anti-CD20 arm from 2H7v16, with 200,000 cynomolgus monkey PBMCs per well according to FACS analysis.

In FIG. 34A is a graph illustrating the percentage killing of endo-B cells compared to an untreated TDB control after 24 hours of incubation of various CD3/CD20 TDBs containing different combinations of anti-CD3 arms with an anti-CD20 arm from 2H7v16, from 200,000 human PBMCs (isolated from donor #2) per well according to FACS analysis.

In FIG. 34B is a graph illustrating the percentage of T cell activation according to CD69 and CD25 surface expression data after 24 h incubation of various CD3/CD20 TDBs containing various combinations of anti-CD3 arms with an anti-CD20 arm from 2H7v16, from 200,000 human PBMCs (isolated from donor #2) per well according to FACS analysis.

In FIG. 35A is a graph illustrating the percentage of endo-B cell kill compared to an untreated TDB control after 24 hours of incubation of various CD3/CD20 TDB containing different combinations of anti-CD3 arms with an anti-CD20 arm from 2H7v16, from 200,000 human PBMCs (isolated from donor #3) per well according to FACS analysis.

In FIG. 35B is a graph illustrating the percentage of T cell activation as measured by CD69 and CD25 surface expression after 24 h incubation of various CD3/CD20 TDBs containing different combinations of anti-CD3 arms with an anti-CD20 arm from 2H7v16 from 200,000 human PBMCs (isolated from donor #3) per well according to FACS analysis.

In FIG. 36A is a graph illustrating the percentage of endo-B cell killing compared to untreated TDB control after 24 h incubation of various CD3/CD20 TDB containing different combinations of anti-CD3 arms with an anti-CD20 arm from 2H7v16, from 200,000 human PBMCs (isolated from donor #4) per well according to FACS analysis.

In FIG. 36B is a graph illustrating the percentage of T cell activation according to CD69 and CD25 surface expression data after 24 h incubation of various CD3/CD20 TDBs containing various combinations of anti-CD3 arms with an anti-CD20 arm from 2H7v16, from 200,000 human PBMCs (isolated from donor #4) per well according to FACS analysis.

In FIG. 37A and 37B are graphs illustrating the percentage of T cell activation.

- 7 040364 according to data on the surface expression of CD69 and CD25 after 24 hours of incubation of various

CD3/CD20 TDB containing different combinations of anti-CD3 arms with an anti-CD20 arm from 2H7v16, with

200,000 human PBMCs (isolated from donor #1) per well according to FACS analysis.

In FIG. 37C is a table summarizing EC50 (ng/mL) for T cell activation.

CD8+ for each CD3/CD20 TDB examined in FIG. 37A and 37B.

In FIG. 38A and 38B are graphs illustrating the percentage of endo-B cell kill compared to an untreated TDB control after 24 h incubation of various CD3/CD20 TDBs containing various combinations of anti-CD3 arms with an anti-CD20 arm from 2H7v16, from 200,000 human PBMCs (isolated from donor #1) per well according to FACS analysis.

In FIG. 38C is a table summarizing EC50 (ng/mL) for endo-B cell killing for each CD3/CD20 TDB examined in FIG. 38A and 38B.

In FIG. 39A and 39B are graphs illustrating the percentage of T cell activation as measured by CD69 and CD25 surface expression after 48 hours of incubation of various CD3/CD20 TDBs containing different combinations of anti-CD3 arms with an anti-CD20 arm from 2H7v16 from 200,000 human PBMCs. (isolated from Donor #1) per well as determined by FACS analysis.

In FIG. 39C is a table summarizing EC50 (ng/mL) for CD8+ T cell activation for each CD3/CD20 TDB examined in FIG. 39A and 39B.

In FIG. 40A and 40B are graphs illustrating the percentage of endo-B cell kill compared to an untreated TDB control after 48 hours of incubation of various CD3/CD20 TDBs containing various combinations of anti-CD3 arms with an anti-CD20 arm from 2H7v16, from 200,000 human PBMCs (isolated from donor #1) per well according to FACS analysis.

In FIG. 40C is a table summarizing EC50 (ng/ml) for endo-B cell killing for each CD3/CD20 TDB examined in FIG. 40A and 40B.

In FIG. 41A and 41B are graphs illustrating the percentage of T cell activation according to CD69 and CD25 surface expression data after 24 h incubation of various CD3/CD20 TDBs containing different combinations of anti-CD3 arms with an anti-CD20 arm from 2H7v16 from 200,000 human PBMCs. (isolated from donor #2) per well as determined by FACS analysis.

In FIG. 41C is a table summarizing EC50 (ng/mL) for CD8+ T cell activation for each CD3/CD20 TDB examined in FIG. 41A and 41B.

In FIG. 42A and 42B are graphs illustrating the percentage of endo-B cell kill compared to an untreated TDB control after 24 h incubation of various CD3/CD20 TDBs containing different combinations of anti-CD3 arms with an anti-CD20 arm from 2H7v16, from 200,000 human PBMCs (isolated from donor #2) per well according to FACS analysis.

In FIG. 42C is a table summarizing EC50 (ng/mL) for endo-B cell killing for each CD3/CD20 TDB examined in FIG. 42A and 42B.

In FIG. 43A and 43B are graphs illustrating the percentage of T cell activation according to CD69 and CD25 surface expression data after 48 hours of incubation of various CD3/CD20 TDBs containing various combinations of anti-CD3 arms with an anti-CD20 arm from 2H7v16 from 200,000 human PBMCs. (isolated from donor #2) per well as determined by FACS analysis.

In FIG. 43C is a table summarizing EC50 (ng/ml) for CD8+ T cell activation for each CD3/CD20 TDB examined in FIG. 43A and 43B.

In FIG. 44A and 44B are graphs illustrating the percentage of endo-B cell kill compared to an untreated TDB control after 48 hours of incubation of various CD3/CD20 TDBs containing various combinations of anti-CD3 arms with an anti-CD20 arm from 2H7v16, from 200,000 human PBMCs (isolated from donor #2) per well according to FACS analysis.

In FIG. 44C is a table summarizing EC50 (ng/mL) for endo-B cell killing for each CD3/CD20 TDB examined in FIG. 44A and 44B.

In FIG. 45A is a graph illustrating that certain CD3/CD20 TDBs, such as an antibody containing an anti-CD20 arm from 2H7v16 and an anti-CD3 arm from 72H6, do not show in vitro efficacy according to the Bjab kill assay.

In FIG. 45B and 45C are graphs illustrating that certain CD3/CD20 TDBs, such as an antibody containing an anti-CD20 arm from 2H7v16 and an anti-CD3 arm from 72H6, are not effective in vitro according to an endo-B cell killing assay (B ) and T cell activation (C).

In FIG. 46A is a graph illustrating that certain CD3/CD20 TDBs, such as an antibody containing an anti-CD20 arm from 2H7v16 and an anti-CD3 arm from 13A3, show low in vitro potency according to the Bjab killing assay.

In FIG. 46B is a graph illustrating that certain CD3/CD20 TDBs, such as an antibody containing an anti-CD20 arm from 2H7v16 and an anti-CD3 arm from 30A1, show low in vitro potency according to the Bjab killing assay.

In FIG. 46C is a graph illustrating that certain CD3/CD20 TDBs, such as an antibody containing an anti-CD20 arm from 2H7v16 and an anti-CD3 arm from 41D9a, show low in vitro potency according to the Bjab killing assay. EC50 values (ng/mL) for Bjab cell kill are shown for each CD3/CD20 TDB tested.

In FIG. 46D is a graph illustrating that certain CD3/CD20 TDBs, such as an antibody containing an anti-CD20 arm from 2H7v16 and an anti-CD3 arm from 41D9a, show low in vitro potency as measured by an endo-B cell killing assay. Shown are EC50 values (ng/mL) for endo-B cell killing for each CD3/CD20 TDB tested.

In FIG. 46E is a graph illustrating that certain CD3/CD20 TDBs, such as an antibody containing an anti-CD20 arm from 2H7v16 and an anti-CD3 arm from 41D9a, show poor in vitro efficacy as measured by T cell activation assay.

In FIG. 47A is a graph illustrating that certain CD3/CD20 TDBs, such as TDBs containing the anti-CD20 arm from 2H7v16 and the anti-CD3 arm from UCHT1v9, 21A9, and 40G5c, show high in vitro potency in an endo-B cell killing assay. using 200,000 human PBMCs (isolated from Donor #1) per well according to FACS analysis.

In FIG. 47B is a graph illustrating that certain CD3/CD20 TDBs, such as TDBs containing the anti-CD20 arm from 2H7v16 and the anti-CD3 arm from UCHT1v9, 21A9, and 40G5c, show high in vitro potency as measured by T cell activation assay using 200,000 human PBMCs (isolated from donor #1) per well according to FACS analysis.

In FIG. 48A is a graph illustrating that certain CD3/CD20 TDBs, such as TDBs containing the anti-CD20 arm from 2H7v16 and the anti-CD3 arm from UCHT1v9, 21A9, and 40G5c, show high in vitro potency in an endo-B cell killing assay. using 200,000 human PBMCs (isolated from donor #2) per well according to FACS analysis.

In FIG. 48B is a graph illustrating that certain CD3/CD20 TDBs, such as TDBs containing the anti-CD20 arm from 2H7v16 and the anti-CD3 arm from UCHT1v9, 21A9, and 40G5c, show high in vitro efficacy as measured by T cell activation assay using 200,000 human PBMCs (isolated from donor #2) per well according to FACS analysis.

In FIG. 49 is a table summarizing the in vitro efficacy of various CD3/CD20 TDBs containing various combinations of anti-CD3 arms with an anti-CD20 arm from 2H7v16.

In FIG. 50 shows the amino acid sequences of the light chain variable domain (top) and the heavy chain variable domain (bottom) of the anti-CD20 antibody 2H7.v16.

In FIG. 51 shows the amino acid sequences of the light chain variable domain (top) and the heavy chain variable domain (bottom) of the hu40G5c anti-CD3 antibody.

Fig. 52A and 52B illustrate that purified CD3/CD20 TDB (40G5c/2H7v16) has no detectable aggregate formation according to size exclusion chromatography (SEC) (A) and no detectable homodimer formation (i.e. formation of CD3/CD3 or CD20/CD20 antibodies) according to mass spectrometry data (B).

In FIG. 53A is a graph illustrating the pharmacokinetics of serum CD3/CD20 TDB concentrations at different doses in Sprague-Dawley (SD) rats over time (by day) according to Generic Immunoglobulin Pharmacokinetics (GRIP) or Specific Assay data.

In FIG. 53B is a table summarizing the quantified clearances (mL/day/kg) of test CD3/CD20 TDB antibodies at each dosage tested in FIG. 53A.

In FIG. 54A is a graph illustrating that the F(ab') ₂ portion of CD20 TDB retains the same potency as full-length IgG CD20 TDB in killing B cells (killing Bjab) in vitro. 20,000 Bjab cells and 200,000 PBMCs from a healthy donor were incubated with different concentrations of full length CD20 TDB or F(ab')2 CD20 TDB for 24 h.

In FIG. 54B is a graph illustrating that CD20 TDB B cell killing activity is T cell dependent, as no B cell killing was detected for PBMC with reduced CD3+ T cell count. 20,000 Bjab cells and 200,000 PBMCs from a healthy donor or 200,000 PBMCs depleted of CD3+ T cells were incubated with different concentrations of CD20 TDB for 24 hours.

In FIG. 54C is a graph illustrating that comparable B cell killing can be achieved with both CD4+ and CD8+ T cells as effectors. 20,000 Bjab cells and 100,000 purified CD8+ T cells or CD4+ T cells were incubated with various concentrations of CD20 TDB for 24 hours. Cell killing and activation of T cells, designated CD69+CD25+, were determined and calculated as described below.

In FIG. 54D is a graph illustrating that CD20 TDB is able to activate both CD4+ and CD8+ T cells. 20,000 Bjab cells and 100,000 purified CD8+ T cells or CD4+ T cells were incubated with various concentrations of CD20 TDB for 24 hours. Cell killing and activation of T cells, designated CD69+CD25+, were determined and calculated as described below.

In FIG. 54E is a graph illustrating that the increase in granzymes in CD8+ T cells is more pronounced after the addition of CD20 TDB. 20,000 Bjab cells and 100,000 purified CD8+ T cells or CD4+ T cells were incubated with different concentrations of CD20 TDB for

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h. Induction of granzyme B was detected by FACS.

In FIG. 54F is a graph illustrating that after addition of CD20 TDB for T cells

CD8+ has a higher level of perforin release. 20,000 Bjab cells and 100,000 purified CD8+ T cells or CD4+ T cells were incubated with different concentrations of CD20 TDB for 24 hours. The concentration of perforin in the medium was determined by ELISA.

In FIG. 55 is a series of flow cytometric graphs showing that activated T cells are able to proliferate in the presence of CD20 TDB and Bjab cells.

In FIG. 56A is a series of graphs illustrating dose-response curves for killing B cells of 8 leukemia/lymphoma tumor B cell lines (left) and CD20 expression levels for these B cell lines according to FACS data, where isotype control is shown in gray. B cells were cultured in RPMI 1640 supplemented with 10% FBS. For kill assay, 20,000 B cells were incubated with 200,000 PBMCs from a healthy donor at different concentrations of CD20 TDB for 24 hours.

In FIG. 56B is a graph illustrating the wide range of CD20 expression for the 8 B cell lines examined in FIG. 56A. CD4+ T cells or CD8+ T cells derived from healthy donor whole blood and labeled with CFSE were first incubated alone, with Bjab only, with CD20 TDB only, or with Bjab and CD20 TDB for 24 h, then the cells were washed and fresh medium was added for another 48 hours. The intensity of CFSE T cells was detected by FACS, which shows the proliferation of only T cells in the presence of Bjab and CD20 TDB.

In FIG. 56C is a group of graphs illustrating that CD20 TDB effectively killed all 8 lines in a dose dependent manner with EC50 values for B cell killing (ng/mL) (top) and percentage B cell killing (bottom) plotted as a function of CD20 expression. on the target B cell.

In FIG. 56D is a graph illustrating that TDBs targeting 5 different B cell antigens are comparable in terms of mediating Bjab cell killing by T cells. B cells were cultured in RPMI 1640 supplemented with 10% FBS. For kill assay, 20,000 B cells were incubated with 100,000 purified CD8+ T cells from a healthy donor with CD20 TDB (TDB A: 2H7v16/UCHT1v9) or TDB targeting different B cell antigens (i.e. TDB B-E, each targeting various B-cell antigens), at a concentration of 1000 ng / ml for 24 hours.

In FIG. 56E is a graph illustrating the extent of B cell killing for 10 leukemia/lymphoma tumor B cell lines. B cells were cultured in RPMI 1640 supplemented with 10% FBS. For kill assay, 20,000 B cells were incubated with 100,000 purified CD8+ T cells from a healthy donor and 1000 ng/ml CD20 TDB (2H7v16/UCHT1v9) for 24 h.

In FIG. 56F is a graph illustrating kill dose-response curves for 8 random donors.

In FIG. 56G is a summary plot of EC50 (left) and B cell kill rate (right) with 1000 ng/mL antibody in a 24 hour assay for 30 donors.

In FIG. 56H is a group of graphs illustrating that the rate of B cell killing within 24 hours by CD20 TDB is comparable to or greater than B cell killing by CD19 scFv. For autologous killing of B cells, 200,000 PBMCs from a healthy donor were incubated for 24 hours with CD20 TDB at the indicated concentration. Cell kill was calculated as described below.

In FIG. 56I is a group of graphs illustrating that the rate of B cell killing within 24 hours by CD20 TDB is comparable to or greater than B cell killing by CD19-TDB or CD22-TDB (upper panel) or CD79a or CD79b (lower panel). For autologous killing of B cells, 200,000 PBMCs from a healthy donor were incubated with 40,000 BJAB cells for 24 hours with CD20, CD19, CD22, CD79a, or CD79b TDB at the indicated concentration. Cell kill was calculated as described below.

In FIG. 57A is a series of graphs illustrating the relative expression levels for human CD3ε recorded in CD4+ T cells (left panel) and CD8+ T cells (center panel); and human CD20 in CD19+ B cells (right panel) detected in murine (mu) or human (hu) PBMCs according to FACS data.

Mouse PBMCs were obtained from the blood of doubly transgenic huCD3/huCD20 mice; human PBMCs were obtained from the blood of a healthy donor.

In FIG. 57B is a graph illustrating that CD20 TDB cannot recruit mouse T cells to reduce B cells without human CD3 expression in human CD20 transgenic mice. huCD20 transgenic mice or huCD20/CD3 doubly transgenic mice were treated once intravenously with antibodies as indicated (10 mg/kg for rituximab, 0.5 mg/kg for CD20 TDB and HER2 TDB). Mouse spleens were obtained at D7 (7 days after antibody treatment). The anti-human CD20 antibody rituximab was used as a positive control. CD3/HER2 TDB was used as a negative isotype control.

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In FIG. 57C is a graph illustrating that CD20 TDB is able to recruit murine huCD3-expressing T cells in doubly human CD3/CD20 transgenic mice to effectively reduce the number of murine huCD20-expressing B cells. huCD20 transgenic mice or huCD20/CD3 doubly transgenic mice were treated once intravenously with antibodies as indicated (10 mg/kg for rituximab, 0.5 mg/kg for CD20 TDB and HER2 TDB). Mouse spleens were obtained at D7 (7 days after antibody treatment). CD3/HER2 TDB was used as a negative isotype control.

In FIG. 58A is a series of time plots showing that CD20 TDB treatment resulted in a sustained reduction in B cells up to D15 (15 days post dosing). Doubly transgenic huCD20/CD3 mice were treated once intravenously with different doses of CD20 TDB. They took the blood of mice (D1, D8 and D15).

In FIG. 58B is a graph illustrating that a nearly complete reduction in B cells in mouse spleens was only achieved at D7 after a single dose of 0.5 mg/kg, while a lower dose of 0.05 mg/kg only resulted in partial reduction in the number of B-cells in the spleen. Doubly transgenic huCD20/CD3 mice were treated once intravenously with different doses of CD20 TDB. Received the spleen (D7).

In FIG. 58C is a graph illustrating that a robust reduction in B cells per D7 was observed in the circulatory system of CD20 TDB-treated huCD20/CD3 doubly transgenic mice. Doubly transgenic huCD20/CD3 mice were treated once intravenously with 0.5 mg/kg CD20 TDB. Blood was taken at D0-5 min (5 min after treatment), D0-2 h, D0-8 h, D1, D2, D3 and D7. B cells expressing huCD20 were determined by FACS.

In FIG. 58D is a series of graphs illustrating T cell activation in huCD20/CD3 doubly transgenic mice treated with CD20 TDB. Treated huCD3/huCD20 doubly transgenic mice showed up to 80% increase in human CD3ε expressing CD8+ T cells 2 hours after CD20 TDB treatment, which returned to baseline at D2 and D7 (upper panel). Similarly, the number of human CD3ε expressing CD4+ T cells increased by 80% 2 hours after CD20 TDB treatment and subsequently returned to baseline at D2. Doubly transgenic huCD20/CD3 mice were treated once intravenously with 0.5 mg/kg CD20 TDB. Blood was taken at D0-5 min (5 min after treatment), D0-2 h, D0-8 h, D1, D2, D3 and D7. CD4+ and CD8+ T cells expressing CD3ε were detected by FACS.

In FIG. 59A is a series of flow cytometry graphs illustrating that CD20 TDB reduces marginal zone B cells (MZC) as efficiently as follicular B cells (FOC) after TDB administration to doubly transgenic huCD3/huCD20 mice. Two doubly transgenic animals (left and right panels, respectively) were treated with stock solution (upper panels) or a single intravenous dose of 0.5 mg/kg TDB (lower panels). Mouse spleens were collected at D7 and analyzed by FACS.

In FIG. 59B-59E are a series of graphs illustrating that CD20 TDB reduces marginal zone B cells (MZ) (B) as effectively as follicular B cells (FOC) (C) after a single intravenous dose of 0.5 mg/d. kg TDB along with activation of CD8+ T cells (D) and proliferation of CD8+ T cells (E) in the spleen at the indicated time points. Mouse spleens were obtained at D1, D2, D3, D5, D7 and D14.

In FIG. 60A is a graph illustrating that humanized NSG mice treated with 3-week doses of CD20 TDB at 0.5 mg/kg (repeated dosing regimen) showed reduced blood levels of B-cells at D7, with virtually none at D21. B cells. Humanized NSG mice were intravenously treated once a week with 3 doses of 0.5 mg/kg CD20 TDB. Blood was taken at D-5 (5 days before treatment), D7, D14 and D21. The number of mouse B-cells in the blood was determined by FACS.

In FIG. 60B is a graph illustrating that a robust reduction in B cells at D21 was observed in the spleens of humanized NSG mice treated with CD20 TDB. Humanized NSG mice were intravenously treated once a week with 3 doses of 0.5 mg/kg CD20 TDB. Blood was taken at D21. The number of mouse B-cells in the blood was determined by FACS.

In FIG. 60C is a series of flow cytometry plots illustrating that huCD8+ T cells proliferate and huCD19+ B cells decrease 7 days after treatment (D7) of humanized NSG CD20 TDB mice. Humanized NSG mice were treated with stock solution or 0.5 mg/kg CD20 TDB (2H7v16/UCHT1v9). Spleens from control and CD20 TDB-treated humanized NSG mice were obtained at D7. B cells expressing huCD19 and T cells expressing huCD8 were detected by FACS.

In FIG. 60D is a graph illustrating that humanized NSG mice treated with 3-week doses of CD20 TDB at 0.5 mg/kg (repeated dosing regimen) showed a 10-fold increase in CD8+ T-cells at D7 that returned to baseline or below. on D14 and D21. Humanized NSG mice were treated iv once a week with 3 doses of 0.5 mg/kg CD20 TDB. Blood was taken at D-5 (5 days before treatment), D7, D14 and D21. The number of mouse CD8+ T-cells in the blood and the activation of T-cells were determined by FACS.

In FIG. 60E is a series of flow cytometry plots illustrating baseline levels of huCD20+ B cells (center panels) and huCD8+ and huCD4+ T cells (right panels) from two humanized NSG mice according to FACS data.

In FIG. 60F is a series of graphs illustrating the levels of huCD3ε cell surface expression and CD20 expression on CD19+ B cells (left), CD8+ T cells (center), and CD4+ T cells (right) according to FACS data.

In FIG. 61A is a graph illustrating that CD20 TDB effectively kills CLL B cells via autologous T cells. 200,000 PBMCs were incubated with various concentrations of CD20 TDB for 48 hours in RPMI supplemented with 10% PBS.

In FIG. 61B is a graph illustrating that CD20 TDB effectively induces autologous T cell activation in the presence of CLL B cells. 200,000 PBMCs were incubated with various concentrations of CD20 TDB for 48 hours in RPMI supplemented with 10% PBS.

In FIG. 61C is a group of graphs illustrating that T cell count is highly correlated with ex vivo CLL B cell killing. 200,000 PBMCs were incubated with 1,000 ng/ml CD20 TDB for 48 hours, alone or supplemented with CD8+ T cells obtained from a healthy donor. The percentage of CD19+CD5+ B cells and CD8+ T cells in CLL PBMC was 90/0.55 for A1645, 76/3.5 for A1957, 87/0.63 for A1978, 69/1.3 for A1980. Cell killing, granzyme B induction, and T cell activation were determined by FACS as described below.

In FIG. 62A is a group of graphs illustrating that T cell activation (left) after 0.1 or 0.5 mg/kg CD20 TDB doses in NSG mice inoculated with CLL leukemia cells correlates with an effective reduction in engrafted CLL B cells (right).

In FIG. 62B is a group of immunohistochemical images of spleen sections from NSG mice inoculated with CLL leukemia cells illustrating that only a small number of B cells are detected after CD20 TDB treatment. B cells and T cells were grafted into NSG mice as described below. Mice were treated once intravenously with HER2 TDB and rituximab at a concentration of 0.5 mg/kg, CD20 TDB at a concentration of 0.1 and 0.5 mg/kg, and spleens were obtained for FACS analysis 14 days after treatment.

In FIG. 63 is a graph illustrating approximate tumor volume over time for grafted Bjab tumors in SCID mice for group 1 (stock solution: 20 mM histidine/acetate, pH 5.5, 240 mM sucrose, 0.02% Tween 20);

group 2 (CD20 TDB: 2H7v114/UCHT1.v9; 0.5 mg/kg);

group 3 (stock solution: 20 mM histidine/acetate, pH 5.5, 240 mM sucrose, 0.02% Tween 20, PBMC); and group 4 (CD20 TDB: CD20 2H7v114/CD3 UCHT1.v9; 0.5 mg/kg, PBMC).

PBMCs obtained from a healthy human donor served as effector cells. Mice were treated for two weeks once a week.

In FIG. 64A is a graph illustrating the relative level of CD20 expression on Bjab, NALM-6, SC-1, and OCI-LY 19 cells. B cells and T cells were grafted into NSG mice as described below. Mice were treated once intravenously with HER2 TDB rituximab at a concentration of 0.5 mg/kg, CD20 TDB at a concentration of 0.1 and 0.5 mg/kg, and spleens were obtained for IHC analysis 14 days after treatment.

In FIG. 64B is a graph illustrating that rituximab and CD20 TDB are comparable in efficacy in killing Bjab cells in vitro that express high levels of CD20 on their cell surface. PBMCs obtained from a healthy donor contained no B cells and were used as effector cells in an in vitro cell killing assay. 20,000 B cells and 200,000 effector cells were incubated with different concentrations of CD20 TDB or rituximab for 24 hours. CD20 TDB expression was determined by FACS.

In FIG. 64C is a graph illustrating that CD20 TDB, but not rituximab, is able to kill NALM-6, SC-1 and OCI-LY 19 cells that contain relatively low levels of CD20 on their cell surface. PBMCs obtained from a healthy donor contained no B cells and were used as effector cells in an in vitro cell killing assay. 20,000 B cells and 200,000 effector cells were incubated with different concentrations of CD20 TDB or rituximab for 24 hours. CD20 TDB expression was determined by FACS.

In FIG. 64D is a graph illustrating B cell surface expression levels of unblocked CD20 antigen as a function of rituximab-DANA concentration according to FACS data. CD20/CD3 doubly transgenic mice were treated with a single dose of stock solution or rituximab-DANA (10 mg/kg). Spleens were collected 5 days after treatment.

In FIG. 65A and 65B are graphs illustrating that CD20 TDB is active in killing B cells in vitro in the presence of high levels of rituximab (A) or dexamethasone (B). 200,000 PBMCs from a healthy donor were first incubated with rituximab-DANA at the indicated concentration for 1 h, then CD20 TDB was added and incubated for 24 h. For dexamethasone assay, cells were pretreated overnight with 1 μM dexamethasone before adding CD20 TDB. Cell kill was calculated as described below.

In FIG. 66 is a group of graphs illustrating that CD20 TDB is active in reducing the number of B cells in the blood (left) and spleen (right) of mice pretreated with rituximab-DANA. In the case of single agent treatment, huCD20/CD3 doubly transgenic mice were treated once intravenously at the indicated dosage; in the combination treatment, mice were first treated intravenously with rituximab-DANA and CD20 TDB was injected intravenously 30 minutes later. Blood was taken at D-7, D0-2 h (2 h after TDB treatment) and D7; spleens were collected at D7. The number of B cells was determined by the FACS method, as described below.

In FIG. 67A is a group of graphs illustrating the number of B cells (left), CD4+ T cells (middle), and CD8+ T cells (right) in blood samples from 3 cynomolgus monkeys before and 7 days after a single intravenous treatment with 1 mg/kg CD20 TDB. Three cynomolgus monkeys were treated once intravenously with 1 mg/kg CD20 TDB. Blood was taken at D-7 (7 days before dosing), D0-4 h (4 h immediately after dosing) and D7.

In FIG. 67B is a group of graphs illustrating the levels of B cells, CD4+ T cells, and CD8+ T cells in the spleen (left), submandibular lymph nodes (middle) and mesenteric lymph nodes (right) of 3 cynomolgus monkeys 7 days after a single 1 mg intravenous treatment. /kg CD20 TDB. Three cynomolgus monkeys were treated once intravenously with 1 mg/kg CD20 TDB. Blood was taken at D-7 (7 days before dosing), D0-4 h (4 h immediately after dosing) and D7.

In FIG. 67C is a group of graphs illustrating the levels of B cells, CD4+ T cells, and CD8+ T cells in the spleen (left), submandibular lymph nodes (middle) and mesenteric lymph nodes (right) of 3 cynomolgus monkeys prior to a single intravenous treatment with a dose of 1 mg/kg CD20 TDB. Three cynomolgus monkeys were treated once intravenously with 1 mg/kg CD20 TDB. Blood was taken at D-7 (7 days before dosing), D0-4 h (4 h immediately after dosing) and D7.

In FIG. 67D is a group of graphs illustrating baseline levels of B cells, CD4+ T cells, and CD8+ T cells as a percentage of total lymphocytes detected in the spleen (left) and submandibular lymph nodes (right) of stock solution-treated control animals.

In FIG. 68A is a group of graphs illustrating the serum concentration of CD20 TDB in collected blood and serum samples from four cynomolgus monkeys treated 4 times weekly with 1 mg/kg CD20 TDB by intravenous injection.

In FIG. 68B is a group of graphs illustrating CD20 TDB concentration in serum samples obtained from the animals described in FIG. 65 and 66A. The graph shows the mean values ± s.d.

In FIG. 69A is a histogram illustrating PD-L1 expression on A20-huCD20 cells from A20-huCD20 syngeneic Balb/C mice as measured by flow cytometry.

In FIG. 69B is a graph illustrating over time the relative tumor volume for group 1 (stock solution), group 2 (CD20 TDB at 0.5 mg/kg), group 3 (anti-PD-L1 antibody at 10 mg/kg), and group 4 (CD20 TDB at 0.5 mg/kg + anti-PD-L1 antibody).

In FIG. 70 is a graph illustrating binding curves for each of the three FcRH5 TDBs tested for in vitro binding to CD3-expressing CD8+ T cells.

In FIG. 71A is a graph illustrating percentage target killing of MOLP-2 cells as a function of FcRH5 TDB concentration with CD8+ T cells isolated from human PBMCs from donor #1.

In FIG. 71B is a graph illustrating percentage target killing of MOLP-2 cells as a function of FcRH5 TDB concentration with CD8+ T cells isolated from human PBMCs from donor #2.

In FIG. 72A is a graph illustrating the percentage of CD8+CD69+ T cells as a function of FcRH5 TDB concentration according to FACS analysis. Target cells were MOLP-2 and CD8+ T cells were obtained from donor #1.

In FIG. 72B is a graph illustrating the percentage of CD8+CD107a+ T cells as a function of FcRH5 TDB concentration according to FACS analysis. Target cells were MOLP-2 and CD8+ T cells were obtained from donor #1.

In FIG. 72C is a graph illustrating the percentage of CD8+CD69+ T cells as a function of FcRH5 TDB concentration according to FACS analysis. Target cells were MOLP-2 and CD8+ T cells were obtained from donor #2.

In FIG. 72D is a graph illustrating the percentage of CD8+CD107a+ T cells as a function of FcRH5 TDB concentration according to FACS analysis. Target cells were MOLP-2 and CD8+ T cells were obtained from donor #2.

In FIG. 73 is a group of graphs illustrating the binding curves for each of the three

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HER2 TDB tested for in vitro binding to HER2-expressing SKBR3 cells (top) and CD3-expressing CD8+ T cells (bottom).

In FIG. 74A is a graph illustrating binding curves for trastuzumab (bivalent), trastuzumab (Fab), and HER2 TDB (UCHT1v9/hu4D5) (bispecific) for in vitro binding to

HER2-expressing SKBR3 cells.

In FIG. 74B is a graph illustrating the percentage of viable SKBR3 cells as a function of concentration of trastuzumab (bivalent), trastuzumab (Fab) and HER2 TDB (UCHT1v9/hu4D5) (bispecific) according to the fluorescent cell viability assay CELLTITERGLO®.

In FIG. 74C is a graph illustrating the percentage of target cell killing of SKBR cells mediated by antibody-dependent cell-mediated cytotoxicity (ADCC) in the presence of trastuzumab (T-mab), trastuzumab produced in E. coli (E. coli T-mab), and HER2 TDB. (UCHT1v9/hu4D5) according to lactate dehydrogenase (LDH) release from lysed cells.

In FIG. 75 is a graph illustrating percentage target killing of SKBR3 cells as a function of HER2 TDB concentration (hu4D5-TDB, hu4D5.91A-TDB and hu4D5.Y100A-TDB).

In FIG. 76A shows a series of panels. The upper panel shows the crystal structure of the extracellular domain (ECD) of HER2 associated with hu4D5 Fab (trastuzumab), 2C4 Fab (pertuzumab), and 7C2. The bottom panel shows the band structure of CD3ε bound 2C11, 38E4v1, and 40G5c.

In FIG. 76B is a table showing the binding affinity, represented by the dissociation constant Kd (nM), of HER2-TDB for three different arms of HER2: hu4D5, 2C4, and 7C2. The lower right panel is a table showing the binding affinity, represented by the dissociation constant Kd (nM), of HER2-TDB for three different arms of CD3ε: 38E4v1, 40G5c and 2C11.

In FIG. 76C is a graph illustrating percentage target killing of HER2 expressing MCF7 cells as a function of HER2-TDB concentration (hu4D5-TDB, 2C4-TDB and 7C2-TDB). Cytotoxicity was determined by the release of lactate dehydrogenase (LDH).

In FIG. 77 is a graph illustrating that the hu4D5 and 2C4 HER2 arms are effective mediators of cell killing, as indicated by the maximum percentage of targeted SKBR3 cell killing achieved when treated with the following HER2-TDB variants: hu4D5-38E4v1, hu4D5-40G5c, 2C4-38E4v1, 2C4-40G5c, 7C2-38E4v1 and 7C2-40G5c.

In FIG. 78 is a series of graphs illustrating the dose-dependent efficacy of HER2-TDB variants in killing HER2-expressing SKBR3 cell lines (left) and HER2-expressing MCF7 cell lines (right) with EC50 values for targeted cell killing (pM).

In FIG. 79 is a series of graphs illustrating the fraction of targeted killing of HER2 expressing SKBR3 cells for different TDBs with HER2 arms (hu4D5, 2C4 and 7C2) paired with high affinity (38E4v1) or low affinity (40G5c) CD3 arms as a function of TDB concentration (ng/mL). ).

In FIG. 80 shows a series of panels. The left panel shows the dose-dependent efficacy of HER2-TDB variants (hu4D5-38E4v1, 2C4-38E4v1, 7C2-38E4v1; hu4D5-40G5c, 2C4-40G5c, 7C2-40G5c) in killing HER2-expressing SKBR3 and HER2-expressing cell lines. cell lines MCF7 with EC50 values for targeted cell killing (pM). The panel on the right shows a table with the EC50 ratio of these HER2-TDB variants for MCF7 and SKBR3 target cells for three experiments.

In FIG. 81 shows a series of panels. Top panel lists hu4D5 HER2 arm variants (hu4D5v7, hu4D5v5, hu4D5v10, hu4D5v31, hu4D5.Y100A) for HER2-TDB (CD3 arm 40G5c) and corresponding EC50 (ng/mL) for targeted cell killing by SKBR3, HER2 binding affinity (Kd, nM) in addition to the ratio of HER2 and EC50 Kd binding affinity to target SKBR3 cells between hu4D5 and hu4D5 variants. The bottom panel is a graph illustrating the correlation between the EC50 SKBR3 ratio for hu4D5 HER2-TDB variants (hu4D5, hu4D5v7, hu4D5v5, hu4D5v10 and hu4D5v31) and the corresponding Kd ratio for hu4D5 HER2-TDB variants.

In FIG. 82 is a series of graphs illustrating the percentage of targeted killing of SKBR3 and MCF7 cells as a function of the concentration of the following HER2-TDB variants: hu4D540G5c (upper left), hu4D5v7-40G5c (upper center), hu4D5v5-40G5c (upper right), hu4D5v1040G5c ( bottom left), hu4D5v31-40G5c (bottom center), hu4D5.Y100A-40G5c (bottom right).

In FIG. 83 shows a series of graphs. The graph on the left illustrates the percentage of targeted cell killing as a function of concentration (µg/mL) of HER2 blocking bivalent monospecific antibodies specific for the indicated HER2 arm from HER2-TDB (HER2 blocking antibodies: bivalent monospecific antibodies to hu4D5, 2C4 and 7C2; HER2 -TDB: hu4D5-40G5c, 2C4-40G5c and 7C2-38E4v1 at a fixed concentration of 10 ng/ml). The graph on the right illustrates the percentage of viable cells as a function of the concentration of anti-HER2 antibody (hu4D5) trastuzumab in the presence and absence of HER2-TDB hu4D5-40G5c.

In FIG. 84 shows a series of panels. The top panel is a table showing the reactivity of HER2 arm variants with HER2 according to different binding assays in addition to the reactivity of HER2 clones with the anti-hu4D5 antibody trastuzumab. The bottom panel is a graph illustrating the percentage of targeted cell killing as a function of concentration (pM) of the HER2 bispecific Fab for the given clones (hu4D5, 3H4 and 2H11). EC50 values are given for each clone in pM.

In FIG. 85 is a table with affinity and reactivity information for HER2-TDB CD3 arm variants (38E4v1, 38E4, SP34, 40G5c and 2C11).

In FIG. 86 is a graph illustrating targeted killing of HER2-expressing CT26 cells as a function of concentration (ng/mL) of HER2-TDB variants (hu4D5-2C11, hu4D5-SP34, 7C2-2C11 and 2C4-2C11). Effector cells: derived from CD3-TG T cells.

In FIG. 87A is a graph illustrating tumor volume (mm ³ ) measured over time (0-5 days) in animals treated with stock solution or HER2-TDB (0.5 mg/kg).

In FIG. 87B is a series of graphs. The upper left graph illustrates the percentage of peripheral CD45+ cells per 5 cells detected on day 6 after treatment with stock solution or HER2-TDB (0.5 mg/kg). The upper right graph illustrates the percentage of peripheral CD45+ cells, which are CD8+ cells detected on day 6 after treatment with stock solution or HER2-TDB (0.5 mg/kg). The lower left graph illustrates the percentage of peripheral CD45+ cells, which are CD4+ cells detected on day 6 after treatment with stock solution or HER2-TDB (0.5 mg/kg). The lower left graph illustrates the percentage of peripheral CD8+ cells, which are IFN+, detected on day 6 after treatment with stock solution or HER2-TDB (0.5 mg/kg).

In FIG. 88A is a series of graphs. The top graph illustrates a cascade histogram of percent change in tumor volume in animals treated with stock solution or HER2-TDB variant (hu4D5-SP34 or hu4D5-2C11; 0.5 mg/kg; BB, once a week, 5 weeks). The lower graph illustrates a cascading histogram of percent change in tumor volume in animals treated with the HER2-TDB variant (2C4-38E4; 0.5 mg/kg; BB, once a week, 5 weeks).

In FIG. 88B is a series of graphs. The top graph illustrates tumor volume as a percentage of baseline as a function of time (in days) for animals treated with stock solution or HER2-TDB (hu4D5-SP34). The bottom graph illustrates tumor volume as a percentage of baseline as a function of time (in days) for animals treated with stock solution or HER2-TDB (hu4D5-2C11). (HER2-TDB: 0.5 mg/kg; BB, once a week, 5 weeks).

In FIG. 89 is a graph illustrating the percentage of CD8+CD107a+ T cells as a function of HER2 TDB (hu4D5-TDB, hu4D5.91A-TDB and hu4D5.Y100A-TDB) hu4D5 concentration according to FACS analysis. The target cells were SKBR3 cells; effector cells were CD8+ T cells; the ratio of effector cells:target cells=3:1.

In FIG. 90A is a graph illustrating percentage target killing of SKBR3 cells as a function of HER2 TDB concentration (UCHT1v9/hu4D5 and SP34/hu4D5).

In FIG. 90B is a graph illustrating percentage target killing of SKBR3 cells as a function of HER2 TDB concentration (SP34/hu4D5, 38E4c/hu4D5 and 40G5c/hu4D5).

In FIG. 90C is a graph illustrating percentage target killing of SKBR3 cells as a function of HER2 TDB concentration (SP34/hu4D5, 38E4c/hu4D5 and 40G5c/hu4D5).

In FIG. 91A is a graph illustrating the binding curve for each of the three HER2-TDBs (SP34/hu4D5, 38E4c/hu4D5, and 40G5c/hu4D5) tested for in vitro binding to CD3-expressing CD8+ T cells, according to FACS analysis.

In FIG. 91B is a graph illustrating the percentage of CD8+CD69+ T cells as a function of HER2-TDB concentration (SP34/hu4D5, 38E4c/hu4D5 and 40G5c/hu4D5).

In FIG. 92A is a graph illustrating the binding curve for two HER2 TDBs (38E4c/hu4D5 and 38E4/hu4D5) tested for in vitro binding to CD3-expressing CD8+ T cells according to FACS analysis.

In FIG. 92B is a graph illustrating the binding curve for two HER2 TDBs (38E4c/hu4D5 and 38E4/hu4D5) tested for in vitro binding to HER2-expressing SKBR3 cells according to FACS analysis.

In FIG. 92C is a graph illustrating percentage target killing of SKBR3 cells as a function of HER2 TDB concentration (38E4c/hu4D5 and 38E4/hu4D5) according to FACS analysis. The effector cells were human CD8+ T cells; the ratio of effector cells: target cells = 3: 1.

In FIG. 92D is a graph illustrating the percentage of CD8+CD69+ T cells as a function of HER2-TDB concentration (38E4c/hu4D5 and 38E4/hu4D5).

In FIG. 93A is a graph illustrating the percentage of CD8+CD69+granzyme T cells.

- 15 040364

B+ as a function of HER2 TDB concentration (UCHT1v9/hu4D5) according to FACS analysis.

The target cells were SKBR3 cells; effector cells were CD8+ T cells; the ratio of effector cells: target cells = 3: 1.

In FIG. 93B is a series of graphs illustrating T-cell-mediated HER2 TDB (UCHT1v9/hu4D5) target cell granule exocytosis as measured by ELISA for perforin and granzymes A and B, and percent targeted cell killing as measured by LDH release. The target cells were SKBR3 cells; effector cells were PBMCs; the ratio of effector cells:target cells=30:1.

In FIG. 93C is a series of graphs illustrating T-cell mediated HER2 TDB (UCHT1v9/hu4D5) target cell apoptosis as determined by caspase-3 and caspase-7 activity in the CASPASE-GLO® 3/7 assay, apoptosis as determined by the ELISA ^plus cell death detection assay. and release of LDH. The target cells were SKBR3 cells; effector cells were PBMCs; the ratio of effector cells:target cells=10:1.

In FIG. 93D shows Western blot data (top) illustrating HER2 expression in 3T3 transfected cells, graph (bottom) illustrating percent targeted cell killing by activated T cells as a function of HER2 TDB (UCHT1v9/hu4D5) concentration as measured by LDH release. Target cells were 3T3-vector and 3T3-HER2 cells; effector cells were PBMCs; the ratio of effector cells:target cells=10:1.

In FIG. 93E is a graph illustrating percentage target killing of BT474 cells as a function of HER2 TDB (UCHT1v9/hu4D5) concentration in the presence of trastuzumab Fab (T-Fab) or HER2 soluble extracellular domain (VKD) as measured by LDH release. Effector cells were CD8+ T cells; the ratio of effector cells:target cells=5:1.

In FIG. 93F is a graph illustrating percentage target killing of SKBR3 cells as a function of HER2 TDB concentration (UCHT1v9/hu4D5) after reduction of CD3+ cells from the PBMC effector cell population. The ratio of effector cells:target cells=20:1.

In FIG. 94A is a series of graphs illustrating the percentage of CD8+CD69+ T cells (left) and CD8+CD107a+ T cells (middle) as a function of HER2 TDB concentration (UCHT1v9/hu4D5) according to FACS analysis and the percentage of target killing of SKBR3 cells as a function of HER2 TDB concentration (UCHT1v9/hu4D5) (right). The target cells were SKBR3 cells; effector cells were CD8+ T cells; the ratio of effector cells: target cells = 3: 1.

In FIG. 94B is a series of graphs illustrating the percentage of targeted killing of BT474 cells as a function of HER2 TDB concentration (UCHT1v9/hu4D5) (left) and the percentage of CD8+CD69+Granzyme B+ T cells as a function of HER2 TDB concentration (UCHT1v9/hu4D5). ) (right) according to FACS analysis. Target cells were BT474 cells; effector cells were CD8+ T cells; the ratio of effector cells: target cells is indicated.

In FIG. 95A is a series of graphs illustrating CFSE expression in CD8+ T cells in the presence of SKBR3 and/or HER2 TDB (UCHT1v9/hu4D5) target cells.

In FIG. 95B is a graph illustrating the fold change in CD8+ cell count as a function of time after incubation with SKBR3 and HER2 TDB (UCHT1v9/hu4D5) target cells according to FACS analysis.

In FIG. 95C is a series of graphs illustrating the fold change in CD8+ cell count as a function of time after incubation with SKBR3, HER2 TDB (UCHT1v9/hu4D5) target cells and 20 ng/mL IL-2 by FACS analysis.

In FIG. 96A shows Western blot data illustrating the level of HER2 expression for a panel of human tumor cell lines.

In FIG. 96B is a graph illustrating percent target cell killing as a function of HER2 TDB (UCHT1v9/hu4D5) concentration as measured by LDH release. The target cells were BJAB, MDA435, MDA231, MCF7, MDA453, SKBR3 and BT474; effector cells were PBMCs; the ratio of effector cells:target cells=25:1.

In FIG. 96C is a graph illustrating percentage target cell killing as a function of HER2 TDB (UCHT1v9/hu4D5) concentration according to FACS analysis. The target cells were MCF7 and SKBR3; effector cells were PBMCs; the ratio of effector cells:target cells=20:1.

In FIG. 96D is a graph illustrating percentage target cell killing as a function of HER2 TDB (UCHT1v9/hu4D5) concentration according to FACS analysis. The target cells were BJAB and SKBR3; effector cells were PBMCs; the ratio of effector cells:target cells=20:1.

In FIG. 96E is a table illustrating the number of HER2 copies for a panel of target cells and for each EC50 HER2 TDB and the percentage of HER2 occupancy at that concentration. The target cells are MDA435, MDA231, MCF7, MDA453, BT474, and SKBR3.

In FIG. 97A is a graph illustrating percentage target cell killing as a function of HER2 TDB (UCHT1v9/hu4D5) concentration as measured by LDH release.

Target cells were SKBR3, HCC1569, KPL4, HCC202, JIMT1 and CALU3; effector cells were PBMCs; the ratio of effector cells:target cells=10:1.

In FIG. 97B is a graph illustrating the percentage of viable target cells as a function of trastuzumab emtansine (T-DM1) concentration as measured by the CELLTITERGLO® Fluorescent Cell Viability Assay. Target cells were parental BT474-M1 and T-DM1 resistant BT474-M1; effector cells were CD8+ T cells; the ratio of effector cells:target cells=3:1.

In FIG. 97C is a graph illustrating the percentage of viable target cells as a function of HER2 TDB concentration (UCHT1v9/hu4D5) according to FACS analysis. Target cells were parental BT474-M1 and T-DM1 resistant BT474-M1; effector cells were CD8+ T cells; the ratio of effector cells:target cells=3:1.

In FIG. 98 is a graph and table illustrating the pharmacokinetics (PK) of HER2 TDB (UCHT1v9/hu4D5) in Sprague-Dawley rats according to ELISA data.

In FIG. 99A is a graph showing relative tumor volume over time for group 1 (0.5 mg/kg stock solution), group 2 (PBMC(1)+0.5 mg/kg stock solution), group 3 (MCPC(1)+HER2 TDB (UCHT1v9/hu4D5) at 0.5mg/kg), Group 4 (MCPC(2)+stock solution at 0.5mg/kg) and Group 5 (MCPC(2) +HER2 TDB (UCHT1v9/hu4D5) at 0.5 mg/kg).

In FIG. 99B is a graph illustrating the percentage change in tumor volume over time for group 1 (stock solution at 0.5 mg/kg) and group 2 (HER2 TDB (hu4D5/2C11) at 0.5 mg/kg).

In FIG. 99C is a bar graph showing percent change in tumor volume over time for group 1 (stock solution at 0.5 mg/kg) and group 2 (HER2 TDB (hu4D5/2C11) at 0.5 mg/kg).

In FIG. 99D is a graph illustrating relative tumor volume over time for group 1 (stock solution at 0.5 mg/kg) and group 2 (HER2 TDB (hu4D5/2C11) at 0.5 mg/kg). Responders included tumors that were larger than 1000 mm ³ at the start of treatment.

In FIG. 99E is a graph illustrating the percentage change in tumor volume over time for group 1 (CD3 arm control HER2 TDB (hu4D5/SP34) at 0.5 mg/kg) and group 2 (control TDB (2C11) at 0, 5 mg/kg).

In FIG. 99F is a graph illustrating relative tumor volume over time for group 1 (stock solution at 0.5 mg/kg) and group 2 (HER2 TDB (hu4D5/SP34) at 0.5 mg/kg).

In FIG. 99G is a graph showing relative tumor volume over time for group 1 (stock solution at 0.5 mg/kg), group 2 (HER2 TDB (hu4D5/2C11) at 0.5 mg/kg), group 3 (control TDB (2C11) at 0.5 mg/kg) and group 4 (T-DM1 at 15 mg/kg).

In FIG. 100A is a graph illustrating relative tumor volume over time for group 1 (untreated) and group 2 (HER2 TDB (UCHT1v9/hu4D5) at 0.5 mg/kg).

In FIG. 100B is a graph illustrating relative tumor volume over time for group 1 (0.5 mg/kg stock solution), group 2 (PBMC(3)+0.5 mg/kg stock solution), and group 3 (PBMC(3)+control TDB (2C11) at 0.5 mg/kg).

In FIG. 101A is a graph illustrating the binding affinity for the CD3-UCHT1 antibody tested for in vitro binding to human CD3 on human T cells, CD3 TG T cells, and BALB/c T cells according to FACS analysis.

In FIG. 101B is a graph illustrating the binding affinity for the CD3-2C11 antibody assayed for in vitro binding to mouse CD3 on CD3 TG T cells and BALB/c T cells according to FACS analysis.

In FIG. 102A is a graph illustrating percentage target killing of CT26-HER2 cells as a function of HER2 TDB concentration (UCHT1v9/hu4D5) according to FACS analysis. The effector cells were isolated human peripheral blood T cells, transgenic huCD3 spleen T cells, and BALB/c spleen T cells.

In FIG. 102B is a graph illustrating percentage target killing of CT26-HER2 cells as a function of HER2 TDB concentration (hu4D5/2C11) according to FACS analysis. The effector cells were isolated human peripheral blood T cells, transgenic huCD3 spleen T cells, and BALB/c spleen T cells.

In FIG. 103 is a graph illustrating the relative tumor volume over time for group 1 (stock solution at 0.5 mg/kg) and group 2 (HER2 TDB (hu4D5/SP34) in

- 17 040364 concentration 0.5 mg/kg).

In FIG. 104 is a graph illustrating the binding curves for each of the three LYPD1

TDB tested for in vitro binding to CD3-expressing CD8+ T cells.

In FIG. 105 is a graph illustrating the percentage of targeted cell killing

OVCAR3.Luc as a function of LYPD1 TDB concentration.

In FIG. 106 is a group of graphs illustrating the percentage of CD8+CD69+ (left) and CD8+CD25+ (right) T cells as a function of LYPD1 TDB concentration according to FACS analysis. The effector cells were OVCAR3.Luc cells; the ratio of effector cells: target cells = 3: 1.

In FIG. 107 shows the amino acid sequences of the light chain variable domain (top) and the heavy chain variable domain (bottom) of anti-RET antibody 41205.v6.

In FIG. 108A is a graph illustrating tumor volume (mm ³ ) as a function of time (in days) for group 1 (stock solution, qwx3, BB; n=9), group 2 (CD20 TDB (2H7-mu2C11), 0.5 mg/kg, qwx3, BB; n=9), group 3 (anti-PD1 (mu8F11 DANA), 10 mg/kg, tiwx3, WB; n=9) and group 4 (anti-PD1 (mu8F11 DANA), 10 mg/kg, tiwx3, WB+CD20 TDB (2H7-mu2C11), 0.5 mg/kg, qwx3, BB; n=9).

In FIG. 108B is a graph illustrating tumor volume (mm ³ ) as a function of time (in days) for group 1 (stock solution, qwx3, BB; n=9), group 2 (CD20 TDB (2H7-mu2C11), 0.5 mg/kg, qwx3, BB; n=9), group 3 (anti-PD1 (mu8F11 DANA), 10 mg/kg, tiwx3, WB; n=9) and group 4 (anti-PD1 (mu8F11 DANA), 10 mg/kg, tiwx3, WB+CD20 TDB (2H7-mu2C11), 0.5 mg/kg, qwx3, BB; n=9). The solid thick line represents the approximate tumor volume for this group.

Detailed description of embodiments of the invention

I. Definitions.

As used herein, the term roughly refers to the usual range of errors for the corresponding value, well known to a person skilled in the art. As used herein, application to about a value or parameter includes (and describes) embodiments that refer directly to that value or parameter.

As used herein, an acceptor human framework is a framework containing the amino acid sequence of a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework derived from a human immunoglobulin framework or a human consensus framework as defined below. definition. An acceptor human framework derived from a human immunoglobulin framework or human consensus framework may contain a similar amino acid sequence, or it may contain alterations in the amino acid sequence. In some embodiments, the number of amino acid changes is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. In some embodiments, the human VL acceptor framework is identical in sequence to a human immunoglobulin VL framework or human consensus framework.

Affinity refers to the strength of the overall non-covalent interaction between one binding site of a molecule (eg, an antibody) and its binding partner (eg, an antigen). Unless otherwise indicated, in the context of this document, binding affinity refers to a characteristic binding affinity that represents a 1:1 interaction between members of a binding pair (eg, antibody and antigen). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (Kd). Affinity can be measured by conventional methods known in the art, including those described herein. Specific illustrative and exemplary embodiments for measuring binding affinity are described below.

An affinity matured antibody refers to an antibody with one or more changes in one or more hypervariable regions (HVRs) compared to a parent antibody that does not contain such changes, said changes resulting in an improvement in the affinity of the antibody for the antigen.

The terms anti-CD3 antibody and antibody that binds to CD3 refer to an antibody that is capable of binding CD3 with sufficient affinity such that the antibody can be used as a diagnostic and/or therapeutic agent to target CD3. In one embodiment, the degree of binding of an anti-CD3 antibody to an unrelated, non-CD3 protein is less than about 10% of the binding of the antibody to CD3, as determined by, for example, radioimmunoassay (RIA). In certain embodiments, an antibody that binds to CD3 has a dissociation constant (Kd) of <1 μM, <100, <10, <1, <0.1, <0.01, or <0.001 nM (e.g., 10 ^{- 8} M or less, for example from 10 ^-8 to 10 ^-13 M, for example from 10 ^-9 to 10 ^-13 M). In certain embodiments, an anti-CD3 antibody binds to a CD3 epitope,

- 18 040364 which is conserved for CD3 from different species.

The term antibody is used herein in its broadest sense and includes various antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, as long as they exhibit the required antigen-binding activity. .

An antibody fragment refers to a molecule, other than an intact antibody, that contains a portion of the intact antibody that binds the antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; diabody; linear antibodies; single chain antibody molecules (eg scFv); and multispecific antibodies formed from antibody fragments.

By binding domain is meant the portion of a compound or molecule that specifically binds to a target epitope, antigen, ligand, or receptor. Binding domains include, but are not limited to, antibodies (e.g., monoclonal, polyclonal, recombinant, humanized, and chimeric antibodies), antibody fragments, or portions thereof (e.g., Fab fragments, Fab'2 fragments, scFv antibodies, SMIP, domain antibodies, diabodies , minibodies, scFv-Fcs, affibodies, nanobodies, and VH and/or VL domains of antibodies), receptors, ligands, aptamers, and other molecules having a specific binding partner.

A chemotherapeutic agent is a chemical compound used in the treatment of cancer. Examples of chemotherapeutic agents include alkylating agents such as thiotepa or cyclophosphamide (CYTOXAN®); alkylsulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carbokwon, meturedopa and uredopa; ethyleneimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylomelamin; acetogenins (especially bullatacin and bullatacinone); delta-9tetrahydrocannabinol (dronabinol, MARINOL®); beta-lapachone; lapachol; colchicines; betulinic acid; camptothecin (including the synthetic analog of topotecan (HYCAMTIN®), CPT-11 (irinotecan, CAMPTOZAR®), acetylcamptothecin, scopolelectin and 9-aminocamptothecin); bryostatin; callistatin; CC-1065 (including its synthetic analogues adozelesin, carzelesin and bizelesin); podophyllotoxin; podophyllic acid; teniposide; cryptophycins (in particular, cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including synthetic analogues of KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphasine, chlorophosphamide, estramustine, ifosfamide mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterin, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine and ranimnustine; antibiotics such as enediine antibiotics (for example, calicheamicin, especially calicheamicin gamma 1I and calicheamicin omega Il (see, for example, Nicolaou et al., Angew. Chem Intl. Ed. Engl, 33:183-186 (1994)); CDP323 , an oral alpha-4 integrin inhibitor; dynemycin, including dynemycin A; esperamycin; also neocarcinostatin chromophore and related chromoprotein enediine antibiotic chromophores), aclacinomysins, actinomycin, autramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carcinophilin, dactinomycins, chromophores daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including ADRIAMICIN®, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolidino-doxorubicin, liposomal doxorubicin HCl for injection (DOXIL®), liposomal doxorubicin TLC D-99 (MYOCET®), pegylated liposomal doxorubicin (KELIX®) and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rhodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate, gemcitabine (GEMZAR®), tegafur (UFTORAL®), capecitabine (XELODA®), epothilone and 5-fluorouracil (5-FU); combretastatin; folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprin, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxyfluridine, enocytabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; adrenal depressants such as aminoglutethimide, mitotane, trilostane; a folic acid deficiency supplement such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraksat; defofamine; demecolcin; diaziquon; elfornitin; elliptinium acetate; epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainin; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerin; pentostatin; phenamet; pyrarubicin; losoxantrone; 2-ethylhydrazide; procarbazine; polysaccharide complex PSK® (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2'-trichlorotriethylamine; trichothecenes (especially toxin T-2, verracurin A, rhoridin A and anguidin); urethane; vindesine (ELDIZIN®, FILDEZIN®); dacarbazine; mannomustine; mitobronitol; mitolactol;

- 19 040364 pipobroman; hacytosine; arabinoside (Ara-C); thiotepa; a taxoid such as paclitaxel (TAXOL®, Bristol Myers Squibb Oncology, Princeton, N.J.), albumin-stabilized nanoparticulate paclitaxel (ABRAXAN™) and docetaxel (TAXOTHER®, Rhome-Poulene Rorer, Antony, France); chlorambucil; 6thioguanine; mercaptopurine; methotrexate; platinum agents such as cisplatin, oxaliplatin (eg ELOXATIN®) and carboplatin; vinca alkaloids that prevent tubulin polymerization leading to microtubule formation, including vinblastine (VELBAN®), vincristine (ONKOVIN®), vindesine (ELDIZIN®, FILDEZIN®) and vinorelbine (NAVELVIN®); etoposide (VP16); ifosfamide; mitoxantrone; leucovorin; novantron; edatrexate; daunomycin; aminopterin; ibandronate; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid, including bexarotene (TARGRETIN®); bisphosphonates such as clodronate (e.g. BONEFOS® or OSTAC®), etidronate (DIDROCAL®), NE-58095, zoledronic acid/zoledronate (ZOMETA®), alendronate (FOSAMAX®), pamidronate (AREDIA®), tiludronate (SKELID®) ) or risedronate (ACTONEL®); troxocitabine (analogue of 1,3-dioxolane-nucleoside-cytosine); antisense oligonucleotides, in particular those that inhibit the expression of genes in signaling cascades involved in aberrant cell proliferation, such as, for example, PKC-alpha, Raf, H-Ras, and epidermal growth factor receptor (EGF-R) (e.g., erlotinib ( Tartseva™)); and VEGF-A, which reduces cell proliferation; vaccines such as TERATOP® vaccine and gene therapy vaccines such as ALLOVECTIN® vaccine, LEUVECTIN® vaccine and VAKSID® vaccine; a topoisomerase 1 inhibitor (eg LURTOTECAN®); rmRH (eg ABARELIX®); BAY439006 (sorafenib; Bayer); SU-11248 (sunitinib, SUTENT®, Pfizer); perifosine, COX-2 inhibitor (eg celecoxib or etoricoxib), proteasome inhibitor (eg PS341); bortezomib (VELCADE®); CCI-779; tipifarnib (R11577); sorafenib, ABT510; a Bcl-2 inhibitor such as oblimersen sodium (GENASENS®); pixantrone; EGFR inhibitors; tyrosine kinase inhibitors; serine-threonine kinase inhibitors such as rapamycin (sirolimus, RAPAMUN®); farnesyl transferase inhibitors such as lonafarnib (SCH 6636, CAPACAR™); and pharmaceutically acceptable salts, acids or derivatives of any of the above compounds; as well as combinations of two or more of the above compounds, such as CHOP - an abbreviation for combined therapy with cyclophosphamide, doxorubicin, vincristine and prednisolone; and FOLFOX, an abbreviation for an oxaliplatin (ELOXATIN™) treatment regimen in combination with 5-FU and leucovorin, and pharmaceutically acceptable salts, acids, or derivatives of any of the above compounds; as well as combinations of two or more of the above compounds.

A chemotherapeutic agent as defined herein includes antihormonal agents or endocrine therapeutics that act to regulate, reduce, block or inhibit the actions of hormones that can stimulate cancer growth. These may be hormones proper, including but not limited to: antiestrogen and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX® tamoxifen), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone and FARESTON (toremifene); aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, megestrol acetate MEGAS®, exemestane AROMAZIN®, formestanine, fadrozole, vorozol RIVISOR®, letrozole FEMARA® and anastrozole ARIMIDEKS®; and antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; as well as troxocitabine (an analogue of 1,3-dioxolannucleoside-cytosine); antisense oligonucleotides, in particular those that inhibit the expression of genes in signaling cascades involved in aberrant cell proliferation, such as, for example, PKC-alpha, Raf and H-Ras; ribozymes such as an inhibitor of VEGF expression (eg ribozyme ANGIOZYME®) and an inhibitor of HER2 expression; vaccines such as gene therapy vaccines, eg ALLOVECTIN® vaccine, LEUVECTIN® vaccine and VAKSID® vaccine; PROLEUKIN® rIL-2; topoisomerase 1 inhibitor LURTOTEKAN®; rmRH ABARELIX®; vinorelbine and esperamycins (see US patent No. 4675187) and pharmaceutically acceptable salts, acids or derivatives of any of the above compounds; as well as combinations of two or more of the above compounds.

The term chimeric antibody refers to an antibody in which a portion of the heavy and/or light chains is derived from a particular source or species, while the remainder of the heavy and/or light chains are derived from a different source or species.

As used herein, the term cluster of differentiation 3 or CD3 refers, unless otherwise indicated, to any native CD3 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), including, for example, CD3ε, CD3y, CD3a and CD3e chains. The term includes full-length unprocessed CD3 (eg, unprocessed or unmodified CD3ε or CD3y) as well as any form of CD3 that results from cellular processing. The term also includes naturally occurring CD3 variants, including, for example, splice variants or allelic variants. CD3 includes, for example, the human CD3ε protein (NCBI RefSeq No. NP_000724) which is 207 amino acids long and the human CD3y protein (NCBI RefSeq No. NP_000064) which is 182 amino acids long.

The class of an antibody refers to the type of constant domain or constant region that characterizes its heavy chain. There are five main classes of antibodies: IgA, IgD, IgE, IgG and IgM, and some of them can be further divided into subclasses (isotypes), such as IgG1, IgG ₂ , IgG ₃ , IgG ₄ , IgA1 and IgA ₂ . The heavy chain constant domains that correspond to different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

It is understood that the aspects and embodiments of the invention described herein include comprising, consisting of, and predominantly consisting of aspects and embodiments.

As used herein, the term cytotoxic agent refers to a substance that inhibits or interferes with cellular function and/or results in cell death or destruction. Cytotoxic agents include, but are not limited to, radioactive isotopes (eg, At ²¹¹ , I ¹³¹ , I ¹²⁵ , Y ⁹⁰ , Re ¹⁸⁶ , Re ¹⁸⁸ , Sm ¹⁵³ , Bi ²¹² , P ³² , Pb ²¹² and Lu radioactive isotopes); chemotherapeutic agents or drugs (eg methotrexate, adriamycin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other intercalating agents); growth inhibitors; enzymes and fragments thereof, such as nucleolytic enzymes; antibiotics; toxins such as low molecular weight toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin; and various antitumor and anticancer agents disclosed below.

A disorder is any condition that can be ameliorated by treatment, including, but not limited to, chronic and acute disorders or diseases, including those pathological conditions that cause a corresponding disorder in a mammal.

The terms cell proliferative disorder and proliferative disorder refer to disorders that are associated with some degree of abnormal cell proliferation. In one embodiment, the cell proliferative disorder is cancer. In one embodiment, the cell proliferative disorder is a tumor.

The terms cancer and cancerous refer to or describe the physiological state of mammals, which is typically characterized by uncontrolled cell growth. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphocytic leukemias. More specific examples of such cancers include, but are not limited to, squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), lung cancer, including small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma and squamous cell lung carcinoma, abdominal cancer, hepatocellular carcinoma, gastric cancer including gastrointestinal and gastrointestinal stromal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, urinary tract cancer, hepatoma, breast cancer, colon cancer, rectal cancer colon, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatocarcinoma, anal carcinoma, penile carcinoma, melanoma, superficial spreading melanoma, lentigo melanoma, acral lentiginous melanoma, nodular melanomas, multiple myeloma and B-cell lymphoma (including low-grade/f ollicular non-Hodgkin's lymphoma (NHL); NHL from small lymphocytes (ML); moderate/follicular NHL; diffuse NHL of moderate degree; high-grade immunoblastic NHL; high-grade lymphoblastic NHL; NHL from small lymphocytes with high uncleaved nuclei; NHL with massive lesions of the lymph nodes; mantle cell lymphoma; AIDS-associated lymphoma; and Waldenström's macroglobulinemia); chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); hairy cell leukemia; chronic myeloid leukemia; post-transplant lymphoproliferative disorder (PTLD), as well as abnormal vascular proliferation associated with phakomatosis, edema (for example, associated with brain tumors), Meigs' syndrome, brain and head and neck cancer and associated metastases. In certain embodiments, cancers to be treated with antibodies of the invention include breast cancer, colorectal cancer, rectal cancer, non-small cell lung cancer, glioblastoma, non-Hodgkin's lymphoma (NHL), renal cell carcinoma, prostate cancer, liver cancer, cancer pancreas, soft tissue sarcoma, Kaposi's sarcoma, carcinoid carcinoma, head and neck cancer, ovarian cancer, mesothelioma and multiple myeloma. In some embodiments, the cancer is selected from small cell lung cancer, glioblastoma, neuroblastoma, melanoma, breast carcinoma, gastric cancer, colorectal cancer (CRC), and hepatocellular carcinoma. In some embodiments, the cancer is selected from non-small cell lung cancer, colorectal cancer, glioblastoma, and breast carcinoma, including metastatic forms of these cancers. In other embodiments, the cancer is selected from a class of mature B cell cancers, excluding Hodgkin's lymphoma, but including DLBCL from germinal center (GCC) B cell-like cells,

- 21 040364

DLBCL from activated B cell-like cells (AVK), follicular lymphoma (FL), mantle cell lymphoma (MCL), acute myeloid leukemia (AML), chronic lymphoid leukemia (CLL), marginal zone lymphoma (MLZ), small lymphocyte lymphoma (LML), lymphoplasmacytic lymphoma (LL), Waldenström macroglobulinemia (MB), central nervous system lymphoma (LCNS), Burkitt's lymphoma (BL), B-cell prolymphocytic leukemia, splenic marginal zone lymphoma, hairy cell leukemia, splenic lymphoma/leukemia, unclassifiable, diffuse B-cell lymphoma of the red pulp of the spleen, variant hairy cell leukemia, Waldenström macroglobulinemia, heavy chain diseases, heavy chain disease α, heavy chain disease γ, heavy chain disease μ plasma cell myeloma, solitary plasmacytoma of bone, extraosseous plasmacytoma, extranodal marginal zone lymphoma from mucosal lymphoid tissue (MALT-lymphomas), nodal marginal zone lymphoma, pediatric nodal marginal zone lymphoma, childhood follicular lymphoma, primary cutaneous follicular center cell lymphoma, B-cell large cell lymphoma with a predominance of T-cells / histiocytes, primary DLBCL of the CNS, primary cutaneous DLBCL of the foot type, EBV-positive DLBCL of the elderly, DLBCL, associated with chronic inflammation, Hodgkin's disease, primary mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, KAL-positive large B-cell lymphoma, plasmablastic lymphoma, HHV-8 associated large B-cell lymphoma multifocal Castleman disease, primary effusion lymphoma: unclassifiable B-cell lymphoma with features of diffuse large B-cell lymphoma and Burkitt's lymphoma, and unclassifiable B-cell lymphoma with features of diffuse large B-cell lymphoma and classic Hodgkin's lymphoma.

As used herein, tumor refers to any growth and proliferation of neoplastic cells, whether malignant or benign, and to all precancerous and cancerous cells and tissues. In the context of this document, the terms cancer, cancerous, cell proliferative disorder, proliferative disorder, and tumor are not mutually exclusive.

As used herein, the term tumor antigen is to be understood as those antigens that are presented on tumor cells. These antigens can be presented on the cell surface with an extracellular portion that is often associated with the transmembrane and cytoplasmic portion of the molecule. Sometimes these antigens can only be presented by tumor cells, but never by normal cells. Tumor antigens may be expressed exclusively on tumor cells or may represent a tumor-specific mutation compared to normal cells. In this case, they are called tumor-specific antigens. More common are tumor antigens that are presented by tumor cells and normal cells and are called tumor-associated antigens. Such tumor-associated antigens may be overexpressed compared to normal cells or be available for antibody binding in tumor cells due to the less compact structure of tumor tissue compared to normal tissue. In one aspect, the tumor antigen is selected from those in Table 1 below. 1.

Effector functions refer to the biological activity associated with the Fc region of an antibody, which may vary depending on the isotype of the antibody. Examples of antibody effector functions include C1q binding and complement dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (eg, B cell receptors); and activation of B cells.

An effective amount of a compound, e.g., an anti-CD3 antibody of the invention or a composition (e.g., a pharmaceutical composition) containing it, is at least the minimum amount necessary to achieve a desired therapeutic or prophylactic result, such as a measurable improvement or prevention of a particular disorder (e.g., cell proliferative disorder such as cancer). Herein, the effective amount may vary according to factors such as the disease state, age, sex, and weight of the patient, and the ability of the antibody to elicit the desired response in the patient. An effective amount is also that for which the therapeutically beneficial effect outweighs any toxic or deleterious effects of the treatment. In the case of prophylactic use, beneficial or desirable outcomes include outcomes such as elimination or reduction of risk, reduction in severity or delay in onset of the disease, including biochemical, histological and/or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes present during the development of the disease. In the case of therapeutic use, beneficial or desirable results include clinical outcomes such as a reduction in one or more of the symptoms associated with the disease, an improvement in the quality of life of those suffering from the disease, a reduction in the dose of other medications required to treat the disease, an increase in

- 22 040364 the effectiveness of other medicines, for example, by targeting, slowing down the progression of the disease and/or prolonging life. In the case of cancer or tumor, the effect of an effective amount of the drug may be to reduce the number of cancer cells; decrease in tumor volume; inhibiting (ie, slowing down to some extent or, preferably, stopping) the infiltration of cancer cells into peripheral organs; inhibition (ie, slowing down to some extent and, preferably, stopping) tumor metastases; inhibition to some extent of tumor growth; and/or alleviate to some extent one or more of the symptoms associated with the disorder. An effective amount can be administered in one or more doses. In the context of this invention, an effective amount of a drug, compound or pharmaceutical composition is an amount sufficient to carry out prophylactic or therapeutic treatment in a direct or indirect manner. As will be apparent from the clinical context, an effective amount of a drug, compound, or pharmaceutical composition may or may not be made in combination with another drug, compound, or pharmaceutical composition. Thus, an effective amount can be considered in the context of administering one or more therapeutic agents, and one agent can be considered to be used in an effective amount if, in combination with one or more other agents, the desired result can be achieved or achieved.

As used herein, the term Fc region is used to refer to the C-terminal region of an immunoglobulin heavy chain that contains at least a portion of a constant region. The term includes native sequence Fc regions and variants of Fc regions. In one embodiment, the human IgG heavy chain Fc region extends from Cys226 or Pro230 to the carboxy-terminus of the heavy chain. The C-terminal lysine (Lys447) of the Fc region may or may not be present. Unless otherwise indicated herein, the amino acid residue numbering of the Fc region or constant region follows the European (EU) numbering system, also referred to as the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

Framework region or FR refers to variable domain residues other than hypervariable region (HVR) residues. The variable domain FR generally consists of four FR domains: FR1, FR2, FR3, and FR4. Accordingly, the HVR and FR sequences are generally in the following sequence in VH (or VL): FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

The terms full-length antibody, intact antibody, and whole antibody are used interchangeably herein to refer to an antibody having a structure substantially similar to that of a native antibody, or containing heavy chains that contain an Fc region, as defined herein.

As used herein, the expression growth inhibitory agent refers to a compound or composition that inhibits cell growth in vitro or in vivo. In one embodiment, the growth inhibitory agent is a growth inhibitory antibody that prevents or reduces the proliferation of a cell expressing an antigen to which the antibody binds. In another embodiment, the growth inhibitory agent may be an agent that significantly reduces the percentage of cells in S phase. Examples of growth inhibitory agents include agents that block cell cycle progression (at a location other than S phase), such as agents that induce G1 blocking and M phase blocking. Classical M-phase blockers include vinca alkaloids (vincristine and vinblastine), taxanes, and topoisomerase II inhibitors such as doxorubicin, epirubicin, daunorubicin, etoposide, and bleomycin. Those agents that block G1 also extend to S-phase blocking, such as DNA alkylating agents such as tamoxifen, prednisone, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5-fluorouracil, and ara-C. Further information can be found in Mendelsohn, Israel, eds., The Molecular Basis of Cancer, Chapter 1, titled Cell cycle regulation, oncogenes, and antineoplastic drugs by Murakami et al. (W.B. Saunders, Philadelphia, 1995), for example, p. 13. Taxanes (paclitaxel and docetaxel) are anti-cancer drugs derived from the yew tree. Docetaxel (TAXOTHER®, Rhone-Poulenc Rorer), derived from European yew, is a semi-synthetic analog of paclitaxel (TAXOL®, Bristol-Myers Squibb). Paclitaxel and docetaxel stimulate the assembly of microtubules from tubulin dimers and stabilize microtubules, preventing depolymerization, which leads to inhibition of mitosis in cells.

The term HER2 positive cancer includes cancer cells that have higher than normal levels of HER2. Examples of HER2 positive cancers include HER2 positive breast cancer and HER2 positive stomach cancer. Optionally, the HER2 positive cancer has an immunohistochemical index (IHC) of 2+ or 3+ and/or an in situ hybridization (ISH) to amplification ratio >2.0.

The terms host cell, host cell line, and host cell culture are used interchangeably and refer to cells into which an exogenous nucleic acid has been introduced, including

- 23 040364 progeny of such cells. Host cells include transformants and transformed cells, which include primary transformed cells and their progeny, regardless of the number of passages. The offspring may not be completely identical in nucleic acid content to the parent cell and may contain mutations. This document includes mutant progeny that have the same function or biological activity that is the subject of research or selection in the originally transformed cell.

A human antibody is an antibody that has an amino acid sequence that corresponds to that of an antibody produced by a human body or a human cell, or derived from a non-human source, that uses a set of human antibodies or other human antibody-coding sequences. This definition of a human antibody explicitly excludes a humanized antibody containing non-human antigen-binding residues. Human antibodies can be generated by various methods known in the art, including phage display libraries. Hoogenboom, Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991). Also available for the preparation of human monoclonal antibodies are the methods described in Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boerner et al., J. Immunol., 147(1):86-95 (1991). See also van Dijk, van de Winkel, Curr. Opin. Pharmacol. 5:368-74 (2001). Human antibodies can be generated by administering an antigen to a transgenic animal that has been modified to produce such antibodies in response to antigen challenge, such as an immunized xenomouse (see, for example, US Pat. Nos. 6,075,181 and 6,150,584 for XENOMOUSE™ technology). See also, for example, Li et al., Proc. Natl. Acad. Sci., USA, 103:3557-3562 (2006) for human B-cell hybridoma-derived human antibodies.

The human consensus framework is a framework that represents the most frequently occurring amino acid residues in a sample of human immunoglobulin VL or VH framework sequences. In general, a selection of human immunoglobulin VL or VH sequences is derived from a subset of variable domain sequences. In general, a subset of sequences is a subset according to Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication, 91-3242, Bethesda MD (1991), vol. 1-3. In one embodiment of the invention, in the case of VL, the subgroup corresponds to the kappa I subgroup according to Kabat et al. higher. In one embodiment, for VH, the subgroup corresponds to subgroup III according to Kabat et al. higher.

A humanized antibody refers to a chimeric antibody containing amino acid residues from non-human HVRs and amino acid residues from human FRs. In certain embodiments, the humanized antibody contains substantially all of at least one, and typically two, variable domains wherein all or substantially all of the HVRs (e.g., CDRs) are derived from the non-human antibody and all or substantially all of the FRs are derived from the non-human antibody. from a human antibody. Optionally, a humanized antibody may comprise at least a portion of an antibody constant region derived from a human antibody. A humanized form of an antibody, such as a non-human antibody, refers to an antibody that has been humanized.

As used herein, the term hypervariable region or HVR refers to each of the regions of an antibody variable domain that are characterized by a hypervariable sequence (complementarity determining regions or CDRs) and/or form structurally defined loops (hypervariable loops) and/or contain antigen-containing residues (antigenic contacts). In general, antibodies contain six HVRs: three in VH (H1, H2, H3) and three in VL (L1, L2, L3). Exemplary HVRs according to this document include (a) hypervariable loops corresponding to amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2) and 96-101 (H3) (Chothia, Lesk, J. Mol. Biol., 196:901-917 (1987));

(b) CDRs corresponding to amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2) and 95-102 (H3) ( Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991));

(c) antigenic contacts corresponding to amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2) and 93-101 (H3) (MacCallum et al., J. Mol. Biol., 262:732-745 (1996)); and (d) combinations of (a), (b) and/or (c) including HVR amino acid residues 46-56 (L2), 47-56 (L2), 48-56 (L2), 49-56 (L2) , 26-35 (H1), 26-35b (H1), 49-65 (H2), 93-102 (H3), and 94-102 (H3).

Unless otherwise indicated, HVR residues and other residues in the variable domain (eg, FR residues) are numbered according to Kabat et al. higher.

An immunoconjugate is an antibody conjugated to one or more heterologous molecules, including, but not limited to, a cytotoxic agent.

The subject or individual is a mammal. Mammals include, but are not limited to, domestic animals (eg, cows, sheep, cats, dogs, and horses), primates (eg, humans and non-human primates such as monkeys), rabbits, and rodents (eg, we necks and rats). In certain embodiments of the invention, the subject or individual is a human.

An isolated antibody is one that has been separated from components of its natural environment. In some embodiments, the antibody is purified to greater than 95% or 99% purity, as determined by, for example, electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reverse phase HPLC). ). For a review of antibody purification methods, see, for example, Flatman et al., J. Chromatogr. B, 848:79-87 (2007).

An isolated nucleic acid refers to a nucleic acid molecule that has been separated from components of its natural environment. An isolated nucleic acid includes a nucleic acid molecule in cells that normally contain the nucleic acid molecule, but the nucleic acid molecule is outside the chromosome or at a chromosomal location other than its usual chromosomal location.

An isolated nucleic acid encoding an anti-CD3 antibody refers to one or more nucleic acid molecules encoding heavy and light chains of an antibody (or fragments thereof), including nucleic acid molecules in a single vector or separate vectors, and nucleic acid molecules present in one or more locations in the host cell.

As used herein, the term monoclonal antibody refers to an antibody derived from a population of substantially homogeneous antibodies, ie. the individual antibodies that make up the population are identical and/or bind the same epitope, with the exception of possible variant antibodies, for example, containing mutations of natural origin or arising during the preparation of the monoclonal antibody preparation, while such variants are generally present in a small amount. Unlike polyclonal antibody preparations, which typically contain different antibodies directed against different determinants (epitopes), each monoclonal antibody from a monoclonal antibody preparation is directed against a single determinant on the antigen. Thus, the definition of monoclonal indicates that the antibody has been generated from a substantially homogeneous population of antibodies and should not be construed as requiring the production of the antibody by any particular method. For example, monoclonal antibodies for use in accordance with the present invention can be obtained by various methods, including, but not limited to, the hybridoma method, recombinant DNA methods, phage display methods, and methods using transgenic animals containing all or part of the human immunoglobulin loci, when however, such methods, as well as other typical methods for obtaining monoclonal antibodies are described in this document.

A naked antibody refers to an antibody that is not conjugated to a heterologous moiety (eg, a cytotoxic moiety) or a radiolabel. The naked antibody may be in a pharmaceutical formulation.

Native antibodies refer to naturally occurring immunoglobulin molecules with varying structures. For example, native IgG antibodies are heterotetrameric glycoproteins of approximately 150,000 daltons, consisting of two identical light chains and two identical heavy chains that are linked by a disulfide bond. In the N- to C-terminal direction, each heavy chain contains a variable region (VH), also called a heavy chain variable domain or a heavy chain variable domain, followed by three constant domains (CH1, CH2 and CH3). Similarly, in the N- to C-terminal direction, each light chain contains a variable region (VL), also referred to as a variable light domain or a light chain variable domain, followed by a constant light domain (CL). The light chain of an antibody can be assigned to one of two types, called kappa (k) and lambda (λ), based on the amino acid sequence of its constant domain.

The term package insert is used to refer to the instructions traditionally found in commercial packages of therapeutic products that contain information on the indications, use, dosage, administration, combination therapy, contraindications and/or warnings regarding the use of such therapeutic products.

The term antagonist that binds to a component of the PD-1 signaling pathway refers to a molecule that inhibits the interaction of a binding partner of the PD-1 axis with its one or more binding partners to eliminate T-cell dysfunction due to signaling on the PD-1 signaling axis, which would result in restoration or enhancement of T-cell function (eg, proliferation, cytokine production, targeted cell killing). As used herein, an antagonist that binds to a component of the PD-1 signaling pathway includes a PD-1 binding antagonist, a PD-L1 binding antagonist, and a PD-L2 binding antagonist.

The term PD-1 binding antagonist refers to a molecule that reduces, blocks, inhibits, suppresses or prevents signal transduction due to the interaction of PD-1 with one or more of its binding partners such as PD-L1, PD-L2. In some embodiments, a PD-1 binding antagonist is a molecule that inhibits PD-1 binding to

- 25 040364 by one or more of his bonding partners. In a specific aspect, the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 and/or PD-L2. For example, PD-1 binding antagonists include anti-PD-1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, suppress, or interfere with signal transduction due to the interaction of PD-1 with PD- L1 and/or PD-L2. In one embodiment, a PD-1 binding antagonist reduces the negative co-stimulatory signaling mediated by cell surface proteins expressed on T lymphocytes that mediate PD-1 signaling to make dysfunctional T cells less dysfunctional (e.g., by increasing the effector response to antigen recognition). In some embodiments, the PD-1 binding antagonist is an anti-PD-1 antibody. In a specific aspect, the PD-1 binding antagonist is MDX-1106 (nivolumab) as described herein. In another specific aspect, the PD-1 binding antagonist is MK-3475 (lambrolizumab) described herein. In another specific aspect, the PD-1 binding antagonist is

CT-011 (pidilizumab) described in this document. In another specific aspect, the PD-1 binding antagonist is AMP-224 as described herein.

The term PD-L1 binding antagonist refers to a molecule that reduces, blocks, inhibits, suppresses or interferes with signaling due to the interaction of PD-L1 with one or more of its binding partners such as PD-1, B7-1. In some embodiments, a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partners. In a specific aspect, the PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1 and/or B7-1. In some embodiments, PD-L1 binding antagonists include anti-PD-L1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, suppress, or interfere with signaling due to PD-L1 interaction. with one or more of its binding partners such as PD-1, B7-1. In one embodiment, a PD-L1 binding antagonist reduces the negative co-stimulatory signaling mediated by cell surface proteins expressed on T lymphocytes that mediate PD-L1 signaling to make dysfunctional T cells less dysfunctional (eg, by increasing the effector response to antigen recognition). In some embodiments, the PD-L1 binding antagonist is an anti-PD-1 antibody. In a specific aspect, the anti-PD-L1 antibody is YW243.55.S70 as described herein. In another specific aspect, the anti-PD-L1 antibody is MDX-1105 as described herein. In another specific aspect, the αntu-PD-L1 antibody is MPDL3280A as described herein. In another specific aspect, the anti-PD-L1 antibody is MEDI4736 as described herein.

The term PD-L2 binding antagonist refers to a molecule that reduces, blocks, inhibits, suppresses or interferes with signal transduction due to the interaction of PD-L2 with one or more of its binding partners, such as PD-1. In some embodiments, a PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to one or more of its binding partners. In a specific aspect, the PD-L2 binding antagonist inhibits the binding of PD-L2 to PD-1. In some embodiments, PD-L2 binding antagonists include anti-PD-L2 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, suppress, or interfere with signaling due to PD-L2 interaction. with one or more of its binding partners such as PD-1. In one embodiment, a PD-L2 binding antagonist reduces the negative co-stimulatory signaling mediated by cell surface proteins expressed on T lymphocytes that mediate PD-L2 signaling to make dysfunctional T cells less dysfunctional (e.g., by increasing the effector response to antigen recognition). In some embodiments, the PD-L2 binding antagonist is an immunoadhesin.

As used herein, the term protein refers to any native protein from any vertebrate source, including mammals such as primates (eg, humans) and rodents (eg, mice and rats), unless otherwise noted. The term includes the full-length full-length protein, as well as any form of protein that is the result of processing in a cell. The term also includes naturally occurring protein variants, such as splice variants or allelic variants. Proteins according to the invention include, for example, any protein listed in table. 1.

Percentage (%) amino acid sequence identity relative to a control polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to amino acid residues in a control polypeptide sequence, after sequence alignment and gaps, if necessary, to achieve maximum sequence identity, but excluding

- 26 040364 any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be obtained by various methods within the skill of the art, for example using open source software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for sequence alignment, including any algorithms necessary to achieve maximum alignment over the entire length of the compared sequences. For the purposes of this document, percent (%) amino acid sequence identity values are obtained using the ALIGN-2 sequence alignment software. The ALIGN-2 sequence alignment computer program was developed by Genentech, Inc., and the source program was filed with user documentation to the United States Copyright Office, Washington, D.C. 20559, where it was registered under US Copyright Registry No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, CA, or may be compiled from the source program. The ALIGN-2 program requires compilation for use on the UNIX operating system, including Digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.

When ALIGN-2 is used to compare amino acid sequences, the percentage (%) of amino acid sequence identity of a given amino acid sequence A with respect to, with, or against a given amino acid sequence B (which can alternatively be rephrased as a given amino acid sequence A that has or is characterized by a percentage (%) amino acid sequence identity with respect to, with or against a given amino acid sequence B) is calculated as follows:

100 times the X/Y ratio, where X is the number of amino acid residues corresponding to identical matches according to the ALIGN-2 sequence alignment program in the A and B alignment performed by this program, a

Y is the total number of amino acid residues in B.

It should be understood that if the length of the amino acid sequence of A is not equal to the length of the amino acid sequence of B, the percentage (%) of amino acid sequence identity of A to B is not equal to the percentage (%) of amino acid sequence identity of B to A. Unless expressly stated otherwise, all percent values (% ) the amino acid sequence identities used herein are obtained as described in the previous paragraph using the ALIGN-2 computer program.

The term pharmaceutical formulation refers to a formulation which is in such a form as to render the biological activity of the active ingredient contained therein effective and which does not contain additional components that are unacceptably toxic to the subject to whom the formulation is administered.

A pharmaceutically acceptable carrier refers to an ingredient in a pharmaceutical composition, other than the active ingredient, that is non-toxic to the subject. Pharmaceutically acceptable carriers include, but are not limited to, a buffer, excipient, stabilizer, or preservative.

In the context of this document, treatment (and its grammatical variations, such as treat) refers to clinical intervention in an attempt to alter the natural course of a disease in a treated subject, and may be carried out for prophylaxis or during the course of clinical pathology. The desired effects of treatment include, but are not limited to, preventing the onset or reappearance of the disease, alleviating symptoms, reducing any direct or indirect pathological consequences of the disease, preventing the occurrence of metastases, reducing the rate of disease progression, improving or alleviating the condition of the disease, and remission or improving prognosis. In some embodiments, the antibodies of the invention are used to slow the progression of a disease or slow the progression of a disease.

As used herein, slowing down the progression of a disorder or disease means to delay, inhibit, retard, delay, stabilize, and/or delay the development of a disease or disorder (eg, a cell proliferative disorder, eg, cancer). This slowdown may take different lengths of time depending on the history of the disease and/or the individual being treated. One of ordinary skill in the art will appreciate that significant or significant delay may in practice include preventing the development of a disease in a subject. For example, you can slow down the late stage of cancer, such as the development of metastases.

By reducing or inhibiting is meant the ability to result in an overall reduction of, for example, 20% or more, 50% or more, or 75%, 85%, 90%, 95% or more. In certain embodiments of the invention, the terms reduce or inhibit may refer to the effector function of an antibody, which is mediated by the Fc region of the antibody, such effector

- 27 040364 functions include, in particular, complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP).

The term variable region or variable domain refers to the heavy or light chain domain of an antibody that is involved in the binding of an antibody to an antigen. The heavy chain and light chain variable domains (VH and VL, respectively) of a native antibody generally have similar structures, with each domain containing four conserved framework regions (FRs) and three hypervariable regions (HVRs) (see, e.g., Kindt et al. ., Kuby Immunology, 6th ed., W. H. Freeman and Co., p. 91 (2007)). A single VH or VL domain may be sufficient to confer antigen-binding specificity. In addition, antibodies that bind a particular antigen can be isolated by using the VH or VL domain from an antibody that binds the antigen to screen for a library of complementary VL or VH domains, respectively. See, for example, Portolano et al., J. Immunol., 150:880-887 (1993); Clarkson et al., Nature, 352:624-628 (1991).

As used herein, the term vector refers to a nucleic acid molecule capable of reproducing another nucleic acid to which it is associated. This term includes a vector as a self-replicating nucleotide structure, as well as a vector included in the genome of the host cell into which it has been introduced. Certain vectors are capable of directing the expression of the nucleic acids to which they are operatively linked. Such vectors are referred to herein as expression vectors.

In the context of this document, administration means a method of administering to a subject a dose of a compound (for example, an anti-CD3 antibody of the invention or a nucleic acid encoding an anti-CD3 antibody of the invention) or a composition (for example, a pharmaceutical composition, for example a pharmaceutical composition containing an anti-CD3 antibody, according to the invention). The compositions used in the methods described herein can be administered, for example, intramuscularly, intravenously, intradermally, transdermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, rectally, topically, intratumorally , peritoneal, subcutaneous, subconjunctival, intravesicular, mucosal, intrapericardial, intraumbilical, intraocular, oral, topical, local, by inhalation, by injection, by infusion, by continuous infusion, by localized perfusion directly through target cells, by catheter, by lavage, in creams or in lipid formulations. The route of administration may vary depending on various factors (eg, the compound or composition administered and the severity of the condition, disease, and disorder being treated).

II. Compositions and methods.

In one aspect, the invention is based in part on anti-CD3 antibodies. In certain embodiments, anti-CD3 antibodies are multispecific (eg, bispecific) and bind, in addition to CD3 or a fragment thereof, a second biological molecule (eg, a cell surface antigen, eg, a tumor antigen). The antibodies of the invention are useful, for example, in treating or slowing the progression of a cell proliferative disorder (eg, cancer) or an autoimmune disorder, or in improving immune function in a subject having such a disorder.

A. Typical anti-CD3 antibodies.

In one aspect, the invention provides isolated antibodies that bind to CD3 (eg, CD3ε and/or CD3y).

For example, in one aspect, the invention provides an anti-CD3 antibody comprising a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence SEQ ID NO: 1;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 2;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 3;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 4;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 5; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 6.

In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the FR-H1, FR-H2, FR-H3, and FR-H4 heavy chain framework regions containing the sequences of SEQ ID NO: 301-304, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of FR-L1, FR-L2, FR-L3, and FR-L4 light chain framework regions comprising the sequences of SEQ ID NO: 305-308 respectively. In some instances, the anti-CD3 antibody may comprise a heavy chain variable domain (VH) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 184, and/or a light chain variable domain (VL) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93 , 94, 95, 96, 97, 98 or 99%

- 28 040364 sequence identity) c, or the sequence of SEQ ID NO: 185. In other cases, the anti-CD3 antibody contains at least one (for example, 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3 and FR-H4 containing the sequences of SEQ ID NOs: 293-296, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions of FR-L1, FRL2, FR- L3 and FR-L4 containing the sequences of SEQ ID NO: 297-300, respectively. In some instances, the anti-CD3 antibody may comprise a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity). ) c, or the sequence of SEQ ID NO: 186, and/or a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 187. In a particular case, the anti-CD3 antibody may be 40G5c or a derivative or clonally related antibody.

In another aspect, an antibody of the invention comprises (a) a VH domain comprising at least one, at least two, or all three HVR VH sequences selected from (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1, (ii ) HVR-H2 containing the amino acid sequence of SEQ ID NO: 2, and (iii) HVR-H3 containing the amino acid sequence selected from SEQ ID NO: 3; and (b) a VL domain comprising at least one, at least two, or all three HVR VL sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5, and (iii) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 6.

In some cases, the anti-CD3 antibody may contain a VH domain containing the amino acid sequence of SEQ ID NO: 184 and a VL domain containing the amino acid sequence of SEQ ID NO: 185. In some cases, the anti-CD3 antibody may contain a VH domain containing the amino acid sequence of SEQ ID NO: 186, and a VL domain containing the amino acid sequence of SEQ ID NO: 187. In a specific case, the anti-CD3 antibody may be 40G5c or a derivative or clonally related antibody.

In one aspect, the invention provides an anti-CD3 antibody comprising a binding domain comprising at least one, two, three, four, five, or six HVRs selected from (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 181;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 182.

In certain embodiments of the invention, any one or more amino acids of the anti-CD3 antibody proposed above are substituted at the following positions in the HVR:

in HVR-H3 (SEQ ID NO: 181): positions 1, 2, 5, 6 and 7; and in HVR-L3 (SEQ ID NO: 182): positions 1, 2, 4 and 5.

In certain embodiments of the invention, the substitutions are conservative substitutions according to this document. In certain embodiments of the invention, any one or more of the following substitutions can be made in any of the following combinations:

in HVR-H3 (SEQ ID NO: 181): D1T or S; S1D or T; T1D or S; G2A or S; A2G or S; S2A or G; R5N; N5R; Y6A; A6Y; A7Y; and Y7A; and in HVR-L3 (SEQ ID NO: 182): K1T; T1K; Q2A; A2Q; F4A; A4F; I5A and A5I.

For example, in some instances, the invention provides an anti-CD3 antibody comprising a binding domain comprising at least one, two, three, four, five, or six HVRs selected from (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 12.

In some instances, the anti-CD3 antibody may comprise a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity). ) c, or the sequence of SEQ ID NO: 188, and/or a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least

- 29 040364

91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or sequence

SEQ ID NO: 189. In a specific instance, the anti-CD3 antibody may be 38E4v1 or a derivative or clonally related antibody thereof.

In some instances, the invention provides an anti-CD3 antibody comprising a binding domain comprising at least one, two, three, four, five, or six HVRs selected from (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 13;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 12.

In some instances, the anti-CD3 antibody may comprise a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity). ) c, or the sequence of SEQ ID NO: 190, and/or a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 191. In a particular case, the anti-CD3 antibody may be 38E4v2 or a derivative or clonally related antibody.

In some instances, the invention provides an anti-CD3 antibody comprising a binding domain comprising at least one, two, three, four, five, or six HVRs selected from (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 14.

In some instances, the anti-CD3 antibody may comprise a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity). ) c, or the sequence of SEQ ID NO: 192, and/or a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 193. In a specific case, the anti-CD3 antibody may be 38E4v3 or a derivative or clonally related antibody.

In some instances, the invention provides an anti-CD3 antibody comprising a binding domain comprising at least one, two, three, four, five, or six HVRs selected from (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 15.

In some instances, the anti-CD3 antibody may comprise a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity). ) c, or the sequence of SEQ ID NO: 194, and/or a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 195. In a particular case, the anti-CD3 antibody may be 38E4v4 or a derivative or clonally related antibody.

In some instances, the invention provides an anti-CD3 antibody comprising a binding domain comprising at least one, two, three, four, five, or six HVRs selected from (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 16.

In some instances, the anti-CD3 antibody may comprise a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity). ) with, or

- 30 040364 the sequence of SEQ ID NO: 196, and/or a VL domain containing an amino acid sequence having at least 90% sequence identity (for example, at least

91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or sequence

SEQ ID NO: 197. In a particular instance, the anti-CD3 antibody may be 38E4v5 or a derivative or clonally related antibody thereof.

In some instances, the invention provides an anti-CD3 antibody comprising a binding domain comprising at least one, two, three, four, five, or six HVRs selected from (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 17;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 12.

In some instances, the anti-CD3 antibody may comprise a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity). ) c, or the sequence of SEQ ID NO: 198, and/or a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 199. In a specific case, the anti-CD3 antibody may be 38E4v6 or a derivative or clonally related antibody.

In some instances, the invention provides an anti-CD3 antibody comprising a binding domain comprising at least one, two, three, four, five, or six HVRs selected from (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 18;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 12.

In some instances, the anti-CD3 antibody may comprise a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity). ) c, or the sequence of SEQ ID NO: 200, and/or a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 201. In a specific case, the anti-CD3 antibody may be 38E4v7 or a derivative or clonally related antibody.

In some instances, the invention provides an anti-CD3 antibody comprising a binding domain comprising at least one, two, three, four, five, or six HVRs selected from (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 19;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 12.

In some instances, the anti-CD3 antibody may comprise a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity). ) c, or the sequence of SEQ ID NO: 202, and/or a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 203. In a specific case, the anti-CD3 antibody may be 38E4v8 or a derivative or clonally related antibody.

In some instances, the invention provides an anti-CD3 antibody comprising a binding domain comprising at least one, two, three, four, five, or six HVRs selected from (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 20;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 12.

In some instances, the anti-CD3 antibody may comprise a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 204, and/or a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96 , 97, 98, or 99% sequence identity) c, or the sequence of SEQ ID NO: 205. In a specific instance, the anti-CD3 antibody may be 38E4v9 or a derivative or clonally related antibody thereof.

In some instances, the invention provides an anti-CD3 antibody comprising a binding domain comprising at least one, two, three, four, five, or six HVRs selected from (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 21;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 22.

In some instances, the anti-CD3 antibody may comprise a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity). ) c, or the sequence of SEQ ID NO: 206, and/or a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 207. In a specific case, the anti-CD3 antibody may be 38E4c or a derivative or clonally related antibody.

In some instances, any of the anti-CD3 antibodies 38E4v1-38E4v9 and 38E4c may contain at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR- H4 containing the sequences of SEQ ID NOs: 309-312, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR- L4 containing the sequences of SEQ ID NO: 313-316, respectively.

In one aspect, the invention provides an anti-CD3 antibody comprising a binding domain comprising at least one, two, three, four, five, or six HVRs selected from (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 183;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 28.

In certain embodiments of the invention, any one or more amino acids of the anti-CD3 antibody proposed above are substituted at the following positions in the HVR:

in HVR-H2 (SEQ ID NO: 183): positions 9, 12, 13, 14, 15 and 17.

In certain embodiments of the invention, the substitutions are conservative substitutions according to this document. In certain embodiments of the invention, any one or more of the following substitutions can be made in any of the following combinations:

in HVR-H2 (SEQ ID NO: 183): S9T; T9S; N12A; A12N; Q13D; D13Q; K14S; S14K; F15V; V15F; D17G; and G17D.

For example, in some cases, the invention provides an anti-CD3 antibody comprising a binding domain comprising at least one, two, three, four, five, or six HVRs selected from (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO : 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 24;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 28.

In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the FR-H1, FR-H2, FR-H3, and FR-H4 heavy chain framework regions containing the sequences of SEQ ID NO: 317-320, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of FR-L1, FR-L2, FR-L3, and FR-L4 light chain framework regions comprising the sequences of SEQ ID NO: 321-324 respectively. In some instances, the anti-CD3 antibody may comprise a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity). ) c, or the sequence of SEQ ID NO: 208, and/or a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least

- 32 040364

91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or sequence

SEQ ID NO: 209. In a particular instance, the anti-CD3 antibody may be UCHT1v9 or a derivative or clonally related antibody thereof.

In some instances, the invention provides an anti-CD3 antibody comprising a binding domain comprising at least one, two, three, four, five, or six HVRs selected from (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 29;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 28.

In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the FR-H1, FR-H2, FR-H3, and FR-H4 heavy chain framework regions containing the sequences of SEQ ID NO: 325-328, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of FR-L1, FR-L2, FR-L3, and FR-L4 light chain framework regions comprising the sequences of SEQ ID NO: 329-332, respectively. In some instances, the anti-CD3 antibody may comprise a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity). ) c, or the sequence of SEQ ID NO: 210, and/or a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 211. In a specific case, the anti-CD3 antibody may be UCHT1v1 or a derivative or clonally related antibody.

In some instances, the invention provides an anti-CD3 antibody comprising a binding domain comprising at least one, two, three, four, five, or six HVRs selected from (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 30;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 28.

In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the FR-H1, FR-H2, FR-H3, and FR-H4 heavy chain framework regions containing the sequences of SEQ ID NO: 333-336, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of FR-L1, FR-L2, FR-L3, and FR-L4 light chain framework regions comprising the sequences of SEQ ID NO: 337-340 respectively. In some instances, the anti-CD3 antibody may comprise a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity). ) c, or the sequence of SEQ ID NO: 212, and/or a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 213. In a particular case, the anti-CD3 antibody may be UCHT1vM1 or a derivative or clonally related antibody.

In one aspect, the invention provides an anti-CD3 antibody comprising a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 32;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 33;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 34;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 35; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 36.

In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the FR-H1, FR-H2, FR-H3, and FR-H4 heavy chain framework regions containing the sequences of SEQ ID NO: 341-344, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the FR-L1, FR-L2, FR-L3, and FR-L4 light chain framework regions comprising the sequences of SEQ ID NO: 345-348 respectively. In some instances, the anti-CD3 antibody may comprise a heavy chain variable domain (VH) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 214, and/or a light chain variable domain (VL) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93 , 94, 95, 96, 97, 98 or 99%

- 33 040364 sequence identity) c, or the sequence of SEQ ID NO: 215. In other cases, the anti-CD3 antibody contains at least one (for example, 1, 2, 3 or 4) of the framework regions of the heavy chain FR-H1, FR-H2, FR-H3 and FR-H4 containing the sequences of SEQ ID NOs: 349-352, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions of FR-L1, FR-L2, FR-L3 and FR-L4 containing the sequences of SEQ ID NO: 353-356, respectively. In some instances, the anti-CD3 antibody may comprise a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity). ) c, or the sequence of SEQ ID NO: 216, and/or a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 217. In a particular case, the anti-CD3 antibody may be SP34v52 or a derivative or clonally related antibody.

In one aspect, the invention provides an anti-CD3 antibody comprising a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 37;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 38;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 39;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 40;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 41; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 42.

In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the FR-H1, FR-H2, FR-H3, and FR-H4 heavy chain framework regions containing the sequences of SEQ ID NO: 357-360, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of FR-L1, FR-L2, FR-L3, and FR-L4 light chain framework regions comprising the sequences of SEQ ID NO: 361-364 respectively. In some instances, the anti-CD3 antibody may comprise a heavy chain variable domain (VH) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 218, and/or a light chain variable domain (VL) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93 , 94, 95, 96, 97, 98, or 99% sequence identity) c, or the sequence of SEQ ID NO: 219. In other cases, the anti-CD3 antibody contains at least one (e.g., 1, 2, 3, or 4) of the framework regions heavy chain FR-H1, FR-H2, FR-H3, and FR-H4 containing the sequences of SEQ ID NO: 365-368, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the framework regions light chain FR-L1, FR-L2, FR-L3 and FR-L4 containing SE sequences Q ID NO: 369-372, respectively. In some instances, the anti-CD3 antibody may comprise a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity). ) c, or the sequence of SEQ ID NO: 220, and/or a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 221. In a particular case, the anti-CD3 antibody may be 41D9a or a derivative or clonally related antibody.

In one aspect, the invention provides an anti-CD3 antibody comprising a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 48.

In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the FR-H1, FR-H2, FR-H3, and FR-H4 heavy chain framework regions containing the sequences of SEQ ID NO: 373-376, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of FR-L1, FR-L2, FR-L3, and FR-L4 light chain framework regions comprising the sequences of SEQ ID NO: 377-380 respectively. In some instances, the anti-CD3 antibody may comprise a heavy chain variable domain (VH) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 222, and/or the variable domain

- 34 040364 light chain (VL), containing an amino acid sequence having at least 90% sequence identity (for example, at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) with, or the sequence of SEQ ID NO: 223. In other instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4, containing the sequences of SEQ ID NOs: 381-384, respectively, and/or at least one (for example, 1, 2, 3, or 4) of the FR-L1, FR-L2, FR-L3, and FR-L4 light chain framework regions, containing the sequence of SEQ ID NO: 385-388, respectively. In some instances, the anti-CD3 antibody may comprise a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity). ) c, or the sequence of SEQ ID NO: 226, and/or a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 227. In a particular case, the anti-CD3 antibody may be 13A3 or a derivative or clonally related antibody.

In some instances, the invention provides an anti-CD3 antibody comprising a binding domain comprising at least one, two, three, four, five, or six HVRs selected from (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 48.

In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the FR-H1, FR-H2, FR-H3, and FR-H4 heavy chain framework regions containing the sequences of SEQ ID NO: 389-392, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the FR-L1, FR-L2, FR-L3, and FR-L4 light chain framework regions comprising the sequences of SEQ ID NO: 393-396 respectively. In some instances, the anti-CD3 antibody may comprise a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity). ) c, or the sequence of SEQ ID NO: 224, and/or a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 225. In a particular case, the anti-CD3 antibody may be 13A3.v2 or a derivative or clonally related antibody.

In one aspect, the invention provides an anti-CD3 antibody comprising a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 49;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 50;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 51;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 52;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 53; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 54.

In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the FR-H1, FR-H2, FR-H3, and FR-H4 heavy chain framework regions containing the sequences of SEQ ID NO: 397-400, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of FR-L1, FR-L2, FR-L3, and FR-L4 light chain framework regions comprising the sequences of SEQ ID NO: 401-404 respectively. In some instances, the anti-CD3 antibody may comprise a heavy chain variable domain (VH) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 228, and/or a light chain variable domain (VL) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93 , 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 229. In other cases, the anti-CD3 antibody contains at least one (e.g., 1, 2, 3, or 4) of the framework regions heavy chain FR-H1, FR-H2, FR-H3, and FR-H4 containing the sequences of SEQ ID NO: 405-408, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the framework regions light chain FR-L1, FR-L2, FR-L3 and FR-L4 containing SE sequences Q ID NO: 409-412, respectively. In some instances, the anti-CD3 antibody may comprise a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity). ) c, or the sequence of SEQ ID NO: 230, and/or a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93,

94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 231.

In a specific instance, the anti-CD3 antibody may be 30A1 or a derivative or clonally related antibody thereof.

In one aspect, the invention provides an anti-CD3 antibody comprising a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 56;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 57;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 58;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 59; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 60.

In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the FR-H1, FR-H2, FR-H3, and FR-H4 heavy chain framework regions containing the sequences of SEQ ID NO: 413-416, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the FR-L1, FR-L2, FR-L3, and FR-L4 light chain framework regions comprising the sequences of SEQ ID NO: 417-420, respectively. In some instances, the anti-CD3 antibody may comprise a heavy chain variable domain (VH) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 232, and/or a light chain variable domain (VL) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93 , 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 233. In a particular case, the anti-CD3 antibody may be 30A1.v2 or a derivative or clonally related antibody.

In one aspect, the invention provides an anti-CD3 antibody comprising a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 62;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 63;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 64;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 65; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 66.

In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the FR-H1, FR-H2, FR-H3, and FR-H4 heavy chain framework regions containing the sequences of SEQ ID NO: 421-424, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the FR-L1, FR-L2, FR-L3, and FR-L4 light chain framework regions comprising the sequences of SEQ ID NO: 425-428 respectively. In some instances, the anti-CD3 antibody may comprise a heavy chain variable domain (VH) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 234, and/or a light chain variable domain (VL) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93 , 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 235. In a particular case, the anti-CD3 antibody may be h21A9 or a derivative or clonally related antibody.

In one aspect, the invention provides an anti-CD3 antibody comprising a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 68;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 69;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 70;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 71; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 72.

In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the FR-H1, FR-H2, FR-H3, and FR-H4 heavy chain framework regions containing the sequences of SEQ ID NO: 429-432, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the FR-L1, FR-L2, FR-L3, and FR-L4 light chain framework regions comprising the sequences of SEQ ID NO: 433-436

- 36 040364 respectively. In some instances, the aHTu-CD3 antibody may comprise a heavy chain variable domain (VH) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 236, and/or a light chain variable domain (VL) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93 , 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 237. In a particular case, the anti-CD3 antibody may be 21B2 or a derivative or clonally related antibody.

In one aspect, the invention provides an anti-CD3 antibody comprising a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 74;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 75;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 76;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 77; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 78.

In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the FR-H1, FR-H2, FR-H3, and FR-H4 heavy chain framework regions containing the sequences of SEQ ID NO: 437-440, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of FR-L1, FR-L2, FR-L3, and FR-L4 light chain framework regions comprising the sequences of SEQ ID NO: 441-444 respectively. In some instances, the anti-CD3 antibody may comprise a heavy chain variable domain (VH) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 238, and/or a light chain variable domain (VL) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93 , 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 239. In a particular case, the anti-CD3 antibody may be 125A1 or a derivative or clonally related antibody.

In one aspect, the invention provides an anti-CD3 antibody comprising a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 80;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 81;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 82;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 83; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 84.

In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the FR-H1, FR-H2, FR-H3, and FR-H4 heavy chain framework regions containing the sequences of SEQ ID NO: 445-448, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of FR-L1, FR-L2, FR-L3, and FR-L4 light chain framework regions comprising the sequences of SEQ ID NO: 449-452 respectively. In some instances, the anti-CD3 antibody may comprise a heavy chain variable domain (VH) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 240, and/or a light chain variable domain (VL) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93 , 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 241. In a particular case, the anti-CD3 antibody may be 72H6 or a derivative or clonally related antibody.

In one aspect, the invention provides an anti-CD3 antibody comprising a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 86;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 87;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 88;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 89; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 90.

- 37 040364

In some instances, the aHTu-CD3 antibody contains at least one (e.g., 1, 2, 3, or 4) of the FR-H1, FR-H2, FR-H3, and FR-H4 heavy chain framework regions containing the sequences of SEQ ID NO: 453-456, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of FR-L1, FR-L2, FR-L3, and FR-L4 light chain framework regions comprising the sequences of SEQ ID NO: 457-460 respectively. In some instances, the anti-CD3 antibody may comprise a heavy chain variable domain (VH) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 242, and/or a light chain variable domain (VL) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93 , 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 243. In a particular case, the anti-CD3 antibody may be 19B1 or a derivative or clonally related antibody.

In one aspect, the invention provides an anti-CD3 antibody comprising a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 91;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 92;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 93;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 94;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 95; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 96.

In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the FR-H1, FR-H2, FR-H3, and FR-H4 heavy chain framework regions containing the sequences of SEQ ID NO: 461-464, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of FR-L1, FR-L2, FR-L3, and FR-L4 light chain framework regions comprising the sequences of SEQ ID NO: 465-468 respectively. In some instances, the anti-CD3 antibody may comprise a heavy chain variable domain (VH) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 244, and/or a light chain variable domain (VL) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93 , 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 245. In a specific case, the anti-CD3 antibody may be 71H7 or a derivative or clonally related antibody.

In one aspect, the invention provides an anti-CD3 antibody comprising a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 97;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 98;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 99;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 100;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 101; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 102.

In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the FR-H1, FR-H2, FR-H3, and FR-H4 heavy chain framework regions containing the sequences of SEQ ID NO: 469-472, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of FR-L1, FR-L2, FR-L3, and FR-L4 light chain framework regions comprising the sequences of SEQ ID NO: 473-476 respectively. In some instances, the anti-CD3 antibody may comprise a heavy chain variable domain (VH) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 246, and/or a light chain variable domain (VL) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93 , 94, 95, 96, 97, 98, or 99% sequence identity) c, or the sequence of SEQ ID NO: 247. In a particular case, the anti-CD3 antibody may be 14C7 or a derivative or clonally related antibody.

In one aspect, the invention provides an anti-CD3 antibody comprising a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 104;

- 38 040364 (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 105;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 106;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 107; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 108.

In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the FR-H1, FR-H2, FR-H3, and FR-H4 heavy chain framework regions containing the sequences of SEQ ID NO: 477-480, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the FR-L1, FR-L2, FR-L3, and FR-L4 light chain framework regions comprising the sequences of SEQ ID NO: 481484 respectively. In some instances, the anti-CD3 antibody may comprise a heavy chain variable domain (VH) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 248, and/or a light chain variable domain (VL) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93 , 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 249. In a particular case, the anti-CD3 antibody may be 127B3 or a derivative or clonally related antibody.

In one aspect, the invention provides an anti-CD3 antibody comprising a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 110;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 111;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 112;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 113; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 114.

In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the FR-H1, FR-H2, FR-H3, and FR-H4 heavy chain framework regions containing the sequences of SEQ ID NO: 485-488, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of FR-L1, FR-L2, FR-L3, and FR-L4 light chain framework regions comprising the sequences of SEQ ID NO: 489492 respectively. In some instances, the anti-CD3 antibody may comprise a heavy chain variable domain (VH) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 250, and/or a light chain variable domain (VL) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93 , 94, 95, 96, 97, 98, or 99% sequence identity) c, or the sequence of SEQ ID NO: 251. In a specific instance, the anti-CD3 antibody may be 18F12 or a derivative or clonally related antibody thereof.

In one aspect, the invention provides an anti-CD3 antibody comprising a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 116;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 117;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 118;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 119; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 120.

In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the FR-H1, FR-H2, FR-H3, and FR-H4 heavy chain framework regions containing the sequences of SEQ ID NO: 493-496, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the FR-L1, FR-L2, FR-L3, and FR-L4 light chain framework regions comprising the sequences of SEQ ID NO: 497500 respectively. In some instances, the anti-CD3 antibody may comprise a heavy chain variable domain (VH) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 252, and/or a light chain variable domain (VL) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93 , 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 253. In a particular case, the anti-CD3 antibody may be 27H5-1 or a derivative or clonally related antibody.

In one aspect, the invention provides an anti-CD3 antibody comprising a binding domain,

- 39 040364 containing at least one, two, three, four, five or six hypervariable regions (HVR) selected from (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 121;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 122;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 123;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 124;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 125; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 126.

In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the FR-H1, FR-H2, FR-H3, and FR-H4 heavy chain framework regions containing the sequences of SEQ ID NO: 501-504, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of FR-L1, FR-L2, FR-L3, and FR-L4 light chain framework regions comprising the sequences of SEQ ID NO: 505508 respectively. In some instances, the anti-CD3 antibody may comprise a heavy chain variable domain (VH) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 254, and/or a light chain variable domain (VL) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93 , 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 255. In a particular case, the anti-CD3 antibody may be 39B7 or a derivative or clonally related antibody.

In one aspect, the invention provides an anti-CD3 antibody comprising a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 128;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 129;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 130;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 131; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 132.

In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the FR-H1, FR-H2, FR-H3, and FR-H4 heavy chain framework regions containing the sequences of SEQ ID NO: 509-512, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of FR-L1, FR-L2, FR-L3, and FR-L4 light chain framework regions comprising the sequences of SEQ ID NO: 513516 respectively. In some instances, the anti-CD3 antibody may comprise a heavy chain variable domain (VH) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 256, and/or a light chain variable domain (VL) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93 , 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 257. In a particular case, the anti-CD3 antibody may be 40D2 or a derivative or clonally related antibody.

In one aspect, the invention provides an anti-CD3 antibody comprising a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 134;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 135;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 136;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 137; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 138.

In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the FR-H1, FR-H2, FR-H3, and FR-H4 heavy chain framework regions containing the sequences of SEQ ID NO: 517-520, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of FR-L1, FR-L2, FR-L3, and FR-L4 light chain framework regions comprising the sequences of SEQ ID NO: 521524 respectively. In some instances, the anti-CD3 antibody may comprise a heavy chain variable domain (VH) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 258, and/or a light chain variable domain (VL) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93 , 94, 95, 96, 97, 98 or

- 40 040364

99% sequence identity) c, or the sequence of SEQ ID NO: 259. In a particular case, the aHTu-CD3 antibody may be 79B7 or a derivative or clonally related antibody thereof.

In one aspect, the invention provides an anti-CD3 antibody comprising a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 140;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 141;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 142;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 143; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 144.

In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the FR-H1, FR-H2, FR-H3, and FR-H4 heavy chain framework regions containing the sequences of SEQ ID NO: 525-528, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the FR-L1, FR-L2, FR-L3, and FR-L4 light chain framework regions comprising the sequences of SEQ ID NO: 529532 respectively. In some instances, the anti-CD3 antibody may comprise a heavy chain variable domain (VH) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 260, and/or a light chain variable domain (VL) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93 , 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 261. In a particular case, the anti-CD3 antibody may be 95A2 or a derivative or clonally related antibody.

In one aspect, the invention provides an anti-CD3 antibody comprising a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 146;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 147;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 148;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 149; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 150.

In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the FR-H1, FR-H2, FR-H3, and FR-H4 heavy chain framework regions containing the sequences of SEQ ID NO: 533-536, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of FR-L1, FR-L2, FR-L3, and FR-L4 light chain framework regions comprising the sequences of SEQ ID NO: 537540 respectively. In some instances, the anti-CD3 antibody may comprise a heavy chain variable domain (VH) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 262, and/or a light chain variable domain (VL) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93 , 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 263. In a particular case, the anti-CD3 antibody may be 118G9 or a derivative or clonally related antibody.

In one aspect, the invention provides an anti-CD3 antibody comprising a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 152;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 153;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 154;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 155; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 156.

In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the FR-H1, FR-H2, FR-H3, and FR-H4 heavy chain framework regions containing the sequences of SEQ ID NO: 541-544, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of FR-L1, FR-L2, FR-L3, and FR-L4 light chain framework regions comprising the sequences of SEQ ID NO: 545548 respectively. In some instances, the anti-CD3 antibody may comprise a heavy chain variable domain (VH) containing an amino acid sequence having at least 90%

- 41 040364 sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or the sequence of SEQ ID NO: 264, and/or the light chain variable domain ( VL) containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) with, or the sequence of SEQ ID NO: 265. In a specific instance, the anti-CD3 antibody may be Rab17 or a derivative or clonally related antibody thereof.

In any of the above embodiments, the anti-CD3 antibody is humanized. In one embodiment, the anti-CD3 antibody comprises an HVR according to any of the above embodiments and further comprises an acceptor human framework, such as a human immunoglobulin framework or a human consensus framework.

In another aspect, an anti-CD3 antibody is provided, wherein the antibody comprises a VH according to any of the above embodiments and a VL according to any of the above embodiments, wherein one or both of the variable domain sequences contain post-translational modifications.

In a further aspect, an antibody is provided that binds to the same epitope as the anti-CD3 antibody provided herein. For example, in certain embodiments, an antibody is provided that binds to the same epitope as an anti-CD3 antibody comprising the VH sequence of SEQ ID NO: 184 and the VL sequence of SEQ ID NO: 185. In certain embodiments, the antibody is provided that binds to an epitope within a CD3 fragment (eg, human CD3ε) consisting of amino acids 1-26 (SEQ ID NO: 283) or 1-27 (SEQ ID NO: 278) of human CD3ε.

In another aspect, the invention provides an antibody that binds to a unique CD3 epitope. In certain embodiments, an anti-CD3 antibody of the invention forms unique contacts with human CD3ε amino acids at a distance of 3.5 angstroms, 3.25 angstroms, 3.00 angstroms, 2.75 angstroms, or less. In certain embodiments, an antibody is provided that binds to an epitope consisting of one, two, three, four, or five amino acids of human CD3ε at a distance of 3.5 angstroms, 3.25 angstroms, 3.00 angstroms, 2.75 angstroms or less. In one embodiment, an anti-CD3 antibody of the invention makes unique contacts with human CD3ε amino acids at a distance of 3.5 angstroms or less. In certain embodiments, an antibody is provided that binds to an epitope of one, two, three, four, or five amino acids of human CD3ε at a distance of 3.5 angstroms or less. For example, in certain embodiments, an antibody is provided that binds to an epitope consisting of human CD3ε amino acids selected from Gln1, Asp2, Asn4, Glu6, and Met7. In one specific embodiment, the anti-CD3 antibody binds to an epitope that contains, in particular, Glu6. In certain other embodiments, an antibody is provided that does not bind to an epitope that contains the amino acid Glu5 of human CD3ε. In certain other embodiments, an antibody is provided that does not bind to an epitope that contains the amino acids Gly3 and Glu5 of human CD3ε.

The Ahtu-CD3 epitope can be determined by the binding of an anti-CD3 antibody to peptide fragments of the epitope. Alternatively, an anti-CD3 epitope can be determined using alanine scanning mutagenesis. In one embodiment, a decrease in the binding of an anti-CD3 antibody to mutated CD3 by 20%, 30%, 50%, 80% or more indicates that the CD3 amino acid residue mutated during alanine scanning mutagenesis is an epitope residue for that anti-CD3 antibodies. Alternatively, the anti-CD3 epitope can be determined using mass spectrometry. In some embodiments of the invention, the epitope is determined by the method of crystallography (for example, the methods of crystallography described in the examples).

In some embodiments, the epitope determined by crystallography is determined using amino acids Q1-M7 in CD3. In some embodiments, the epitope determined by crystallography is determined using amino acids QDGNEEMGGITQTPYK (SEQ ID NO: 284) of CD3.

In some embodiments, epitope determination by crystallography can be performed by combining Fab anti-CD3 antibodies dissolved in 0.15 M NaCl, 25 mM Tris, pH 7.5, at a concentration of 10 mg/ml, with a 2-fold molar excess ( 1 mg) of the CD3ε peptide, and conducting an initial study of a sparse matrix of precipitates in a sessile drop vapor diffusion format. Optimized crystals can be grown from a 1:1 mixture with a reservoir solution containing 70% v/v. methylpentanediol, and 0.1 M HEPES buffer at pH 7.5. The reservoir can be used as a cryoprotectant. Crystals can be cooled to cryogenic temperatures by rapid dipping in

- 42 040364 liquid nitrogen.

Crystal diffraction data can be acquired on the beam axis of the 22ID Advanced Photon Source using the MAR300 CCD detector. The recorded diffraction data can be combined and recalculated using the HKL2000 software.

The structure can be phased by molecular displacement (MS) using the Phaser software. For example, the MOH search model is a Fab subunit derived from the crystal structure of the HGFA/Fab complex (PDB code: 2R0L). The CD3ε peptide is built into the structure based on the Fo-Fc map. The structure can be subsequently adjusted using the REFMAC5 and PHENIX programs using the maximum similarity of objective functions, anisotropic individual B-factor correlation analysis and least squares correlation analysis to achieve convergence.

In certain other embodiments, an antibody is provided that contains a paratope that binds to the same epitope as the anti-CD3 antibody provided herein. For example, in certain embodiments, an antibody is provided that binds to the same epitope as a paratope of an anti-CD3 antibody containing amino acids that form contacts at a distance of 3.5 angstroms or less. In certain embodiments, an antibody is provided that binds to the same epitope as a paratope of an anti-CD3 antibody, consisting of amino acids of the VH region of an anti-CD3 antibody selected from the group consisting of 33Tyr, 35His, 50Trp, 97Tyr, and 98Ser. In certain embodiments, an antibody is provided that binds to the same epitope as a paratope of an anti-CD3 antibody, consisting of one, two, three, four, or five amino acids of the VH region of an anti-CD3 antibody, selected from the group consisting of 33Tyr, 35His, 50Trp, 97Tyr and 98Ser. In certain embodiments, an antibody is provided that binds to the same epitope as a paratope of an anti-CD3 antibody, consisting of amino acids of the VL region of an anti-CD3 antibody selected from the group consisting of 27Arg, 27Asn, 30Lys, 32Tyr, 92Phe, 94Leu and 96 Arg. In certain embodiments, an antibody is provided that binds to the same epitope as a paratope of an anti-CD3 antibody, consisting of one, two, three, four, five, six, or seven amino acids of the VL region of an anti-CD3 antibody selected from the group , including 27Arg, 27Asn, 30Lys, 32Tyr, 92Phe, 94Leu, and 96Arg. In an optional embodiment, the invention provides an antibody that does not bind to the same epitope as the paratope of an anti-CD3 antibody, consisting of VL region amino acids including 91Ser. In a further aspect of the invention, the anti-CD3 antibody according to any of the above embodiments of the invention is a monoclonal antibody, including a chimeric, humanized, or human antibody. In one embodiment, the anti-CD3 antibody is an antibody fragment, such as a Fv, Fab, Fab', scFv, diabody, or F(ab') _{2 fragment} . In another embodiment, the antibody is a full-length antibody, such as an intact IgG antibody (eg, an intact IgG1 antibody) or a member of another class or isotype of antibodies as defined herein.

In an additional aspect, an anti-CD3 antibody according to any of the above embodiments of the invention may have any of the features alone or in combination, as described below in sections 1-7.

1. Affinity of antibodies.

In certain embodiments, an antibody provided herein has a dissociation constant (Kd) of <1 μM, <100, <10, <1, <0.1, <0.01, or <0.001 nM (e.g., 10 ^-8 M or less, for example from 10 ^-8 to 10 ^-13 M, for example from 10 ^-9 to 10 ^-13 M).

In one embodiment, Kd is measured by a radiolabeled antigen binding assay (RIA) method. In one embodiment, RIA is performed with a Fab version of an antibody of interest and its antigen. For example, the binding affinity of a Fab in solution for an antigen is measured by equilibrating the Fab with a minimum concentration of ( ¹²⁵ I)-labeled antigen in the presence of a series of titers of unlabeled antigen, then immobilizing the bound antigen on an anti-Fab coated plate (see, e.g., Chen et al., J. Mol. Biol., 293:865-881 (1999)). To establish the conditions for the assay, MICROTITER® multiwell plates (Thermo Scientific) are coated overnight with 5 µg/mL capture anti-Fab antibody (Cappel Labs) in 50 mM sodium carbonate (pH 9.6) and then blocked with 2% (m /vol.) bovine serum albumin in PBS for 2 to 5 hours at room temperature (approximately 23°C). In a non-adsorbent plate (Nunc #269620), 100 or 26 pM [ ¹²⁵ I] antigen are mixed with serial dilutions of the Fab of interest (e.g., as assessed by anti-VEGF antibody Fab-12 in Presta et al., Cancer Res. 57: 4593-4599 (1997)). The Fab of interest is then incubated overnight; however, the incubation may last a longer period (eg, about 65 hours) to ensure that equilibrium is reached. The mixtures are then transferred to a capture plate for incubation at room temperature (eg, 1 hour). The solution is then removed and the plate washed eight times with 0.1% polysorbate 20 (TWEEN-20®) in PBS. When the plates are dry, 150 µl/well of scintillator (MICROSCINT-20™; Packard) is added and the plates are read on a TOPCOUNT™ gamma counter (Packard) for 10 minutes. Concentrations of each Fab that give results of 20% or less of maximum binding are selected for use in a competitive binding assay.

According to another embodiment of the invention, Kd is measured by the BIACORE® Surface Plasmon Resonance method. For example, an assay using BIACORE®-2000 or BIACORE®-3000 (BIAcore, Inc., Piscataway, NJ) is performed at 25° C. with immobilized CM5 antigen arrays at ~10 response units (RU). In one embodiment, carboxymethylated dextran biosensor chips (CM5, BIACORE, Inc.) are activated with N-ethyl-N'-(3dimethylaminopropyl)-carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) according to the supplier's instructions. The antigen is diluted with 10 mM sodium acetate, pH 4.8, to 5 μg/ml (~0.2 μM) before injection at a flow rate of 5 μl/min to achieve approximately 10 response units (RU) of the conjugated protein. After injection of the antigen, 1 M ethanolamine is injected to block unreacted groups. For kinetic measurements, two-fold serial dilutions of Fab (from 0.78 to 500 nM) are injected into PBS with 0.05% polysorbate 20 (TWEEN-20™) surfactant (PBST) at 25° C. at a flow rate of approximately 25 μl/min. Association rates (k _acc ) and dissociation rates (k _gu cc) are calculated using a simple one-to-one Langmuir binding model (BIACORE® evaluation software version 3.2) by simultaneously fitting association and dissociation sensorgrams. The equilibrium dissociation constant (Kd) is calculated as the ratio k _a cc _/ kd _U cc. See, for example, Chen et al., J. Mol. Biol., 293:865-881 (1999). If the association rate exceeds 106 M' ¹ s' ¹ according to the above-described surface plasmon resonance, then the association rate can be determined using the fluorescence quenching method, which measures the increase or decrease in fluorescence intensity (excitation=295 nm; emission=340 nm, 16 nm bandwidth) at 25°C for 20 nM Anti-Antibody (Fab Forms) in PBS, pH 7.2, in the presence of increasing concentrations of antigen, as measured by a spectrometer such as a stop-flow spectrophotometer (Aviv Instruments) or a spectrophotometer 8000 series SLM-AMINCO™ (ThermoSpectronic) with agitated cuvette.

2. Fragments of antibodies.

In certain embodiments, an antibody provided herein is an antibody fragment. Antibody fragments include, but are not limited to, Fab, Fab', Fab'-SH, F(ab') ₂ , Fv, and scFv fragments, as well as other fragments described below. For a review of some antibody fragments, see Hudson et al., Nat. Med. 9:129-134 (2003). For a review of scFv fragments, see, for example, Pluckthun, in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds. (Springer-Verlag, New York), p. 269-315 (1994); see also WO 93/16185; and _US Pat.

Diabodies are antibody fragments with two antigen-binding sites, which can be bivalent or bispecific. See, for example, EP 404097; WO 1993/01161; Hudson et al., Nat. Med. 9:129-134 (2003); and Hollinger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993). Triabodies and tetrabodies are also described in Hudson et al., Nat. Med. 9:129-134 (2003).

Single domain antibodies are antibody fragments containing all or part of the heavy chain variable domain or all or part of the light chain variable domain of an antibody. In certain embodiments, the single domain antibody is a human single domain antibody (Domantis, Inc., Waltham, MA; see, for example, US Pat. No. 6,248,516 B1).

Antibody fragments can be obtained by various methods, including, but not limited to, proteolytic cleavage of intact antibodies, as well as obtaining recombinant host cells (eg, E. coli or phage), as described in this document.

3. Chimeric and humanized antibodies.

In certain embodiments, the antibody provided herein is a chimeric antibody. Some chimeric antibodies are described, for example, in US patent No. 4816567; and Morrison et al., Proc. Natl. Acad. Sci. USA 81:6851-6855 (1984). In one example, the chimeric antibody contains a non-human variable region (eg, a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate such as a monkey). In a further example, the chimeric antibody is a class-switched antibody in which the class or subclass has been changed from the parent antibody. Chimeric antibodies include their antigen-binding fragments.

In certain embodiments of the invention, the chimeric antibody is a humanized antibody. Typically, a non-human antibody is humanized to reduce human immunogenicity while retaining the specificity and affinity of the parent non-human antibody. In general, a humanized antibody contains one or more variable domains in which HVRs, such as CDRs (or a portion thereof), are derived from a non-human antibody and FRs (or a portion thereof) are derived from human antibody sequences. Optionally, the humanized antibody also contains at least a portion of a human constant region. In some embodiments, some FR residues in a humanized antibody are replaced with corresponding residues from a non-human antibody (eg, the antibody from which the HVR residues are derived), for example, to restore or improve the specificity or affinity of the antibody.

Humanized antibodies and methods for their preparation are described, for example, in Almagro, Fransson, Front. Biosci. 13:1619-1633 (2008); and are further described, for example, in Riechmann et al., Nature, 332:323-329 (1988); Queen et al., Proc. Nat'l Acad. Sci., USA, 86:10029-10033 (1989); U.S. Patent Nos. 5,821,337; 7,527,791; Kashmiri et al., Methods 36:25-34 (2005) (describing the grafting of a specificity determining region (SDR)); Padlan, Mol. Immunol., 28:489-498 (1991) (describing surface change); Dall'Acqua et al., Methods, 36:43-60 (2005) (describing FR shuffling); and Osbourn et al., Methods, 36:61-68 (2005); and Klimka et al., Br. J. Cancer, 83:252-260 (2000) (describing a controlled selection approach for FR shuffling).

Human frameworks that can be used for humanization include, but are not limited to, best fit frameworks (see, for example, Sims et al., J. Immunol., 151:2296 (1993)); framework regions derived from the consensus sequence of human antibodies of a particular subgroup of light or heavy chain variable regions (see, e.g., Carter et al., Proc. Natl. Acad. Sci., USA, 89:4285 (1992); and Presta et al. ., J. Immunol., 151:2623 (1993)); human mature (somatically mutated) framework regions or human germline framework regions (see, for example, Almagro, Fransson, Front. Biosci., 13:1619-1633 (2008)); and framework regions obtained by screening FR libraries (see, for example, Baca et al., J. Biol. Chem., 272:10678-10684 (1997); and Rosok et al., J. Biol. Chem., 271 :22611-22618 (1996)).

4. Human antibodies.

In certain embodiments, the antibody provided herein is a human antibody. Human antibodies can be obtained by various methods known in the art. For a general description of human antibodies, see van Dijk, van de Winkel, Curr. Opin. Pharmacol. 5:368-74 (2001); and Lonberg, Curr. Opin. Immunol., 20:450-459 (2008).

Human antibodies can be generated by administering an antigen to a transgenic animal that has been modified to produce intact human antibodies or intact antibodies with human variable regions in response to challenge with an antigen. Such animals typically contain all or part of the human immunoglobulin loci that replace endogenous immunoglobulin loci or that are extrachromosomal or randomly integrated into the animal's chromosomes. In such transgenic mice, endogenous immunoglobulin loci are generally inactivated. For a review of methods for obtaining human antibodies from transgenic animals, see Lonberg, Nat. Biotech., 23:1117-1125 (2005). See also, for example, US Pat. Nos. 6,075,181 and 6,150,584 describing XENOMOUSE™ technology; US patent No. 5770429 describing HUMAB® technology; US Pat. No. 7,041,870 describing K-M MOUSE® technology; and US Patent Application No. US 2007/0061900 describing VELOCIMOUSE® technology. The human variable regions produced by such animals can be further modified, for example by combining with different human constant regions.

Human antibodies can also be generated using hybridoma methods. Human myeloma and murine-human heteromyeloma cell lines have been described for the production of human monoclonal antibodies (see, for example, Kozbor, J. Immunol., 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, p. 51-63 (Marcel Dekker, Inc., New York, 1987); and Boerner et al., J. Immunol., 147:86 (1991)). Human antibodies generated using human B-cell hybridoma technology are described in Li et al., Proc. Natl. Acad. Sci., USA, 103:3557-3562 (2006). Additional methods include those described, for example, in US Pat. No. 7,189,826 (describing the preparation of monoclonal human IgM antibodies from hybridoma cell lines) and Ni, Xiandai Mianyixue, 26(4):265-268 (2006) (describing human-human hybridomas). Human hybridoma technology (trioma technology) is described in Vollmers, Brandlein, Histology and Histopathology, 20(3):927-937 (2005); and Vollmers, Brandlein, Methods and Findings in Experimental and Clinical Pharmacology, 27(3):185-91 (2005).

Human antibodies can also be generated by isolating the variable domain sequences of an Fv clone from phage display libraries of human origin. Such variable domain sequences can then be combined with the desired human constant domain. Methods for selecting human antibodies from antibody libraries are described below.

5. Antibodies obtained from libraries.

Antibodies of the invention can be isolated by screening combinatorial libraries for antibodies with the desired activity or activities. For example, many methods are known in the art for generating phage display libraries and screening such libraries for antibodies having the desired binding characteristics. For a review of such methods, see, for example, Hoogenboom et al., Methods in Molecular Biology, 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, 2001); and is further described, for example, in McCafferty et al., Nature, 348:552-554;

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Clackson et al. Nature 352:624-628 (1991); Marks et al., J. Mol. Biol., 222:581-597 (1992); Marks, Bradbury,

Methods in Molecular Biology, 248:161-175 (Lo, ed., Human Press, Totowa, NJ, 2003); Sidhu et al., J. Mol.

Biol., 338(2):299-310 (2004); Lee et al., J. Mol. Biol., 340(5):1073-1093 (2004); Fellouse, Proc. Natl. Acad.

Sci., USA, 101(34):12467-12472 (2004); and Lee et al., J. Immunol. Methods, 284(1-2):119-132 (2004).

In some phage display methods, VH and VL gene repertoires are separately cloned by polymerase chain reaction (PCR) and recombined randomly in phage libraries, which can then be examined for antigen-binding phage as described in Winter et al., Ann. Rev. Immunol., 12: 433-455 (1994). The phage typically presents antibody fragments, both single chain Fv (scFv) fragments and Fab fragments. Libraries from immunized sources provide high affinity antibodies to the immunogen without requiring hybridoma construction. Alternatively, a naive repertoire (e.g., from a human) can be cloned to provide a single source of antibodies to a wide range of non-self as well as self antigens without any immunization, as described in Griffiths et al., EMBO J., 12:725-734 ( 1993). Finally, naïve libraries can also be generated synthetically by cloning non-rearranged V gene segments from stem cells and using random sequence PCR primers to encode highly variable CDR3 regions and to effect rearrangement in vitro as described in Hoogenboom, Winter, J. Mol. . Biol., 227:381-388 (1992). Patent publications describing human antibody phage libraries include, for example, US Patent No. 5,750,373 and US Patent Publications Nos. 2009/0002360.

Antibodies or antibody fragments isolated from human antibody libraries are referred to herein as human antibodies or human antibody fragments.

6. Multispecific antibodies.

In any of the above aspects, the anti-CD3 antibody provided herein is a multispecific antibody, such as a bispecific antibody. Multispecific antibodies are monoclonal antibodies that have binding specificity for at least two different sites. In certain embodiments, the bispecific antibodies can bind to two different CD3 epitopes (eg, CD3ε or CD3y). In certain embodiments, one binding specificity is for CD3 (eg, CD3e or CD3y) and the other is for any other antigen (eg, a second biological molecule, eg, a cell surface antigen, eg, a tumor antigen). Accordingly, a bispecific anti-CD3 antibody may have binding specificity for CD3 and a second biological molecule, such as the second biological molecule (eg, tumor antigen) shown in Table 1. 1 and described in publ. Pat. USA No. 2010/0111856.

Table 1

Tumor antigens-targets of bispecific anti-CD3 antibodies according to the invention

CD20 CD79a ETBR IL13Ralpha2 M-CSF P2X5 SSX-2 0772R CD79b fusion protein ETV6- AML1 IL20Ra MCSP p53 SSX-4 adipophilia n Cdc27 EZH2 intestinal carboxyl terase mdm-2 PAP STEAP1 AIM-2 CDK4 FcRHl IRTA2 MDP PAX5 STEAP1 ALDH1A1 CDKN 2A FcRH2 kallikrein 4 MEI PBF STEAP2

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alpha actinin-4 CEA FcRH5 KIF20A melan-A MART- 1 PMEU17 survivin alphafetoprote in CLL1 FLT3-ITD KK-LC-1 shallow pmlRARalpha fusion protein fusion protein SYT- SSX1 or - SSX2 amphiregulin CLPP FN1 KM-HN-1 MMP-2 PRAME TAG-1 ARTC1 SOA-1 G250/MN/ CAIX K-ras MMP-7 PRDX5 TAG-2 ASLG659 CPSF GAGE- 1,2,8 LAGE-1 MPF PSCA telomerase ASPHD1 CRIPT ABOUT GAGE- 3,4,5,6,7 LDLRfucosyltransferase AS fusion protein MRP4 PSCA hlg TENB2 B7-H4 Cw6 GDNF-Ral lengsin MSG783 PSMA TGF-6e _T aRII BAFF-R CXCR 5 GEDA LGR5 MUC1 PTPRK TMEFF1 BAGE-1 CXOR F61 GFRA1 LY64 MUC5Ac RAB38/NY-MEL1 TMEM118 BCLX(L) cyclin D1 glypican-3 Ly6E mucin RAGE-1 TMEM46 fusion protein BCR-ABL (b3a2) cyclin -A1 GnTVf Ly6G6D MUM If RBAF600 TRAG-3 beta- catenin dek-can fusion protein gplOO / Pmell7 LY6K MUM-2 RET triose phosphate isomerase BING-4 DKK1 GPC3 LYPD1 MUM-3 RGS5 TRP-1/gp75

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B-RAF DR1 GPNMB MAGE-A1 myosin class I RhoC TRP-2 brevican DR13 GPR172A MAGE-A10 NA88-A RNF43 TRP2-INT2 CALCA E16 GPR19 MAGE-A12 Napi2b RNF43 TrpM4 CASP-5 ED AR GPR54 MAGE-A2 NCA RU2AS tyrosinase With ASP-8 EFTU D2 HAVCR1 MAGE-A3 peo-rar SAGE tyrosinase CD19 elongation factor 2 HER2 MAGE-A4 NFYC secernin 1 VEGF CD21 ENAH (hMena) HER-2 / drink MAGE-A6 N-ras Sema 5b WT1 CD22 ErSA M HERV-K- MEL MAGE-A9 NY-BR-1 SIRT2 XAGElb/GAGED2a CD33 EphA3 HLA-DOB MAGE-C1 NYESO1/LAGE- 2 SLC35D3 EGFR-T790M; CD45 EphB2 R hsp70-2 MAGE-C2 OA1 SNRPD1 BMPR1B CD70 epireg ulin IDO1 mammaglobi n-a OGT SOX10 CD72 EGFR IGF2B3 MART2 OS-9 Spl7 EGFRG719A Bispecific EGFR- G719C anti-CD3 EGFRG719S; antibody EGFRL858R (for example, EGFR- S768I any of EGFR- L861Q described higher anti-CDS antibodies)

may have binding specificity for CD3 and a second biological molecule such as the human leukocyte antigen (HLA)-peptide complex presented on the MHC cell surface. A bispecific anti-CD3 antibody (e.g., any of the anti-CD3 antibodies described above) may have binding specificity for CD3 and a second biological molecule containing an HLA-peptide complex selected from the group consisting of 0772P (CA25, MUC16; Genbank accession no. AF36148 ); adipophilin (perilipin-2, adipose differentiation-associated protein, ADRP, ADFP, MGC10598; NCBI standard sequence: NP_001113.2); AIM-2 (absent in melanoma 2, PYHIN4, interferon-inducible protein AIM2; standard NCBI sequence: NP_004824.1); ALDH1A1 (aldehyde dehydrogenase 1 family, member A1, ALDH1, PUMB1, retinaldehyde dehydrogenase 1, ALDC, ALDH-E1, ALHDII, RALDH 1, EC 1.2.1.36, ALDH11, HEL-9, HEL-S-53e, HEL12, RALDH1, acetaldehyde dehydrogenase 1, aldehyde dehydrogenase 1, soluble, aldehyde dehydrogenase, hepatic cytosolic, ALDH class 1, epididymis lumen protein 12, epididymis lumen protein 9, epididymis secretory sperm-binding protein Li 53e, retinal dehydrogenase 1, RalDH1, aldehyde dehydrogenase family 1, member A, aldehyde dehydrogenase, cytosolic, EC 1.2.1, standard NCBI sequence: NP_000680.2); alpha-actinin-4 (ACTN4, actinin, alpha 4, FSGS1, focal segmental glomerulosclerosis 1, non-muscle alpha actinin 4, F-actin cross-linking protein, FSGS, ACTININ-4, actinin alpha 4 isoform, alpha actinin-4; standard NCBI sequence: NP_004915.2); alpha-fetoprotein (AFP, HPAFP, FETA, alpha-1-fetoprotein, alpha-fetoglobulin, alpha-1-fetoprotein, alpha-fetoglobulin, HP; GenBank: AAB58754.1); amphiregulin (AREG, SDGF, schwannoma-derived growth factor, colon-derived growth factor, AR, CRDGF; GenBank: AAA51781.1); ARTC1 (ART1, ADP-ribosyltransferase 1, mono(ADP-ribosyl)transferase 1, ADPribosyltransferase C2 and C3 toxin-like 1, ART2, CD296, RT6, ADP-ribosyltransferase 2, GPI-linked NAD(P)(+)-arginine ADP- ribosyltransferase 1, EC 2.4.2.31, CD296 antigen; NP); ASLG659; ASPFID1 (aspartate beta hydroxylase domain containing 1, aspartate beta hydroxylase domain containing protein 1, EC 1.14.11.-, EC 1.14.11; GenBank: AAI44153.1); B7-H4 (VTCN1, V-Set domain containing inhibitor of T cell activation 1, B7H4, B7 superfamily, member 1, B7-H4 immune costimulatory protein, B7h.5, B7x costimulatory T cell molecule, B7S1, B7X, VCTN1, h4,

- 48 040364 member of the B7 family, PRO1291, member of the B7 family, H4, B7x costimulatory T-cell molecule, containing the V-Set domain, T-cell activation inhibitor 1, B7S1 protein; GenBank: AAZ17406.1); BAFF-R (TNFRSF13C, tumor necrosis factor receptor superfamily, member 13C, BAFFR, B cell activating factor receptor, BAFF receptor, BLyS 3 receptor, CVTD4, BROMIX, CD268, B cell activating factor receptor, prolixin, member 13C tumor necrosis factor receptor superfamily, BR3, CD268 antigen; NCBI standard sequence: NP_443177.1); BAGE-1; BCLX(L); fusion protein BCR-ABL (b3a2); beta-catenin (CTNNB1, catenin (cadherin-associated protein), beta 1, 88 kDa, CTNNB, MRD19, catenin (cadherin-associated protein), beta 1 (88 kDa), armadillo, catenin-beta-1; GenBank: CAA61107 .1); BING-4 (WDR46, WD repeat domains 46, C6orf11, BING4, containing WD repeat domains protein BING4, chromosome 6 open reading frame 11, FP221, UTP7, containing WD repeat domains protein 46; NP); BMPR1B (bone morphogenetic protein type IB receptor, Genbank accession no. NM_00120; NP); B-RAF (brevican (BCAN, BEHAB, Genbank accession no AF22905); brevican (BCAN, chondroitin sulfate proteoglycan 7, brain hyaluronan binding protein, BEHAB, CSPG7, brevican proteoglycan, core protein brevican, chondroitin sulfate proteoglycan BEHAB; GenBank: AAH27971.1); CALCA (calcitonin-related polypeptide alpha, CALC1, calcitonin 1, calcitonin, CGRP alpha-type, calcitonin-related peptide I, CGRP-I, CGRP, CGRP1, CT, KC, calcitonin/calcitonin-related polypeptide , alpha, catacalcin; NP); CASP-5 (CASP5, caspase 5, apoptosis-associated cysteine peptidase, caspase 5, apoptosis-associated cysteine protease, ICH-3 protease, TY protease, ICE(rel)-III, ICE(rel)III , ICEREL-III, ICH-3, caspase-5, TY-protease, EC 3.4.22.58, ICH3, EC 3.4.22; NP); CASP-8; CD19 (CD19 is a precursor of B-lymphocyte antigen CD19 isoform 2, B4 , CVTD3 [Homo sapiens], NCBI standard sequence: NP_001761.3); CD20 (CD20-B lymphocyte antigen CD20, transmembrane 4-domain, superfamily A , representative 1, B1, Bp35, CD20, CVID5, LEU-16, MS4A2, S7; standard NCBI sequence: NP_690605.1); CD21 (CD21 (CR2 (complementary receptor or C3DR (C3d/Epstein-Barr virus receptor)) or Hs.73792, Genbank accession no. M2600))); (CD22 (B cell receptor isoform CD22-B, BL-CAM, Lyb8, Lyb8, SIGLEC-2, FLJ22814, Genbank accession no. AK02646)); CD22; CD33 (CD33 molecule, CD33 antigen (Gp67), sialic acid-binding Ig-like lectin 3, sialic acid-binding Ig-like lectin 3, SIGLEC3, gp67, SIGLEC-3, myeloid cell surface antigen CD33, p67, Siglec-3, antigen CD33 GenBank: AAH28152.1); CD45; CD70 (CD70 - superfamily (ligands) of tumor necrosis factors, representative 7; surface antigen CD70; antigen Ki-24; ligand CD27; CD27-L; representative of the 7 superfamily of ligands of tumor necrosis factors; NCBI standard sequence for the species homo sapiens: NP_001243.1 ); CD72 (CD72 (B cell differentiation antigen CD72, Lyb-; 359 aa, pI: 8.66, MW: 40225, TM: 1 [P] gene chromosome: 9p13.3, Genbank accession no. NP_001773.); CD79a (CD79a ( CD79A, CD79a, immunoglobulin-associated alpha, a B cell specific protein that covalently interacts with Ig beta (CD79B) and forms a surface complex with Ig M molecules, transmits a signal associated with B cell differentiation), pI: 4.84, MW: 25028 TM: 2 [P] chromosome gene: 19q13.2, Genbank accession no NP_001774.1); ); HNUC, NUC2, anaphase stimulating complex, protein 3, cell division cycle homolog 27, cell death cycle protein homologue leniya 27, Nuc2 homologue; GenBank: AAH11656.1); CDK4 (cyclin-dependent kinase 4, cell division protein kinase 4, PSK-J3, EC 2.7.11.22, CMM3, EC 2.7.11; NCBI standard sequence: NP_000066.1); CDKN2A (cyclin-dependent kinase inhibitor 2A, MLM, CDKN2, MTS1, cyclin-dependent kinase 2A inhibitor (melanoma, P16, inhibits CDK4), cyclin-dependent kinase 4 inhibitor A, multiple oncosuppressor 1, CDK4I, MTS-1, CMM2, P16, ARF, INK4, INK4A, P14, P14ARF, P16-INK4A, P16INK4, P16INK4A, P19, P19ARF, TP16, CDK4 inhibitor P16-INK4, cell cycle negative regulator beta, P14ARF, p16-INK4, p16-INK4a, p16INK4A, p19ARF; NP); CEA; CLL1 (CLL-1 (CLEC12A, MICL and DCAL, encodes a member of the C-type lectin/C-type lectin-like domain (CTL/CTLD) superfamily) . Members of this family share the same type of protein folding and have diverse functions such as cell adhesion, cell-to-cell signaling, glycoprotein turnover, and play a role in inflammatory and immune responses. The protein encoded by this gene is a negative regulator of the function of granulocytes and monocytes. Several alternative splice variants of the transcript of this gene have been described, but the full-length nature of some of these variants has not been determined. This gene is closely related to other members of the CTL/CTLD superfamily in the region of the natural killer gene complex on chromosome 12p13 (Drickamer K., Curr. Opin. Struct. Biol., 9:585-90; van Rhenen A. et al., Blood 110 :2659-66; Chen C.H. et al., Blood, 107:1459-67; Marshall A.S. et al., Eur. J. Immunol., 36:2159-69; Bakker A.B. et al., Cancer Res., 64: 8443-50; Marshall A. S. et al., J. Biol. Chem., 279:14792-80). CLL-1 has been shown to be a type II transmembrane receptor containing a single C-type lectin-like domain (which predictably does not bind calcium or sugar), a stalk region, a transmembrane domain, and a short cytoplasmic tail containing an ITIM motif; CLPP (mitochondrial matrix caseinolytic peptidase proteolytic subunit, C1p endopeptidase, EC 3.4.21.92, PRLTS3, ATP-dependent ClpAP protease (E. coli), ClpP homologue (ATP-dependent caseinolytic protease proteolytic subunit, E. coli), ATP proteolytic subunit homologue -dependent caseinolytic peptidase ClpP (E. coli), homologue of the proteolytic subunit of the ATP-dependent caseinolytic protease ClpP (E. coli), proteolytic subunit of the human ATP-dependent protease ClpAP, proteolytic subunit of the human ATP-dependent caseinolytic peptidase ClpP, homolog of the proteolytic subunit of ATP-ATP dependent caseinolytic peptidase ClpP, proteolytic subunit homolog of ATP-dependent caseinolytic protease ClpP, putative mitochondrial proteolytic subunit of ATP-dependent protease Clp; NP); COA-1; CPSF; CRIPTO (CRIPTO (CR, Cr1, CRGF, CRIPTO, TDGF1, teratocarcinoma-derived growth factor, Genbank accession no. NP_003203 or NM_00321))); Cw6; CXCR5 CXCR5 (Burkitt's lymphoma receptor 1, a G protein-coupled receptor that is activated by the chemokine CXCL13, is involved in lymphocyte migration and humoral defense, plays a role in HIV-2 infection and possibly the development of AIDS, lymphoma, myeloma, and leukemia); 372 aa, pI: 8.54 MW: 41959 TM: 7 [P] chromosome of gene 11q23.3, Genbank accession no. NP_001707.; CXORF61 (CXORF61 - X chromosome open reading frame 61 [Homo sapiens], NCBI standard sequence: NP_001017978.1); cyclin D1 (CCND1, BCL1, PRAD1, D11S287E, B-cell CLL/lymphoma protein 1, B-cell lymphoma protein 1, BCL-1 oncogene, PRAD1 oncogene, cyclin D1 (PRAD1: parathyroid adenomatosis 1), G1/S-specific cyclin D1 , parathyroid adenomatosis 1, U21B31, G1/S-specific cyclin-DI, BCL-1; NCBI standard sequence: NP_444284.1); cyclin-A (CCNA1, CT146, cyclin A1; GenBank: AAH36346.1); dek-can fusion protein; DKK1 (Dickkopf signaling pathway inhibitor WNT 1, SK, hDkk-1, Dickkopf (Xenopus Laevis) homologue 1, Dickkopf 1 (Xenopus Laevis) homologue, DKK-1, Dickkopf 1 homologue, Dickkopf-related protein-1, Dickkopf-1- similar, Dickkopf-like protein 1, Dickkopf-related protein 1, Dickkopf-1, Dkk-1; GenBank: AAQ89364.1); DR1 (transcriptional downregulator 1, TBP-binding (negative cofactor 2), negative cofactor 2beta, TATA-binding protein-associated phosphoprotein, NC2, NC2-EETA, Dr1 protein, NC2beta, transcription downregulator 1; standard sequence NCBI: NP_001929.1); DR13 (major histocompatibility complex class II, DR beta 1, HLA-DR1B, DRw10, DW2.2/DR2.2, SS1, DRB1, HLA-DRB, HLA class II histocompatibility antigen, DR-1 beta chain, human lymphocytic antigen DRB1, lymphocytic antigen DRB1, MHC class II antigen, HLA-DR beta 1 chain MHC class II, cell surface protein HLA-DR-beta MHC class II, HLA-DRw10-beta MHC class II, DR-1, DR- 12, DR-13, DR-14, DR-16, DR-4, DR-5, DR-7, DR-8, DR-9, DR1, DR12, DR13, DR14, DR16, DR4, DR5, DR7, DR8, DR9, DRw11, DRw8, HLA-DRB2, clone P2-beta-3, DRB1*1 MHC class II antigen, DRB1*10 MHC class II antigen, DRB1*11 MHC class II antigen, DRB1*12 MHC class II antigen , DRB1*13 MHC class II antigen, DRB1*14 MHC class II antigen, DRB1*15 MHC class II antigen, DRB1*16 MHC class II antigen, DRB1*3 MHC class II antigen, DRB1*4 MHC class II antigen, antigen DRB1*7 MHC class II, DRB1*8 MHC class II antigen, DRB1*9 MHC class II antigen; NP); E16 (E16 (LAT1, SLC7A5, Genbank Access # NM_00348)); EDAR (EDAR - a member of the tumor necrosis factor receptor superfamily, precursor of EDAR, EDA-A1 receptor; downless homologue; ectodysplasin-A receptor; ectodermal dysplasia receptor; anhydrotic ectodysplasin 1 receptor, DL; ECTD10A; ECTD10B; ED1R; ED3; ED5; EDA- A1R; EDA1R; EDA3; HRM1 [Homo sapiens]; NCBI standard sequence: NP_071731.1); EFTUD2 (containing GTP-binding domain of elongation factor Tu 2, containing GTP-binding domain of elongation factor Tu protein 2, hSNU114, homologue of SNU114, U5 SnRNP-specific protein, 116 kDa, MFDGA, KIAA0031, 116 KD, U5 SnRNP-specific protein, 116 kDa small nuclear ribonucleoprotein component U5, MFDM, SNRNP116, Snrp116, Snu114, U5-116KD, SNRP116, U5-116 KDa; GenBank: AAH02360.1); EGFR (epidermal growth factor receptor, ERBB, C-ErbB-1 proto-oncogene, ErbB-1 receptor tyrosine protein kinase, ERBB1, HER1, EC 2.7.10.1, epidermal growth factor receptor (avian erythroblastosis virus (V-Erb-B) oncogene homologue), erythroblastosis virus (V-Erb-B) oncogene homologue (avian), PIG61, avian erythroblastosis virus (V-Erb-B) oncogene homologue, cell growth inhibitory protein 40, cell proliferation inducing 61, mENA, EC 2.7.10; GenBank: AAH94761.1); EGFR-G719A; EGFR-G719C; EGFR-G719S; EGFR-L858R; EGFR-L861Q; EGFR-S768I; EGFR-T790M; elongation factor 2 (EEF2, eukaryotic translation elongation factor 2, EF2, polypeptidyl-TRNA translocase, EF-2, SCA26, EEF-2; standard NCBI sequence: NP_001952.1); ENAH (hMena) (permitted homolog (Drosophila), MENA, resolved mammalian homologue, ENA, NDPP1, protein resolved homologue; GenBank: AAH95481.1) - results for ENAH only, not ENAH (hMena); EpCAM (epithelial cell adhesion molecule, M4S1, MIC18, tumor-associated calcium signal transducer 1, TACSTD1, TROP1, adenocarcinoma-associated antigen, Trop-1 cell surface glycoprotein, epithelial glycoprotein 314, major gastrointestinal tumor-associated protein GA733-2, EGP314, KSA , DIAR5, HNPCC8, monoclonal antigen

- 50 040364 AUA1, EGP-2, EGP40, ESA, KS1/4, MK-1, human epithelial glycoprotein-2, membrane component, chromosome 4, surface marker (35 kDa glycoprotein), EGP, Ep-CAM, GA733- 2, M1S2, CD326 antigen, cell surface epithelial antigen, hEGP314, KS 1/4 antigen, ACSTD1; GenBank: AAH14785.1); EphA3 (EPH A3 receptor, ETK1, ETK, TYRO4, HEK, Eph-like tyrosine kinase 1, ETK1 tyrosine protein kinase receptor, EK4, EPH-like kinase 4, EC 2.7.10.1, EPHA3, HEK4, aphrin A-type 3 receptor, embryonic kinase human 1, TYRO4 protein tyrosine kinase, hEK4, human embryonic kinase, TYRO4 tyrosine protein kinase, EC 2.7.10; GenBank: AAH63282.1); EpB2R; epiregulin (EREG, ER, proepiregulin; GenBank: AAI36405.1); ETBR (EDNRB, Endothelial Type B Receptor, HSCR2, HSCR, Endothelial Type B Receptor, ET-B, ET-BR, ETRB, ABCDS, WS4A, ETB, Endothelial B Receptor; NP); fusion protein ETV6-AML1; EZH2 (Zeste homolog enhancer 2 (Drosophila), Lysine N-methyltransferase 6, ENX-1, KMT6 EC 2.1.1.43, EZH1, WVS, Zeste homolog enhancer (Drosophila) 2, ENX1, EZH2b, KMT6A, WVS2, histone-lysine N α-methyltransferase EZH2, Zeste 2 homologue enhancer, EC 2.1.1; GenBank: AAH10858.1); FcRH1 (FCRL1, Fc receptor-like 1, FCRH1, Fc receptor 1 homologue, FcR-like protein 1, immune receptor translocation-associated protein 5, IFGP1, IRTA5, hIFGP1, IFGP family protein 1, CD307a, Fc receptor- similar protein 1, immunoglobulin superfamily Fc receptor, Gp42, FcRL1, CD307a antigen; GenBank: AAH33690.1); FcRH2 (FCRL2, Fc receptor-like 2, SPAP1 containing SH2 domain phosphatase anchor protein 1, Fc receptor 2 homologue, FcR-like protein 2, immunoglobulin receptor translocation-associated protein 4, FCRH2, IFGP4, IRTA4, IFGP family protein 4, SPAP1A, SPAP1B, SPAP1C, CD307b, Fc receptor-like protein 2, immune receptor translocation-associated protein 4, Fc receptor of the immunoglobulin superfamily, Gp42, SH2 domain-containing phosphatase anchor protein 1, FcRL2, CD307b antigen; GenBank: AAQ88497 .1); FcRH5 (FCRL5, Fc receptor-like 5, IRTA2, Fc receptor homolog 5, FcR-like protein 5, immune receptor translocation-associated protein 2, BXMAS1, FCRH5, CD307, CD307e, PRO820, Fc receptor-like protein 5 receptor translocation-associated immunoglobulin superfamily 2 (IRTA2), FcRL5, CD307e antigen; GenBank: AAI01070.1); FLT3-ITD; FN1 (fibronectin 1, insoluble cryoglobulin, FN, migration stimulating factor, CIG, FNZ, GFNd2, LETS, ED-B, FINC, GFND, mSf, fibronectin; GenBank: AAI43764.1); G250 (MN, CAIX, charcoal anhydrase IX, charcoal dehydratase, RCC-associated protein G250, carbonate dehydratase IX, MN membrane antigen associated with renal cell carcinoma G250, CA-IX, P54/58N, pMW1, RCC-associated antigen G250, carbonic anhydrase 9; NP); similar results for G250 but not G250/MN/CAIX; GAGE-1,2,8; GAGE-3,4,5,6,7; GDNFRa1 (alpha 1 receptor of the GDNF family; GFRA1; GDNFR; GDNFRA; RETL1; TRNR1; RET1L; GDNFRalpha1; GFR-ALPHA-; U95847; BC014962; NM145793 NM_005264); GEDA (Genbank Access No. AY26076); GFRA1 - alpha-1 receptor of the GDNF family; alpha-1 GDNF receptor; GDNFR-alpha-1; GFRalpha-1; ligand RET 1; associated with TGF-beta receptor for neurotrophic factor 1 [Homo sapiens]; ProtKB/Swiss-Prot: P56159.2; glypican-3 (GPC3, glypican 3, SDYS, glypican proteoglycan 3, intestinal protein OCI-5, GTR2-2, MXR7, SGBS1, DGSX, OCI-5. SGB, SGBS, heparan sulfate proteoglycan, secreted glypican-3, OCI5; GenBank: AAH35972.1); GnTVf; gp100 (PMEL, premelanosome protein, SILV, D12S53E, PMEL17, SIL, melanocytic protein Pmel 17, melanocyte lineage-specific antigen GP100, melanoma-associated antigen ME20, Silver locus protein homologue, ME20-M, ME20M, P1, P100 , Sil ver-like (mouse homologue), Silver homologue (mouse), ME20, SI, Mel 17 melanocytic protein, PMEL melanocytic protein, melanosome matrix protein 17, Silver, murine, homologue; GenBank: AAC60634.1); GPC; GPNMB (glycoprotein (transmembrane) Nmb, glycoprotein NMB, protein like glycoprotein Nmb, osteoactivin, transmembrane glycoprotein HGFIN, HGFIN, NMB, transmembrane glycoprotein, transmembrane glycoprotein NMB; GenBank: AAH32783.1); GPR172A (G protein-coupled receptor 172A; GPCR41; FLJ11856; D15Ertd747e); NP_078807.1; NM_024531.3); GPR19 (G protein-coupled receptor 19; Mm.478; NP_006134.1; NM_006143.2); GPR54 (KISS1 receptor; KISS1R; GPR54; HOT7T175; AXOR1; NP_115940.2; NM_032551.4); HAVCR1 (Hepatitis A virus cell receptor 1, member of the T-cell immunoglobulin-mucin family 1, kidney injury molecule 1, KIM-1, KIM1, TIM, TIM-1, TIM1, TIMD-1, TIMD1, T-cell immunoglobulin receptor- mucin 1, T-cell membrane protein 1, HAVCR, HAVCR-1, immunoglobulin T-cell domain protein and mucin domain 1, HAVcr-1, immunoglobulin T-cell domain-containing protein and mucin 1; GenBank: AAH13325.1); HER2 (ERBB2, avian erythroblastosis virus oncogene homologue V-Erb-B2 2, NGL, NEU, neuro/glioblastoma-derived oncogene homologue, lymph node metastasis gene protein 19, C-ErbB-2 proto-oncogene, Neu proto-oncogene, cell surface receptor tyrosine kinase type HER2, MLN 19, p185erbB2, EC 2.7.10.1, avian erythroblastosis virus oncogene homologue V-Erb-B2 2 (neuro/glioblastoma-derived oncogene homologue), CD340, HER-2, HER-2/neu, TKR1, protein C- Erb B2/Neu, gerstatin, neuroblastoma/glioblastoma-derived oncogene homolog, ErbB-2 receptor tyrosine protein kinase, erythroblastosis virus V-Erb-B2 2 oncogene homolog, neuro/glioblastoma-derived oncogene homologue, MLN19, CD340 antigen, EC 2.7.10; NP); HER-2/neu - analogues of the above; HERV-K-MEL; HLA-DOB (beta subunit of the MHC class II molecule (antigen Ia), which

- 51 040364 rai binds peptides and presents them to CD4+ T-lymphocytes); 273 aa, pI: 6.56, MW: 30820.TM: 1 [P] gene chromosome: 6p21.3, Genbank accession no. NP_002111); hsp70-2 (HSPA2, 70 kDa heat shock protein 2, 70 kD heat shock protein 2, HSP70-3, 70 kD heat shock associated protein 2, 70 kD heat shock protein 2; GenBank: AAD21815.1); IDO1 (indolamine-2,3-dioxygenase 1, IDO, INDO, indolamine-pyrrole-2,3-dioxygenase, IDO-1, indolamine-pyrrole 2,3 dioxygenase, indolamine 2,3 dioxygenase, indole 2,3 dioxygenase, EC 1.13.11.52; NCBI standard sequence: NP_002155.1); IGF2B3; IL13Ralpha2 (IL13RA2, interleukin 13 receptor, alpha 2, cancer testicular antigen 19, interleukin 13 binding protein, IL-13R-alpha-2, IL-13RA2, IL-13 receptor alpha-2 subunit, IL alpha-2 subunit -13R, CD213A2, CT19, IL-13R, IL13BP, interleukin 13 binding protein, interleukin 13 receptor alpha 2 chain, interleukin-13 receptor alpha-2 subunit, IL13R, CD213a2 antigen; NP); IL20Ra; intestinal carboxylesterase; IRTA2 (analogue of FcRH5); kallikrein 4 (KLK4, kallikrein-related peptidase 4, PRSS17, EMSP1, enamel matrix serine proteinase 1, kallikrein-like protein 1, serine protease 17, KLK-L1, PSTS, AI2A1, kallikrein 4 (prostasis, enamel matrix, prostate), ARM1, EMSP, androgen-regulated mRNA 1, enamel matrix serine protease 1, kallikrein, kallikrein-4, prostasis, EC 3.4.21.-, prostasis, EC 3.4.21; GenBank: AAX30051.1); KIF20A (member of the 20A kinesin family, RAB6KIFL, RAB6-interacting, kinesin-like (rabkinesinb), mitotic a; LAGE-1; LDLR-fucosyltransferase AS fusion protein; lengzin (LGSN, lengzin, lens bun with glutamine synthetase domain, GLULD1, protein containing glutamate ammonium ligase 1, LGS containing glutamate ammonium ligase (glutamine synthetase) domain 1 containing glutamate ammonium ligase (glutamine synthetase) domain 1 similar to lens glutamine synthetase; GenBank: AAF61255.1); LGR5 (containing leucine-rich repeats G protein-coupled receptor 5; GPR49, GPR6; NP_003658.1; NM_003667.2; LY64 (lymphocyte antigen 64 (RP10, type I membrane protein from the leucine-rich repeat (LRR) family), regulates B-cell activation and apoptosis, its loss functionality is associated with increased disease activity in patients with systemic lupus erythematosus); 661 aa, pI: 6.20, MW: 74147 TM: 1 [P] gene chromosome: 5q12, Genbank accession no. th antigen 6, locus E; Ly67, RIG-E, SCA-2, TSA-; NP_002337.1; NM_002346.2); Ly6G6D (lymphocyte antigen complex 6, G6D locus; Ly6-D, MEGT; NP_067079.2; NM_021246.2); LY6K (lymphocyte antigen complex 6, locus K; LY6K; HSJ001348; FLJ3522; NP_059997.3; NM_017527.3); LyPD1 - domain containing LY6/PLAUR 1, PHTS [Homo sapiens], GenBank: AAH17318.1); MAGE-A1 (melanoma antigen family A, 1 (controls expression of MZ2-E antigen, MAGE1, melanoma antigen A family 1, MAGEA1, melanoma antigen MAGE-1, melanoma-associated antigen 1, melanoma-associated antigen MZ2-E, antigen MZ2 -E, cancer testicular antigen 1.1, CT1.1, MAGE-1 antigen, cancer testicular antigen family 1, representative 1, cancer testicular antigen family 1, representative 1, MAGE1A; NCBI standard sequence: NP_004979.3); MAGE-A10 (MAGEA10, melanoma antigen family A, 10, MAGE10, MAGE-10 antigen, melanoma-associated antigen 10, testicular cancer antigen 1.10, CT1.10, testicular cancer antigen family 1, representative 10, testicular cancer antigen family 1, representative 10; NCBI standard sequence: NP_001238757.1); MAGE-A12 (MAGEA12, melanoma antigen family A, 12, MAGE12, testicular cancer antigen 1.12, CT1.12, MAGE12F antigen, testicular cancer antigen family 1, represent le 12, family of cancer-testicular antigens 1, representative 12, melanoma-associated antigen 12, MAGE-12 antigen; standard NCBI sequence: NP_001159859.1); MAGE-A2 (MAGEA2, melanoma antigen family A, 2, MAGE2, cancer testicular antigen 1.2, CT1.2, MAGEA2A, MAGE-2 antigen, cancer testicular antigen family 1, representative 2, cancer testicular antigen family 1, representative 2, melanoma antigen 2, melanoma-associated antigen 2; NCBI standard sequence: NP_001269434.1); MAGE-A3 (MAGEA3, melanoma antigen family A, 3, MAGE3, MAGE-3 antigen, MZ2-D antigen, melanoma-associated antigen 3, testicular cancer antigen 1.3, CT1.3, testicular cancer antigen family 1, representative 3 , HIP8, HYPD, MAGEA6, cancer testicular antigen family 1, member 3; NCBI standard sequence: NP_005353.1); MAGE-A4 (MAGEA4, melanoma antigen family A, 4, MAGE4, melanoma-associated antigen 4, cancer-testicular antigen 1.4, CT1.4, MAGE-4 antigen, MAGE-41 antigen, MAGEX2 antigen, MAGE4A, MAGE4B, cancer family -testicular antigens 1, representative 4, MAGE-41, MAGE-X2, cancer-testicular antigen family 1, representative 4; NCBI standard sequence: NP_001011550.1); MAGE-A6 (MAGEA6, melanoma antigen family A, 6, MAGE6, MAGE-6 antigen, melanoma-associated antigen 6, testicular cancer antigen 1.6, CT1.6, MAGE3B antigen, testicular cancer antigen family 1, melanoma antigen family A 6, representative 6, MAGE-3b, MAGE3B, cancer-testicular antigen family 1, representative 6; NCBI standard sequence: NP_787064.1); MAGE-A9 (MAGEA9, melanoma antigen family A, 9, MAGE9, antigen MAGE-9, melanoma-associated antigen 9, cancer testicular antigen 1.9, CT1.9, cancer testicular antigen family 1, representative 9, cancer testicular antigen family 1 , representative 9, MAGEA9A; NCBI standard sequence:

- 52 040364

NP_005356.1); MAGE-C1 (MAGEC1, melanoma antigen family C, 1, testicular cancer antigen 7.1, CT7.1, MAGE-C1 antigen, testicular cancer antigen family 7, representative 1, CT7, testicular cancer antigen family 7, representative 1, melanoma-associated C1 antigen, standard NCBI sequence: NP_005453.2); MAGE-C2 (MAGEC2, melanoma antigen family C, 2, MAGEE1, cancer-testicular antigen 10, CT10, HCA587, melanoma antigen, family E, 1, cancer-testicular-specific, hepatocellular carcinoma-associated antigen 587, MAGE-C2 antigen , MAGE-E1 antigen, hepatocellular carcinoma antigen 587, melanoma-associated antigen C2; NCBI standard sequence: NP_057333.1); mammaglobin-A (SCGB2A2, secretoglobin, family 2A, member 2, MGB1, mammaglobin 1, UGB2, mammaglobin A, mammaglobin-A, mammaglobin-1, member 2 of the secretoglobin 2A family; NP); MART2 (HHAT, hedgehog acyltransferase, SKI1, T-cell-recognized melanoma antigen 2, Skinny Hedgehog protein 1, Skn, T-cell-recognized melanoma antigen 2, protein cysteine N-palmitoyltransferase HHAT, EC 2.3.1.-; GenBank: AAH39071 .1); M-CSF (CSF1, colony stimulating factor 1 (macrophage), MCSF, CSF-1, lanimim, macrophage colony stimulating factor 1, lanimim; GenBank: AAH21117.1); MCSP (SMCP, sperm mitochondria-associated cysteine-rich protein, MCS, mitochondrial capsule selenoprotein, HSMCSGEN1, sperm mitochondria-associated cysteine-rich protein; NCBI standard sequence: NP_109588.2); XAGE-1b/GAGED2a; WT1 (Wilms tumor 1, WAGR, GUD, WIT-2, WT33, EWS amino-terminal domain, NPHS4, last three zinc fingers of WT1 DNA-binding domain, AWT1, Wilms tumor protein, EWS-WT1; GenBank: AAB33443.1); VEGF; tyrosinase (TYR; OCAIA; OCA1A; tyrosinase; SHEP; NP_000363.1; NM_000372.4; GenBank: AAB60319.1); TrpM4 (BR22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential cation channel, subfamily M, member 4, Genbank accession no. NM_01763); TRP2-INT2; TRP-2; TRP-1/gp75 (tyrosinase-related protein 1, 5,6-dihydroxyindole-2-carboxylic acid oxidase, CAS2, CATB, TYRP, OCA3, catalase B, b-PROTEIN, glycoprotein 75, EC 1.14.18., melanoma antigen Gp75, TYRP1, TRP, TYRRP, TRP1, SHEP11, DHICA oxidase, EC 1.14.18, GP75, EC 1.14.18.1; triose phosphate isomerase (triose phosphate isomerase 1, TPID, triose phosphate isomerase, HEL-S-49, TIM, epididymis secretory protein Li 49, TPI, triose phosphate isomerase, EC 5.3.1.1; TRAG-3 (CSAG family member 2, cancer testicular antigen family 24, CSAG3B, member 2, CSAG family member 3B, cancer testicular antigen family member 2 24, cancer testicular antigen 24.2, chondrosarcoma-associated gene 2/3 protein, taxol resistance-associated gene 3 protein similar to chondrosarcoma-associated gene 2/3 protein, CT24.2, taxol resistance-associated gene 3, TRAG-3, CSAG3A, TRAG3); TMEM46 ( homolog shisa 2 (Xenopus laevis)); SHISA; NP_001007539.1; NM_001007 538.1; TMEM118 (ring finger protein, transmembrane 2; RNFT2; FLJ1462; NP_001103373.1; NM_001109903.1); TMEFF1 (transmembrane protein with EGF-like and two follistatin-like domains 1; tomoregulin-; H7365; C9orf2; C9ORF2; U19878; X83961; NM_080655; NM_003692); TGF-betaRII (TGFBR2, transforming growth factor, beta receptor II (70/80 kDa), TGFbeta-RII, MFS2, tbetaR-II, TGFR-2, TGF-beta type IIB receptor, TGF-beta type II receptor, receptor TGF-beta type 2, EC 2.7.11.30, transforming growth factor beta receptor type IIC, AAT3, TbetaR-II, transforming growth factor, beta receptor II (70-80 kDa), receptor TGF-beta type II, FAA3, receptor transforming growth factor-beta type II, LDS1B, HNPCC6, LDS2B, LDS2, RIIC, EC 2.7.11, TAAD2); TENB2 (TMEFF2, tomoregulin, TPEF, HPP1, TR, putative transmembrane proteoglycan associated with the EGF/heregulin family of growth factors and follistatin); 374 aa, NCBI access number: AAD55776, AAF91397, AAG49451, NCBI RefSeq: NP_057276; NCBI gene: 23671; OMIM: 605734; SwissProt Q9UIK5; Genbank Access No. AF179274; AY358907, CAF85723, CQ782436; TAG-2; TAG-1 (contactin 2 (axonal), TAG-1, AXT, cell adhesion molecule axonin-1, TAX, contactin 2 (transiently expressed), TAXI, contactin-2, axonal glycoprotein TAG-1, transiently expressed axonal glycoprotein, transient axonal glycoprotein, axonin-1, TAX-1, TAG1, FAME5; PRF: 444868); SYT-SSX1 or -SSX2 fusion protein; survivin; STEAP2 (HGNC_8639, IPCA-1, PCANAP1, STAMP1, STEAP2, STMP, prostate cancer-associated gene 1, prostate cancer-associated protein 1, prostate transmembrane epithelial antigen 6, prostate transmembrane protein 6, Genbank accession no AF45513; STEAP1 ( sixth prostate transmembrane epithelial antigen, Genbank Accession # NM_01244); SSX-4; SSX-2 (SSX2, synovial sarcoma, X break point 2, X break point 2, SSX, X break point 2B, testicular cancer antigen 5.2, linked with X chromosome 2, tumor antigen HOM-MEL-40, CT5.2, FID21, cancer-testicular antigen family 5, HOM-MEL-40, isoform B, member 2a of the cancer-testicular antigen family 5, member 2a, SSX2 protein, sarcoma , sarcoma, synovial, X-linked 2, synovial, synovial sarcoma, X break point 2B, synovial sarcoma, SSX2A); Sp17; SOX10 (SRY (Y sex-determining region) - box 10, murine, PCWH, DOM, WS4 , WS2E, WS4C, dominant megacolon, murine, human homologue, dominant megacolon associated with SRY HMG-Box gene 10, human homologue, transcription factor SOX-10; GenBank: CAG30470.1); SNRPD1 (small nuclear ribonucleoprotein D1, small nuclear ribonucleoprotein D1,

- 53 040364 polypeptide 16 kDa, polypeptide (16 kDa), SNRPD, HsT2456, Sm-D1, SMD1, Sm-D autoantigen, 16 kDa small nuclear ribonucleoprotein D1 polypeptide pseudogene, core protein SnRNP D1, small nuclear ribonucleoprotein Sm D1); SLC35D3 (solute carrier family 35, member D3, FRCL1, Fringe Connection-like protein 1, bA55K22.3, Frc, Fringe-like 1, member D3 solute carrier family 35; NCBI GenBank: NC_000006.11 NC_018917.2 NT_025741. 16); SIRT2 (sirtuin 2, NAD-dependent deacetylase sirtuin-2, SIRL2, silent information regulator 2, regulatory protein homologue SIR2 2, Sir2-related protein type 2, SIR2-like protein 2, sirtuin type 2, sirtuin (silent information regulator homologue by mating type 2) 2 (S. Cerevisiae), sirtuin-2, sirtuin (regulator of silent information on mating type 2, S. Cerevisiae, homologue) 2, EC 3.5.1., SIR2; GenBank: AAK51133.1); Sema 5b (FLJ10372, KIAA1445, Mm.42015, SEMA5B, SEMAG, semaphorin 5b Hlog, sema domain, seven thrombospondin repeats (type 1 and similar to type 1), transmembrane domain (TM) and short cytoplasmic domain (semaphorin) 5B, accession no. in Genbank AB04087; secernin 1 (SCRN1, SES1, KIAA0193, secernin-1; GenBank: EAL24458.1); SAGE (SAGE1, sarcoma antigen 1, testicular cancer antigen 14, CT14, putative tumor antigen; NCBI standard sequence: NP_061136. 2); RU2AS (KAAG1, kidney-associated antigen 1, RU2AS, RU2 antisense gene protein, kidney-associated antigen 1; GenBank: AAF23613.1); RNF43 - precursor of E3 ubiquitin protein ligase RNF43 [Homo sapiens], RNF124; URCC ; NCBI standard sequence: NP_060233.3; RhoC (RGS5 (regulator of G protein signaling, MSTP032, regulator of protein G 5 signal transduction, MSTP092, MST092, MSTP106, MST106, MSTP129, MST129; GenBank: AAB84001.1); RET (proto-oncogene ret; MEN2A; HSCR1; MEN2B; MTC1; PTC; CDHF12; Hs.16 8114; RET51; RET-ELE; NP_066124.1; NM_020975.4); RBAF600 (UBR4, E3 component of ubiquitin protein ligase N-recognin 4, zinc fingers, UBR1 type 1, ZUBR1, ubiquitin protein ligase E3 UBR4, RBAF600, 600 kDa protein-associated retinoblastoma factor, zinc finger protein UBR1 1, EC 6.3 .2., N-recognin-4, KIAA0462, p600, EC 6.3.2, KIAA1307; GenBank: AAL83880.1); RAGE-1 (MOK, MOK protein kinase, renal tumor antigen, RAGE, MAPK/MAK/MRK overlapping kinase, renal tumor antigen 1, renal cell carcinoma antigen, RAGE-1, EC 2.7.11.22, RAGE1; UniProtKB/Swiss-Prot : Q9UQ07.1); RAB38/NY-MEL-1 (RAB38, NY-MEL-1, RAB38, member of the RAS oncogene family, NY-MEL-1 melanoma antigen, Rab-associated GTP-binding protein, Ras-associated protein Rab-38, rrGTPbp; GenBank : AAH15808.1); PTPRK (DJ480J14.2.1 (protein tyrosine phosphatase, receptor type K R-PTPKAPPA, protein tyrosine phosphatase kappa, protein tyrosine phosphatase kappa), protein tyrosine phosphatase, receptor type, K, protein tyrosine phosphatase kappa, protein tyrosine phosphatase, receptor type, kappa, R-PTP-kappa, protein tyrosine phosphatase kappa receptor type, EC 3.1.3.48, PTPK; GenBank: AAI44514.1); PSMA; PSCA hlg (2700050C12Rik, C530008O16Rik, RIKEN cDNA 2700050C12, RIKEN gene cDNA 2700050C12, Genbank accession no. AY358628); PSCA (prostate stem cell antigen precursor, Genbank accession no AJ29743; PRDX5 (peroxiredoxin 5, EC 1.11.1.15, TPx type VI, B166, antioxidant enzyme B166, HEL-S-55, liver tissue 2D-Page Spot 71B, PMP20 , peroxisomal antioxidant enzyme, PRDX6, thioredoxin peroxidase PMP20, PRXV, AOEB166, epididymis secretory protein Li 55, Alu 1 coreceptor, peroxiredoxin-5, mitochondrial, peroxiredoxin V, prx-V, thioredoxin reductase, Prx-V, ACR1, Alu corepressor , PLP; GenBank: CAG33484.1); PRAME (preferably melanoma-expressed antigen, preferably melanoma-expressed antigen, MAPE, OIP-4, OIPA, CT130, testicular cancer antigen 130, melanoma antigen, preferably tumor-expressed, Opa-interacting protein 4, Opa-interacting protein OIP4; GenBank: CAG30435.1); pml-RARalpha fusion protein; PMEL17 (silver homolog; SILV; D12S53E; PMEL17; SI; SIL); ME20; gp10 BC001414; BT007202; M32295; M77348; NM_00692 ; PBF (ZNF395, zinc finger free lok 395, PRF-1, regulatory for Huntington's disease, HD gene regulatory region-binding protein, region-binding protein 2, protein 2, papillomavirus regulatory factor 1, HD-regulatory factor 2, papillomavirus-regulatory factor, PRF1, HDBP-2 , Si-1-8-14, HDBP2, protein that binds the regulatory region of the Huntington's disease gene 2, HDRF-2, human papillomavirus regulatory factor PRF-1, PBF; GenBank: AAH01237.1); PAX5 (paired box 5, homeotic paired box 5, BSAP, paired box protein Pax-5, B cell lineage-specific activator, paired domain gene 5, paired box 5 gene (B-cell lineage-specific protein α-activator), B-cell-specific transcription factor, coupled box gene 5 (B-cell lineage-specific activator)); PAP (REG3A, regenerative, islet-derived 3 alpha, INGAP, PAP-H, hepatointestinal pancreatic protein, PBBCGF, human proislet peptide, REG-III, pancreatitis-associated protein 1, Reg3, Reg III-alpha, hepatocarcinoma-intestinal pancreas, regenerative, islet-derived protein III-alpha, pancreatic beta growth factor, HIP, PAP homologous protein, HIP/PAP, proliferation-inducing protein 34, PAP1, proliferation-inducing protein 42, REG-3-alpha, regenerative, islet-derived 3-alpha protein, pancreatitis-associated protein GenBank: AAH36776.1); p53 (TP53, P53 tumor protein, TPR53, P53, P53 tumor cell antigen, NY-CO-13 antigen, mutant

- 54 040364 tumor protein 53, phosphoprotein P53, tumor suppressor P53, BCC7, transformation-associated protein 53, LFS1, tumor protein 53, Li-Fraumeni syndrome, tumor suppressor P53; P2X5 (P2X purinergic receptor ligand-gated ion channel 5, an ion channel driven by extracellular ATP, may be involved in synaptic transmission and neurogenesis, and its deficiency may affect the pathophysiology of idiopathic detrusor instability); 422 aa, pI: 7.63, MW: 47206 TM: 1 [P] gene chromosome: 17p13.3, Genbank accession no. NP_002552.; OGT (O-linked N-acetylglucosamine (GlcNAc) transferase, O-GlcNAc P110 transferase subunit, O-linked N-acetylglucosamine (GlcNAc) transferase (UDP-N-acetylglucosamine:polypeptide-N-acetylglucosaminyl transferase, 110 kDa UDP-N subunit -acetylglucosamine-peptide N-acetylglucosaminyltransferase, UDP-Nacetylglucosamine:polypeptide-N-acetylglucosaminyltransferase, uridine diphospho-Nacetylglucosamine:beta-N-acetylglucosaminyltransferase polypeptide, O-GlcNAc P110 transferase subunit, EC 2.4.1.255, 110 kDa O-linked N subunit -acetylglucosamine transferase, EC 2.4.1, HRNT1, EC 2.4.1.186, O-GLCNAC; GenBank: AAH38180.1)); OA (Osteoarthritis QTL 1, OASD; GenBank: CAA88742.1); NY-ESO-1/LAGE-2 (cancer testicular antigen 1B, CTAG1B, NY-ESO-1, LAGE-2, ESO1, CTAG1, CTAG, LAGE2B, cancer testicular antigen 1, autoimmunogenic cancer testicular antigen NY-ESO-1 , cancer antigen 3, testicular cancer antigen 6.1, New York squamous cell carcinoma of the esophagus 1, L member of the antigen family 2, LAGE2, CT6.1, LAGE2A; GenBank: AAI30365.1); NY-BR-1 (ANKRD30A, 30A ankyrin repeat domain, NY-BR-1 breast cancer antigen, NY-BR-1 antiserum-typed breast cancer antigen, 30A ankyrin repeat domain containing protein; standard NCBI sequence: NP_443723 .2); N-ras (NRAS, neuroblastoma viral antigen RAS Viral (V-Ras) homologue, NRAS1, N-Ras transforming protein, GTPase NRas, ALPS4, N-Ras protein part 4, NS6, oncogene homologue, HRAS1; GenBank: AAH05219.1 ); NFYC (nuclear transcription factor Y, gamma, HAP5, HSM, nuclear transcription factor C subunit Y, transactivator HSM-1/2, CCAAT binding factor C subunit, NF-YC, CCAAT transcription binding factor gamma subunit, DNA binding protein C subunit Box CAAT, H1 histone transcription factor 2A large subunit, CBFC, gamma nuclear transcription factor Y subunit, CBF-C, HSM-1 transactivator, H1TF2A, NF-Y transcription factor, subunit C; neo-PAP (PAPOLG, poly(A) polymerase gamma, Neo-poly(A) polymerase, nuclear poly(A) polymerase gamma, polynucleotide adenylyl transferase gamma, SRP RNA 3' adenylating enzyme/Pap2, PAP gamma, Neo-PAP, SRP RNA 3' adenylating enzyme, PAP2 , EC 2.7.7.19, PAPG; NCBI standard sequence: NP_075045.2); NCA (CEACAM6, Genbank accession no. M1872); Napi3b (NAPI-3B, NPTIIb, SLC34A2, solute transporter family 34 (sodium phosphate), representative 2 , sodium dependent transporter phosphate 3b type II, Genbank accession no. NM_00642); myosin class I; MUM-3; MUM-2 (TRAPPC1, targeted migration protein-particle complex 1, BET5, BET5 homologue, MUM2, mutated ubiquitous melanoma 2, multiple melanoma protein 2, subunit 1 of targeted migration protein-particle complex; MUM-1f; mucin (MUC1, mucin 1 , cell surface associated, PEMT, PUM, CA 15-3, MCKD1, ADMCKD, medullary cystic nephropathy 1 (autosomal dominant), ADMCKD1, mucin 1, transmembrane, CD227, breast carcinoma associated antigen DF3, MAM6, cancer antigen 15-3, MCD, carcinoma-associated mucin, MCKD, Krebs von den Lungen-6, MUC-1/SEC, peanut-reactive urine mucin, MUC1/ZD, tumor-associated epithelial membrane antigen, DF3 antigen, tumor-associated mucin, episilian, EMA , H23 antigen, H23AG, mucin-1, KL-6, tumor associated epithelial mucin, MUC-1, episilian, PEM, CD227 antigen; UniProtKB/Swiss-Prot: P15941.3); MUC5AC (mucin 5AC, oligomeric mucus/gel- generatrix, tracheobronchial mucin, MUC5, TBM, mu Cin 5, subtypes A and C, tracheobronchial/gastric, 1eB, gastric mucin, mucin 5AC, oligomeric mucus/gel-forming pseudogene, Lewis B blood group antigen, LeB, airway major glycoprotein, MUC-5AC, mucin-5 AC subtype , tracheobronchial); MUC1 (mucin 1, cell surface associated, PEMT, PUM, CA 15-3, MCKD1, ADMCKD, medullary cystic nephropathy 1 (autosomal dominant), ADMCKD1, mucin 1, transmembrane, CD227, breast carcinoma-associated antigen DF3, MAM6, cancer antigen 15-3, MCD, carcinoma-associated mucin, MCKD, Krebs von den Lungen-6, MUC-1/SEC, peanut-reactive urinary mucin, MUC1/ZD, tumor-associated epithelial membrane antigen, DF3 antigen, tumor-associated mucin , episilian, EMA, h23 antigen, H23AG, mucin-1, KL-6, tumor associated epithelial mucin, MUC-1, episilian, PEM, CD227 antigen); MSG783 (RNF124, putative protein FLJ20315, Genbank accession no. NM-01776); MRP4 isoform 3 of multidrug resistance protein 4, MOAT-B; MOATB [Homo sapiens]; standard NCBI sequence: NP_001288758.1; MPF (MPF, MSLN, SMR, megakaryocyte activating factor, mesothelin, Genbank accession no. NM_00582); MMP-7 (MMP7, matrilysin, MPSL1, matrine, matrix metalloproteinase 7 (matrilysin, uterine), uterine matrilysin, matrix metalloproteinase-7, EC 3.4.24.23, Pump-1 protease, matrine, uterine metalloproteinase, PUMP1, MMP-7, EC 3.4.24, PUMP-1 GenBank: AAC37543.1); MMP-2 (MMP2, matrix metalloproteinase 2 (gelatinase A, 72 kDa gelatinase, 72 kDa

- 55 040364 collagenase type IV), MONA, CLG4A, matrix metalloproteinase 2 (gelatinase A, 72 kD gelatinase, kD collagenase type IV), CLG4, 72 kD gelatinase, 72 kD collagenase type IV, matrix metalloproteinase-2, MMP-II, 72 kD gelatinase, collagenase type IV-A, MMP-2, matrix metalloproteinase-P,

TBE-1, neutrophil gelatinase, EC 3.4.24.24, EC 3.4.24; GenBank: AAH02576.1); and other.

For example, in some instances, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 2;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 3;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 4;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 5; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 6, such as 40G5c, may contain a second binding domain that binds to CD20.

The second binding domain that binds to CD20 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 158;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 159;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 160;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 161; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 162, such as those containing the anti-CD20 antibody 2H7.v16 (described in US Pat. No. 7,799,900).

In some instances, the second binding domain that binds CD20 contains at least one (e.g., 1, 2, 3, or 4) of the FR-H1, FR-H2, FR-H3, and FR-H4 heavy chain framework regions containing the sequences SEQ ID NOs: 557-560, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of FR-L1, FR-L2, FR-L3, and FR-L4 light chain framework regions containing the sequences SEQ ID NO: 561-564, respectively. In some instances, the second binding domain that binds to CD20 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 266;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 267; or (c) a VH domain according to (a) and a VL domain according to (b), for example, such that contains the anti-CD20 antibody 2H7.v16 (described in US patent No. 7799900).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 2;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 3;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 4;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 5; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 6, such as 40G5c, may contain a second binding domain that binds to FcRH5.

The second binding domain that binds to FcRH5 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 164;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 165;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 166;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 168, such as those containing the anti-FcRH5 antibody 1G7.

In some instances, the second binding domain that binds FcRH5 contains at least one (e.g., 1, 2, 3, or 4) of the FR-H1, FR-H2, FR-H3, and FR-H4 heavy chain framework regions containing the sequences SEQ ID NOs: 565-568, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of FR-L1, FR-L2, FR-L3, and FR-L4 light chain framework regions containing the sequences SEQ ID NO: 569-572, respectively. In some cases, the second binding domain that binds to FcRH5 may, for example, contain

- 56 040364 (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (for example, at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) with, or the sequence of SEQ ID NO: 268;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 269; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 2;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 3;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 4;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 5; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 6, such as 40G5c, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 170;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 171;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 172;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 173; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 174, such as those containing the hu4D5 anti-HER2 antibody.

In some instances, the second binding domain that binds HER2 contains at least one (e.g., 1, 2, 3, or 4) of the FR-H1, FR-H2, FR-H3, and FR-H4 heavy chain framework regions containing the SEQ sequences ID NOs: 549-552, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of FR-L1, FR-L2, FR-L3, and FR-L4 light chain framework regions containing SEQ sequences ID NO: 553-556, respectively. In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 270;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 271; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 2;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 3;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 4;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 5; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 6, such as 40G5c, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 582;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 583;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 584;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 585; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 586, such as those containing the anti-HER2 antibody 2C4.

In some instances, the second binding domain that binds HER2 contains at least one (e.g., 1, 2, 3, or 4) of the FR-H1, FR-H2, FR-H3, and FR-H4 heavy chain framework regions containing the sequences SEQ ID NOs: 597-600, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of FR-L1, FR-L2, FR-L3, and FR-L4 light chain framework regions containing the sequences SEQ ID NO: 601-604, respectively. In some cases, the second binding domain that binds to HER2 may, for example, contain

- 57 040364 (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (for example, at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) with, or the sequence of SEQ ID NO: 593;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 594; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 2;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 3;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 4;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 5; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 6, such as 40G5c, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 588;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 589;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 590;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 591; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 592, such as those containing the anti-HER2 antibody 7C2.

In some instances, the second binding domain that binds HER2 contains at least one (e.g., 1, 2, 3, or 4) of the FR-H1, FR-H2, FR-H3, and FR-H4 heavy chain framework regions containing the SEQ sequences ID NOs: 605-608, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of FR-L1, FR-L2, FR-L3, and FR-L4 light chain framework regions containing SEQ sequences ID NO: 609-612, respectively. In some instances, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 595;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 596; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 2;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 3;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 4;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 5; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 6, such as 40G5c, may contain a second binding domain that binds to LYPD1.

The second binding domain that binds to LYPD1 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 176;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 177;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 178;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 180, such as those containing the anti-LYPD1 antibody YWO.49.H6.

In some instances, the second binding domain that binds LYPD1 contains at least one (e.g., 1, 2, 3, or 4) of the FR-H1, FR-H2, FR-H3, and FRH4 heavy chain framework regions containing the sequences of SEQ ID NO: 573-576, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of FR-L1, FR-L2, FR-L3, and FR-L4 light chain framework regions containing SEQ ID sequences NO: 577-580 respectively. In some cases, the second binding domain that binds to LYPD1 may, for example, contain

- 58 040364 (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (for example, at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) with, or the sequence of SEQ ID NO: 272;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 273; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 2;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 3;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 4;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 5; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 6, such as 40G5c, may contain a second binding domain that binds to LY6G6D.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 2;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 3;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 4;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 5; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 6, such as 40G5c, may contain a second binding domain that binds to PMEL17.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 2;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 3;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 4;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 5; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 6, such as 40G5c, may contain a second binding domain that binds to LY6E.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 2;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 3;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 4;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 5; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 6, such as 40G5c, may contain a second binding domain that binds to CD19.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 2;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 3;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 4;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 5; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 6, such as 40G5c, may contain a second binding domain that binds to CD33.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 2;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 3;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 4;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 5; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 6, such as 40G5c, may contain a second binding domain that binds to CD22.

In some cases, an anti-CD3 antibody containing a first binding domain containing

- 59 040364 at least one, two, three, four, five or six hypervariable regions (HVR) selected from (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 1;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 2;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 3;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 4;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 5; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 6, such as 40G5c, may contain a second binding domain that binds to CD79A.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 2;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 3;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 4;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 5; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 6, such as 40G5c, may contain a second binding domain that binds to CD79B.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 2;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 3;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 4;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 5; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 6, such as 40G5c, may contain a second binding domain that binds to EDAR.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 2;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 3;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 4;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 5; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 6, such as 40G5c, may contain a second binding domain that binds to GFRA1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 2;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 3;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 4;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 5; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 6, such as 40G5c, may contain a second binding domain that binds to MRP4.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 2;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 3;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 4;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 5; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 6, such as 40G5c, may contain a second binding domain that binds to RET.

The second binding domain that binds to RET may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 614;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 615;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 616;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 617; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 618, such as those containing the anti-RET antibody 41205.v6.

- 60 040364

In some instances, the second binding domain that binds to RET may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 629;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 630; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 2;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 3;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 4;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 5; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 6, such as 40G5c, may contain a second binding domain that binds to Steap1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 2;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 3;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 4;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 5; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 6, such as 40G5c, may contain a second binding domain that binds to TenB2.

Alternatively, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v1, may contain a second binding domain that binds to CD20.

The second binding domain that binds to CD20 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 158;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 159;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 160;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 161; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 162, such as those containing the anti-CD20 antibody 2H7.v16 (described in US Pat. No. 7,799,900).

In some instances, the second binding domain that binds to CD20 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 266;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 267; or (c) a VH domain according to (a) and a VL domain according to (b), for example, such that contains the anti-CD20 antibody 2H7.v16 (described in US patent No. 7799900).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

- 61 040364 (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v1, may contain a second binding domain that binds to FcRH5.

The second binding domain that binds to FcRH5 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 164;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 165;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 166;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 168, such as those containing the anti-FcRH5 antibody 1G7.

In some instances, the second binding domain that binds to FcRH5 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 268;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 269; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v1, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 170;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 171;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 172;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 173; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 174, such as those containing the hu4D5 anti-HER2 antibody.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 270;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 271; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v1, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 582;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 583;

- 62 040364 (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 584;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 585; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 586, such as those containing the anti-HER2 antibody 2C4.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 593;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 594; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v1, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 588;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 589;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 590;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 591; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 592, such as those containing the anti-HER2 antibody 7C2.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 595;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 596; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v1, may contain a second binding domain that binds to LYPD1.

The second binding domain that binds to LYPD1 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 176;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 177;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 178;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 180, such as those containing the anti-LYPD1 antibody YWO.49.H6.

In some instances, the second binding domain that binds to LYPD1 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99%

- 63 040364 sequence identity) c, or the sequence of SEQ ID NO: 272;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 273; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v1, may contain a second binding domain that binds to LY6G6D.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v1, may contain a second binding domain that binds to PMEL17.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v1, may contain a second binding domain that binds to LY6E.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v1, may contain a second binding domain that binds to CD19.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v1, may contain a second binding domain that binds to CD33.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v1, may contain a second binding domain that binds to CD22.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

- 64 040364 (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v1, may contain a second binding domain that binds to CD79A.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v1, may contain a second binding domain that binds to CD79B.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v1, may contain a second binding domain that binds to EDAR.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v1, may contain a second binding domain that binds to GFRA1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v1, may contain a second binding domain that binds to MRP4.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v1, may contain a second binding domain that binds to RET.

The second binding domain that binds to RET may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 614;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 615;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 616;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 617; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 618, such as those containing the anti-RET antibody 41205.v6.

In some cases, the second binding domain that binds to the RET may, for example, contain

- 65 040364 (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (for example, at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) with, or the sequence of SEQ ID NO: 629;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 630; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v1, may contain a second binding domain that binds to Steap1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v1, may contain a second binding domain that binds to TenB2.

Alternatively, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 13;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v2, may contain a second binding domain that binds to CD20.

The second binding domain that binds to CD20 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 158;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 159;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 160;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 161; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 162, such as those containing the anti-CD20 antibody 2H7.v16 (described in US Pat. No. 7,799,900).

In some instances, the second binding domain that binds to CD20 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 266;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 267; or (c) a VH domain according to (a) and a VL domain according to (b), for example, such that contains the anti-CD20 antibody 2H7.v16 (described in US patent No. 7799900).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 13;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 12,

- 66 040364 such as 38E4v2 may contain a second binding domain that binds to FcRH5.

The second binding domain that binds to FcRH5 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 164;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 165;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 166;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 168, such as those containing the anti-FcRH5 antibody 1G7.

In some instances, the second binding domain that binds to FcRH5 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 268;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 269; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 13;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v2, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 170;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 171;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 172;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 173; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 174, such as those containing the hu4D5 anti-HER2 antibody.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 270;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 271; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 13;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v2, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 582;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 583;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 584;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 585; And

- 67 040364 (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 586, such as those containing the anti-HER2 antibody 2C4.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 593;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 594; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 13;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v2, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 588;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 589;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 590;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 591; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 592, such as those containing the anti-HER2 antibody 7C2.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 595;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 596; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 13;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v2, may contain a second binding domain that binds to LYPD1.

The second binding domain that binds to LYPD1 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 176;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 177;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 178;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 180, such as those containing the anti-LYPD1 antibody YWO.49.H6.

In some instances, the second binding domain that binds to LYPD1 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 272;

(b) a VL domain containing an amino acid sequence having at least 90%

- 68 040364 sequence identity (for example, at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 273; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 13;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v2, may contain a second binding domain that binds to LY6G6D.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 13;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v2, may contain a second binding domain that binds to PMEL17.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 13;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v2, may contain a second binding domain that binds to LY6E.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 13;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v2, may contain a second binding domain that binds to CD19.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 13;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v2, may contain a second binding domain that binds to CD33.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 13;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v2, may contain a second binding domain that binds to CD22.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 13;

- 69 040364 (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v2, may contain a second binding domain that binds to CD79A.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 13;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v2, may contain a second binding domain that binds to CD79B.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 13;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v2, may contain a second binding domain that binds to EDAR.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 13;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v2, may contain a second binding domain that binds to GFRA1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 13;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v2, may contain a second binding domain that binds to MRP4.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 13;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v2, may contain a second binding domain that binds to RET.

The second binding domain that binds to RET may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 614;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 615;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 616;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 617; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 618, such as those containing the anti-RET antibody 41205.v6.

In some instances, the second binding domain that binds to RET may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99%

- 70 040364 sequence identity) c, or the sequence of SEQ ID NO: 629;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 630; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 13;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v2, may contain a second binding domain that binds to Steap1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 13;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v2, may contain a second binding domain that binds to TenB2.

Alternatively, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 14, such as 38E4v3, may contain a second binding domain that binds to CD20.

The second binding domain that binds to CD20 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 158;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 159;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 160;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 161; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 162, such as those containing the anti-CD20 antibody 2H7.v16 (described in US Pat. No. 7,799,900).

In some instances, the second binding domain that binds to CD20 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 266;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 267; or (c) a VH domain according to (a) and a VL domain according to (b), for example, such that contains the anti-CD20 antibody 2H7.v16 (described in US patent No. 7799900).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 14, such as 38E4v3, may contain a second binding domain that binds to FcRH5.

The second binding domain that binds to FcRH5 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 containing the amino acid sequence SEQ ID NO: 163;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 164;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 165;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 166;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 168, such as those containing the anti-FcRH5 antibody 1G7.

In some instances, the second binding domain that binds to FcRH5 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 268;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 269; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 14, such as 38E4v3, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 170;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 171;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 172;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 173; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 174, such as those containing the hu4D5 anti-HER2 antibody.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 270;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 271; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 14, such as 38E4v3, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 582;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 583;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 584;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 585; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 586, such as those containing the anti-HER2 antibody 2C4.

- 72 040364

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 593;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 594; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 14, such as 38E4v3, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 588;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 589;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 590;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 591; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 592, such as those containing the anti-HER2 antibody 7C2.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 595;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 596; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 14, such as 38E4v3, may contain a second binding domain that binds to LYPD1.

The second binding domain that binds to LYPD1 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 176;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 177;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 178;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 180, such as those containing the anti-LYPD1 antibody YWO.49.H6.

In some instances, the second binding domain that binds to LYPD1 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 272;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 273; or

- 73 040364 (c) VH domain according to (a) and VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 14, such as 38E4v3, may contain a second binding domain that binds to LY6G6D.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 14, such as 38E4v3, may contain a second binding domain that binds to PMEL17.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 14, such as 38E4v3, may contain a second binding domain that binds to LY6E.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 14, such as 38E4v3, may contain a second binding domain that binds to CD19.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 14, such as 38E4v3, may contain a second binding domain that binds to CD33.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 14, such as 38E4v3, may contain a second binding domain that binds to CD22.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; And

- 74 040364 (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 14, such as 38E4v3, may contain a second binding domain that binds to CD79A.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 14, such as 38E4v3, may contain a second binding domain that binds to CD79B.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 14, such as 38E4v3, may contain a second binding domain that binds to EDAR.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 14, such as 38E4v3, may contain a second binding domain that binds to GFRA1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 14, such as 38E4v3, may contain a second binding domain that binds to MRP4.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 14, such as 38E4v3, may contain a second binding domain that binds to RET.

The second binding domain that binds to RET may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 614;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 615;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 616;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 617; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 618, such as those containing the anti-RET antibody 41205.v6.

In some instances, the second binding domain that binds to RET may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 629;

(b) a VL domain containing an amino acid sequence having at least 90%

- 75 040364 sequence identity (for example, at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 630; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 14, such as 38E4v3, may contain a second binding domain that binds to Steap1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 14, such as 38E4v3, may contain a second binding domain that binds to TenB2.

Alternatively, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 15, such as 38E4v4, may contain a second binding domain that binds to CD20.

The second binding domain that binds to CD20 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 158;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 159;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 160;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 161; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 162, such as those containing the anti-CD20 antibody 2H7.v16 (described in US Pat. No. 7,799,900).

In some instances, the second binding domain that binds to CD20 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 266;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 267; or (c) a VH domain according to (a) and a VL domain according to (b), for example, such that contains the anti-CD20 antibody 2H7.v16 (described in US patent No. 7799900).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 15, such as 38E4v4, may contain a second binding domain that binds to FcRH5.

The second binding domain that binds to FcRH5 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163;

- 76 040364 (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 164;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 165;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 166;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 168, such as those containing the anti-FcRH5 antibody 1G7.

In some instances, the second binding domain that binds to FcRH5 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 268;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 269; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 15, such as 38E4v4, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 170;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 171;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 172;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 173; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 174, such as those containing the hu4D5 anti-HER2 antibody.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 270;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 271; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 15, such as 38E4v4, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 582;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 583;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 584;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 585; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 586, such as those containing the anti-HER2 antibody 2C4.

In some cases, the second binding domain that binds to HER2 may, for example, contain

- 77 040364 (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (for example, at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) with, or the sequence of SEQ ID NO: 593;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 594; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 15, such as 38E4v4, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 588;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 589;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 590;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 591; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 592, such as those containing the anti-HER2 antibody 7C2.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 595;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 596; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 15, such as 38E4v4, may contain a second binding domain that binds to LYPD1.

The second binding domain that binds to LYPD1 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 176;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 177;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 178;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 180, such as those containing the anti-LYPD1 antibody YWO.49.H6.

In some instances, the second binding domain that binds to LYPD1 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 272;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 273; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody containing a first binding domain containing

- 78 040364 at least one, two, three, four, five or six hypervariable regions (HVR) selected from (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 15, such as 38E4v4, may contain a second binding domain that binds to LY6G6D.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 15, such as 38E4v4, may contain a second binding domain that binds to PMEL17.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 15, such as 38E4v4, may contain a second binding domain that binds to LY6E.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 15, such as 38E4v4, may contain a second binding domain that binds to CD19.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 15, such as 38E4v4, may contain a second binding domain that binds to CD33.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 15, such as 38E4v4, may contain a second binding domain that binds to CD22.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 15, such as 38E4v4, may contain a second binding domain that binds to CD79A.

- 79 040364

In some cases, an aHTu-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 15, such as 38E4v4, may contain a second binding domain that binds to CD79B.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 15, such as 38E4v4, may contain a second binding domain that binds to EDAR.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 15, such as 38E4v4, may contain a second binding domain that binds to GFRA1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 15, such as 38E4v4, may contain a second binding domain that binds to MRP4.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 15, such as 38E4v4, may contain a second binding domain that binds to RET.

The second binding domain that binds to RET may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 614;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 615;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 616;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 617; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 618, such as those containing the anti-RET antibody 41205.v6.

In some instances, the second binding domain that binds to RET may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 629;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 630; or

- 80 040364 (c) VH domain according to (a) and VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 15, such as 38E4v4, may contain a second binding domain that binds to Steap1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 15, such as 38E4v4, may contain a second binding domain that binds to TenB2.

Alternatively, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 16, such as 38E4v5, may contain a second binding domain that binds to CD20.

The second binding domain that binds to CD20 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 158;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 159;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 160;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 161; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 162, such as those containing the anti-CD20 antibody 2H7.v16 (described in US Pat. No. 7,799,900).

In some instances, the second binding domain that binds to CD20 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 266;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 267; or (c) a VH domain according to (a) and a VL domain according to (b), for example, such that contains the anti-CD20 antibody 2H7.v16 (described in US patent No. 7799900).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 16, such as 38E4v5, may contain a second binding domain that binds to FcRH5.

The second binding domain that binds to FcRH5 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 164;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 165;

- 81 040364 (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 166;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 168, such as those containing the anti-FcRH5 antibody 1G7.

In some instances, the second binding domain that binds to FcRH5 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 268;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 269; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 16, such as 38E4v5, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 170;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 171;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 172;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 173; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 174, such as those containing the hu4D5 anti-HER2 antibody.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 270;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 271; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 16, such as 38E4v5, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 582;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 583;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 584;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 585; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 586, such as those containing the anti-HER2 antibody 2C4.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99%

- 82 040364 sequence identity) c, or the sequence of SEQ ID NO: 593;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 594; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 16, such as 38E4v5, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 588;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 589;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 590;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 591; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 592, such as those containing the anti-HER2 antibody 7C2.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 595;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 596; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 16, such as 38E4v5, may contain a second binding domain that binds to LYPD1.

The second binding domain that binds to LYPD1 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 176;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 177;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 178;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 180, such as those containing the anti-LYPD1 antibody YWO.49.H6.

In some instances, the second binding domain that binds to LYPD1 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 272;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 273; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

- 83 040364 (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 16, such as 38E4v5, may contain a second binding domain that binds to LY6G6D.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 16, such as 38E4v5, may contain a second binding domain that binds to PMEL17.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 16, such as 38E4v5, may contain a second binding domain that binds to LY6E.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 16, such as 38E4v5, may contain a second binding domain that binds to CD19.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 16, such as 38E4v5, may contain a second binding domain that binds to CD33.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 16, such as 38E4v5, may contain a second binding domain that binds to CD22.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 16, such as 38E4v5, may contain a second binding domain that binds to CD79A.

In some instances, an anti-CD3 antibody comprising a first binding domain containing at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from

- 84 040364 (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 16, such as 38E4v5, may contain a second binding domain that binds to CD79B.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 16, such as 38E4v5, may contain a second binding domain that binds to EDAR.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 16, such as 38E4v5, may contain a second binding domain that binds to GFRA1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 16, such as 38E4v5, may contain a second binding domain that binds to MRP4.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 16, such as 38E4v5, may contain a second binding domain that binds to RET.

The second binding domain that binds to RET may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 614;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 615;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 616;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 617; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 618, such as those containing the anti-RET antibody 41205.v6.

In some instances, the second binding domain that binds to RET may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 629;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 630; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody containing a first binding domain containing

- 85 040364 at least one, two, three, four, five or six hypervariable regions (HVR) selected from (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 16, such as 38E4v5, may contain a second binding domain that binds to Steap1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 9;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 16, such as 38E4v5, may contain a second binding domain that binds to TenB2.

Alternatively, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 17;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v6, may contain a second binding domain that binds to CD20.

The second binding domain that binds to CD20 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 158;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 159;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 160;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 161; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 162, such as those containing the anti-CD20 antibody 2H7.v16 (described in US Pat. No. 7,799,900).

In some instances, the second binding domain that binds to CD20 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 266;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 267; or (c) a VH domain according to (a) and a VL domain according to (b), for example, such that contains the anti-CD20 antibody 2H7.v16 (described in US patent No. 7799900).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 17;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v6, may contain a second binding domain that binds to FcRH5.

The second binding domain that binds to FcRH5 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 164;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 165;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 166;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 167; And

- 86 040364 (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 168, such as those containing anti-FcRH5 antibody 1G7.

In some instances, the second binding domain that binds to FcRH5 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 268;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 269; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 17;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v6, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 170;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 171;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 172;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 173; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 174, such as those containing the hu4D5 anti-HER2 antibody.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 270;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 271; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 17;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v6, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 582;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 583;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 584;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 585; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 586, such as those containing the anti-HER2 antibody 2C4.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 593;

(b) a VL domain containing an amino acid sequence having at least 90%

- 87 040364 sequence identity (for example, at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 594; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 17;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v6, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 588;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 589;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 590;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 591; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 592, such as those containing the anti-HER2 antibody 7C2.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 595;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 596; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 17;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v6, may contain a second binding domain that binds to LYPD1.

The second binding domain that binds to LYPD1 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 176;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 177;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 178;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 180, such as those containing the anti-LYPD1 antibody YWO.49.H6.

In some instances, the second binding domain that binds to LYPD1 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 272;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 273; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 17;

- 88 040364 (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO:

such as 38E4v6 may contain a second binding domain that binds to LY6G6D.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 17;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v6, may contain a second binding domain that binds to PMEL17.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 17;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v6, may contain a second binding domain that binds to LY6E.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 17;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v6, may contain a second binding domain that binds to CD19.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 17;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v6, may contain a second binding domain that binds to CD33.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 17;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v6, may contain a second binding domain that binds to CD22.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 17;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v6, may contain a second binding domain that binds to CD79A.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

- 89 040364 (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 17;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v6, may contain a second binding domain that binds to CD79B.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 17;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v6, may contain a second binding domain that binds to EDAR.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 17;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v6, may contain a second binding domain that binds to GFRA1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 17;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v6, may contain a second binding domain that binds to MRP4.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 17;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v6, may contain a second binding domain that binds to RET.

The second binding domain that binds to RET may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 614;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 615;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 616;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 617; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 618, such as those containing the anti-RET antibody 41205.v6.

In some instances, the second binding domain that binds to RET may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 629;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 630; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

- 90 040364 (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 17;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v6, may contain a second binding domain that binds to Steap1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 17;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v6, may contain a second binding domain that binds to TenB2.

Alternatively, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 18;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v7, may contain a second binding domain that binds to CD20.

The second binding domain that binds to CD20 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 158;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 159;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 160;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 161; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 162, such as those containing the anti-CD20 antibody 2H7.v16 (described in US Pat. No. 7,799,900).

In some instances, the second binding domain that binds to CD20 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 266;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 267; or (c) a VH domain according to (a) and a VL domain according to (b), for example, such that contains the anti-CD20 antibody 2H7.v16 (described in US patent No. 7799900).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 18;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v7, may contain a second binding domain that binds to FcRH5.

The second binding domain that binds to FcRH5 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 164;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 165;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 166;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 168, such as those containing the anti-FcRH5 antibody 1G7.

- 91 040364

In some instances, the second binding domain that binds to FcRH5 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 268;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 269; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 18;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v7, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 170;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 171;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 172;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 173; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 174, such as those containing the hu4D5 anti-HER2 antibody.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 270;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 271; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 18;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v7, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 582;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 583;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 584;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 585; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 586, such as those containing the anti-HER2 antibody 2C4.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 593;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 594; or

- 92 040364 (c) VH domain according to (a) and VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 18;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v7, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 588;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 589;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 590;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 591; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 592, such as those containing the anti-HER2 antibody 7C2.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 595;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 596; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 18;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v7, may contain a second binding domain that binds to LYPD1.

The second binding domain that binds to LYPD1 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 176;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 177;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 178;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 180, such as those containing the anti-LYPD1 antibody YWO.49.H6. In some instances, the second binding domain that binds to LYPD1 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 272;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 273; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 18;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 12,

- 93 040364 such as 38E4v7 may contain a second binding domain that binds to LY6G6D.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 18;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v7, may contain a second binding domain that binds to PMEL17.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 18;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v7, may contain a second binding domain that binds to LY6E.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 18;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v7, may contain a second binding domain that binds to CD19.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 18;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v7, may contain a second binding domain that binds to CD33.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 18;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v7, may contain a second binding domain that binds to CD22.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 18;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v7, may contain a second binding domain that binds to CD79A.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 18;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; And

- 94 040364 (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v7, may contain a second binding domain that binds to CD79B.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 18;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v7, may contain a second binding domain that binds to EDAR.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 18;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v7, may contain a second binding domain that binds to GFRA1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 18;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v7, may contain a second binding domain that binds to MRP4.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 18;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v7, may contain a second binding domain that binds to RET.

The second binding domain that binds to RET may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 614;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 615;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 616;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 617; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 618, such as those containing the anti-RET antibody 41205.v6.

In some instances, the second binding domain that binds to RET may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 629;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 630; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 18;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

- 95 040364 (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v7, may contain a second binding domain that binds to Steap1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 18;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v7, may contain a second binding domain that binds to TenB2.

Alternatively, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 19;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v8, may contain a second binding domain that binds to CD20.

The second binding domain that binds to CD20 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 158;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 159;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 160;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 161; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 162, such as those containing the anti-CD20 antibody 2H7.v16 (described in US Pat. No. 7,799,900).

In some instances, the second binding domain that binds to CD20 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 266;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 267; or (c) a VH domain according to (a) and a VL domain according to (b), for example, such that contains the anti-CD20 antibody 2H7.v16 (described in US patent No. 7799900).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 19;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v8, may contain a second binding domain that binds to FcRH5.

The second binding domain that binds to FcRH5 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 164;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 165;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 166;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 168, such as those containing the anti-FcRH5 antibody 1G7.

In some cases, the second binding domain that binds to FcRH5 may, for example, contain (a) a VH domain containing an amino acid sequence having at least 90%

- 96 040364 sequence identity (for example, at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 268;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 269; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 19;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v8, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 170;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 171;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 172;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 173; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 174, such as those containing the hu4D5 anti-HER2 antibody.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 270;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 271; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 19;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v8, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 582;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 583;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 584;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 585; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 586, such as those containing the anti-HER2 antibody 2C4.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 593;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 594; or (c) a VH domain according to (a) and a VL domain according to (b).

In some instances, an anti-CD3 antibody comprising a first binding domain containing at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from

- 97 040364 (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 19;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v8, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 588;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 589;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 590;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 591; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 592, such as those containing the anti-HER2 antibody 7C2.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 595;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 596; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 19;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v8, may contain a second binding domain that binds to LYPD1.

The second binding domain that binds to LYPD1 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 176;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 177;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 178;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 180, such as those containing the anti-LYPD1 antibody YWO.49.H6.

In some instances, the second binding domain that binds to LYPD1 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 272;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 273; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 19;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v8, may contain a second binding domain that binds to LY6G6D.

In some cases, an anti-CD3 antibody containing a first binding domain containing

- 98 040364 at least one, two, three, four, five or six hypervariable regions (HVR) selected from (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 19;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v8, may contain a second binding domain that binds to PMEL17.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 19;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v8, may contain a second binding domain that binds to LY6E.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 19;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v8, may contain a second binding domain that binds to CD19.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 19;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v8, may contain a second binding domain that binds to CD33.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 19;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v8, may contain a second binding domain that binds to CD22.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 19;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v8, may contain a second binding domain that binds to CD79A.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 19;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v8, may contain a second binding domain that binds to CD79B.

- 99 040364

In some cases, an aHTu-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 19;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v8, may contain a second binding domain that binds to EDAR.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 19;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v8, may contain a second binding domain that binds to GFRA1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 19;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v8, may contain a second binding domain that binds to MRP4.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 19;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v8, may contain a second binding domain that binds to RET.

The second binding domain that binds to RET may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 614;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 615;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 616;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 617; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 618, such as those containing the anti-RET antibody 41205.v6.

In some instances, the second binding domain that binds to RET may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 629;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 630; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 19;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 12,

- 100 040364 such as 38E4v8 may contain a second binding domain that binds to Steapl.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 19;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v8, may contain a second binding domain that binds to TenB2.

Alternatively, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 20;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v9, may contain a second binding domain that binds to CD20.

The second binding domain that binds to CD20 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 158;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 159;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 160;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 161; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 162, such as those containing the anti-CD20 antibody 2H7.v16 (described in US Pat. No. 7,799,900).

In some instances, the second binding domain that binds to CD20 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 266;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 267; or (c) a VH domain according to (a) and a VL domain according to (b), for example, such that contains the anti-CD20 antibody 2H7.v16 (described in US patent No. 7799900).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 20;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v9, may contain a second binding domain that binds to FcRH5.

The second binding domain that binds to FcRH5 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 164;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 165;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 166;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 168, such as those containing the anti-FcRH5 antibody 1G7.

In some instances, the second binding domain that binds to FcRH5 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 268;

- 101 040364 (b) a VL domain containing an amino acid sequence having at least 90% sequence identity (for example, at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or the sequence of SEQ ID NO: 269; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 20;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v9, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 170;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 171;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 172;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 173; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 174, such as those containing the hu4D5 anti-HER2 antibody.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 270;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 271; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 20;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v9, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 582;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 583;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 584;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 585; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 586, such as those containing the anti-HER2 antibody 2C4.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 593;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 594; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

- 102 040364 (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 20;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v9, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 588;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 589;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 590;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 591; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 592, such as those containing the anti-HER2 antibody 7C2.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 595;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 596; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 20;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v9, may contain a second binding domain that binds to LYPD1.

The second binding domain that binds to LYPD1 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 176;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 177;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 178;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 180, such as those containing the anti-LYPD1 antibody YWO.49.H6.

In some instances, the second binding domain that binds to LYPD1 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 272;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 273; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 20;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v9, may contain a second binding domain that binds to LY6G6D.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

- 103 040364 (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 20;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v9, may contain a second binding domain that binds to PMEL17.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 20;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v9, may contain a second binding domain that binds to LY6E.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 20;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v9, may contain a second binding domain that binds to CD19.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 20;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v9, may contain a second binding domain that binds to CD33.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 20;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v9, may contain a second binding domain that binds to CD22.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 20;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v9, may contain a second binding domain that binds to CD79A.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 20;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v9, may contain a second binding domain that binds to CD79B.

In some instances, an anti-CD3 antibody comprising a first binding domain containing at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from

- 104 040364 (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 20;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v9, may contain a second binding domain that binds to EDAR.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 20;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v9, may contain a second binding domain that binds to GFRA1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 20;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v9, may contain a second binding domain that binds to MRP4.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 20;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v9, may contain a second binding domain that binds to RET.

The second binding domain that binds to RET may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 614;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 615;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 616;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 617; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 618, such as those containing the anti-RET antibody 41205.v6.

In some instances, the second binding domain that binds to RET may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 629;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 630; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 20;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v9, may contain a second binding domain that binds to Steap1.

In some cases, an anti-CD3 antibody containing a first binding domain containing

- 105 040364 at least one, two, three, four, five or six hypervariable regions (HVR) selected from (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 20;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 12, such as 38E4v9, may contain a second binding domain that binds to TenB2.

Alternatively, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 21;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 22, such as 38E4c, may contain a second binding domain that binds to CD20.

The second binding domain that binds to CD20 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 158;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 159;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 160;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 161; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 162, such as those containing the anti-CD20 antibody 2H7.v16 (described in US Pat. No. 7,799,900).

In some instances, the second binding domain that binds to CD20 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 266;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 267; or (c) a VH domain according to (a) and a VL domain according to (b), for example, such that contains the anti-CD20 antibody 2H7.v16 (described in US patent No. 7799900).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 21;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 22, such as 38E4c, may contain a second binding domain that binds to FcRH5.

The second binding domain that binds to FcRH5 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 164;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 165;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 166;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 168, such as those containing the anti-FcRH5 antibody 1G7.

In some instances, the second binding domain that binds to FcRH5 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 268;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99%

- 106 040364 sequence identity) c, or the sequence of SEQ ID NO: 269; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 21;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 22, such as 38E4c, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 170;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 171;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 172;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 173; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 174, such as those containing the hu4D5 anti-HER2 antibody.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 270;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 271; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 21;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 22, such as 38E4c, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 582;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 583;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 584;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 585; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 586, such as those containing the anti-HER2 antibody 2C4.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 593;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 594; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 21;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

- 107 040364 (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 22, such as 38E4c, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 588;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 589;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 590;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 591; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 592, such as those containing the anti-HER2 antibody 7C2.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 595;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 596; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 21;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 22, such as 38E4c, may contain a second binding domain that binds to LYPD1.

The second binding domain that binds to LYPD1 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 176;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 177;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 178;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 180, such as those containing the anti-LYPD1 antibody YWO.49.H6.

In some instances, the second binding domain that binds to LYPD1 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 272;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 273; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 21;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 22, such as 38E4c, may contain a second binding domain that binds to LY6G6D.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 21;

- 108 040364 (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 22, such as 38E4c, may contain a second binding domain that binds to PMEL17.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 21;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 22, such as 38E4c, may contain a second binding domain that binds to LY6E.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 21;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 22, such as 38E4c, may contain a second binding domain that binds to CD19.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 21;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 22, such as 38E4c, may contain a second binding domain that binds to CD33.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 21;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 22, such as 38E4c, may contain a second binding domain that binds to CD22.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 21;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 22, such as 38E4c, may contain a second binding domain that binds to CD79A.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 21;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 22, such as 38E4c, may contain a second binding domain that binds to CD79B.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

- 109 040364 (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 21;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 22, such as 38E4c, may contain a second binding domain that binds to EDAR.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 21;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 22, such as 38E4c, may contain a second binding domain that binds to GFRA1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 21;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 22, such as 38E4c, may contain a second binding domain that binds to MRP4.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 21;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 22, such as 38E4c, may contain a second binding domain that binds to RET.

The second binding domain that binds to RET may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 614;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 615;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 616;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 617; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 618, such as those containing the anti-RET antibody 41205.v6.

In some instances, the second binding domain that binds to RET may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 629;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 630; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 21;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 22, such as 38E4c, may contain a second binding domain that binds to Steap1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;

- 110 040364 (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 8;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 21;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 10;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 22, such as 38E4c, may contain a second binding domain that binds to TenB2.

Alternatively, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 24;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1v9, may contain a second binding domain that binds to CD20.

The second binding domain that binds to CD20 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 158;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 159;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 160;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 161; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 162, such as those containing the anti-CD20 antibody 2H7.v16 (described in US Pat. No. 7,799,900).

In some instances, the second binding domain that binds to CD20 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 266;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 267; or (c) a VH domain according to (a) and a VL domain according to (b), for example, such that contains the anti-CD20 antibody 2H7.v16 (described in US patent No. 7799900).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 24;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1v9, may contain a second binding domain that binds to FcRH5.

The second binding domain that binds to FcRH5 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 164;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 165;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 166;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 168, such as those containing the anti-FcRH5 antibody 1G7.

In some instances, the second binding domain that binds to FcRH5 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 268;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 269; or (c) a VH domain according to (a) and a VL domain according to (b).

- 111 040364

In some cases, an aHTu-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 24;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1v9, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 170;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 171;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 172;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 173; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 174, such as those containing the hu4D5 anti-HER2 antibody.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 270;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 271; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 24;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1v9, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 582;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 583;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 584;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 585; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 586, such as those containing the anti-HER2 antibody 2C4.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 593;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 594; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from \(a) HVR-H1 containing the amino acid sequence of SEQ ID NO : 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 24;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 28,

- 112 040364 such as UCHT1v9 may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 588;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 589;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 590;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 591; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 592, such as those containing the anti-HER2 antibody 7C2.

In some instances, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 595;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 596; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 24;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1v9, may contain a second binding domain that binds to LYPD1.

The second binding domain that binds to LYPD1 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 176;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 177;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 178;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 180, such as those containing the anti-LYPD1 antibody YWO.49.H6.

In some instances, the second binding domain that binds to LYPD1 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 272;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 273; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 24;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1v9, may contain a second binding domain that binds to LY6G6D.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 24;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

- 113 040364 (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1v9, may contain a second binding domain that binds to PMEL17.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 24;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1v9, may contain a second binding domain that binds to LY6E.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 24;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1v9, may contain a second binding domain that binds to CD19.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 24;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1v9, may contain a second binding domain that binds to CD33.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 24;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1v9, may contain a second binding domain that binds to CD22.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 24;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1v9, may contain a second binding domain that binds to CD79A.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 24;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1v9, may contain a second binding domain that binds to CD79B.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 24;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

- 114 040364 (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1v9, may contain a second binding domain that binds to EDAR.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 24;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1v9, may contain a second binding domain that binds to GFRA1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 24;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1v9, may contain a second binding domain that binds to MRP4.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 24;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1v9, may contain a second binding domain that binds to RET.

The second binding domain that binds to RET may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 614;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 615;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 616;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 617; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 618, such as those containing the anti-RET antibody 41205.v6.

In some instances, the second binding domain that binds to RET may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 629;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 630; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 24;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1v9, may contain a second binding domain that binds to Steap1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 24;

- 115 040364 (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1v9, may contain a second binding domain that binds to TenB2.

Alternatively, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 29;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1v1, may contain a second binding domain that binds to CD20.

The second binding domain that binds to CD20 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 158;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 159;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 160;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 161; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 162, such as those containing the anti-CD20 antibody 2H7.v16 (described in US Pat. No. 7,799,900).

In some instances, the second binding domain that binds to CD20 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 266;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 267; or (c) a VH domain according to (a) and a VL domain according to (b), for example, such that contains the anti-CD20 antibody 2H7.v16 (described in US patent No. 7799900).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 29;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1v1, may contain a second binding domain that binds to FcRH5.

The second binding domain that binds to FcRH5 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 164;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 165;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 166;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 168, such as those containing the anti-FcRH5 antibody 1G7.

In some instances, the second binding domain that binds to FcRH5 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 268;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 269; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody containing a first binding domain containing

- 116 040364 at least one, two, three, four, five or six hypervariable regions (HVR) selected from (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 29;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1v1, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 170;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 171;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 172;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 173; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 174, such as those containing the hu4D5 anti-HER2 antibody.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 270;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 271; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 29;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1v1, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 582;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 583;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 584;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 585; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 586, such as those containing the anti-HER2 antibody 2C4.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 593;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 594; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 29;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1v1, may contain a second binding domain that binds to HER2.

- 117 040364

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 588;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 589;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 590;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 591; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 592, such as those containing the anti-HER2 antibody 7C2.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 595;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 596; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 29;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1v1, may contain a second binding domain that binds to LYPD1.

The second binding domain that binds to LYPD1 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 176;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 177;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 178;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 180, such as those containing the anti-LYPD1 antibody YWO.49.H6.

In some instances, the second binding domain that binds to LYPD1 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 272;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 273; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 29;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1v1, may contain a second binding domain that binds to LY6G6D.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 29;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; And

- 118 040364 (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1v1, may contain a second binding domain that binds to PMEL17.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 29;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1v1, may contain a second binding domain that binds to LY6E.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 29;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1v1, may contain a second binding domain that binds to CD19.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 29;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1v1, may contain a second binding domain that binds to CD33.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 29;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1v1, may contain a second binding domain that binds to CD22.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 29;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1v1, may contain a second binding domain that binds to CD79A.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 29;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1v1, may contain a second binding domain that binds to CD79B.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 29;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

- 119 040364 (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1v1, may contain a second binding domain that binds to EDAR.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 29;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1v1, may contain a second binding domain that binds to GFRA1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 29;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1v1, may contain a second binding domain that binds to MRP4.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 29;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1v1, may contain a second binding domain that binds to RET.

The second binding domain that binds to RET may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 614;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 615;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 616;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 617; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 618, such as those containing the anti-RET antibody 41205.v6.

In some instances, the second binding domain that binds to RET may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 629;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 630; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 29;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1v1, may contain a second binding domain that binds to Steap1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 29;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

- 120 040364 (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1v1, may contain a second binding domain that binds to TenB2.

Alternatively, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 30;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1vM1, may contain a second binding domain that binds to CD20.

The second binding domain that binds to CD20 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 158;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 159;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 160;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 161; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 162, such as those containing the anti-CD20 antibody 2H7.v16 (described in US Pat. No. 7,799,900).

In some instances, the second binding domain that binds to CD20 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 266;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 267; or (c) a VH domain according to (a) and a VL domain according to (b), for example, such that contains the anti-CD20 antibody 2H7.v16 (described in US patent No. 7799900).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 30;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1vM1, may contain a second binding domain that binds to FcRH5.

The second binding domain that binds to FcRH5 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 164;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 165;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 166;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 167; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 168, such as those containing the anti-FcRH5 antibody 1G7.

In some instances, the second binding domain that binds to FcRH5 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 268;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 269; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody containing a first binding domain containing

- 121 040364 at least one, two, three, four, five or six hypervariable regions (HVR) selected from (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 30;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1vM1, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 170;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 171;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 172;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 173; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 174, such as those containing the hu4D5 anti-HER2 antibody.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 270;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 271; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 30;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1vM1, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 582;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 583;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 584;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 585; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 586, such as those containing the anti-HER2 antibody 2C4.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 593;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 594; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 30;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1vM1, may contain a second binding domain that binds to HER2.

- 122 040364

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 588;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 589;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 590;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 591; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 592, such as those containing the anti-HER2 antibody 7C2.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 595;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 596; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 30;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1vM1, may contain a second binding domain that binds to LYPD1.

The second binding domain that binds to LYPD1 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 176;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 177;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 178;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 180, such as those containing the anti-LYPD1 antibody YWO.49.H6.

In some instances, the second binding domain that binds to LYPD1 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 272;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 273; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 30;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1vM1, may contain a second binding domain that binds to LY6G6D.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 30;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

- 123 040364 (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1vM1, may contain a second binding domain that binds to

PMEL17.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 30;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1vM1, may contain a second binding domain that binds to LY6E.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 30;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1vM1, may contain a second binding domain that binds to CD19.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 30;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1vM1, may contain a second binding domain that binds to CD33.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 30;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1vM1, may contain a second binding domain that binds to CD22.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 30;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1vM1, may contain a second binding domain that binds to CD79A.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 30;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1vM1, may contain a second binding domain that binds to CD79B.

In some instances, an anti-CD3 antibody comprising a first binding domain containing at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from

- 124 040364 (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 30;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1vM1, may contain a second binding domain that binds to EDAR.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 30;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1vM1, may contain a second binding domain that binds to GFRA1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 30;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1vM1, may contain a second binding domain that binds to MRP4.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 30;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1vM1, may contain a second binding domain that binds to RET.

The second binding domain that binds to RET may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 614;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 615;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 616;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 617; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 618, such as those containing the anti-RET antibody 41205.v6.

In some instances, the second binding domain that binds to RET may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 629;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 630; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 30;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1vM1, may contain a second binding domain that binds to Steap1.

- 125 040364

In some cases, an aHTu-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 30;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 25;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 26;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 27; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 28, such as UCHT1vM1, may contain a second binding domain that binds to TenB2.

Alternatively, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 32;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 33;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 34;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 35; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 36, such as SP34v52, may contain a second binding domain that binds to CD20.

The second binding domain that binds to CD20 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 158;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 159;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 160;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 161; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 162, such as those containing the anti-CD20 antibody 2H7.v16 (described in US Pat. No. 7,799,900).

In some instances, the second binding domain that binds to CD20 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 266;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 267; or (c) a VH domain according to (a) and a VL domain according to (b), for example, such that contains the anti-CD20 antibody 2H7.v16 (described in US patent No. 7799900).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 32;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 33;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 34;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 35; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 36, such as SP34v52, may contain a second binding domain that binds to FcRH5.

The second binding domain that binds to FcRH5 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 164;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 165;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 166;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 168, such as those containing the anti-FcRH5 antibody 1G7.

In some instances, the second binding domain that binds to FcRH5 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 268;

(b) a VL domain containing an amino acid sequence having at least 90%

- 126 040364 sequence identity (for example, at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) with, or the sequence of SEQ ID NO: 269; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 32;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 33;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 34;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 35; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 36, such as SP34v52, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 170;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 171;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 172;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 173; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 174, such as those containing the hu4D5 anti-HER2 antibody.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 270;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 271; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 32;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 33;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 34;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 35; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 36, such as SP34v52, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 582;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 583;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 584;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 585; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 586, such as those containing the anti-HER2 antibody 2C4.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 593;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 594; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 32;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 33;

- 127 040364 (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 34;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 35; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 36, such as SP34v52, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 588;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 589;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 590;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 591; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 592, such as those containing the anti-HER2 antibody 7C2.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 595;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 596; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 32;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 33;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 34;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 35; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 36, such as SP34v52, may contain a second binding domain that binds to LYPD1.

The second binding domain that binds to LYPD1 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 176;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 177;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 178;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 180, such as those containing the anti-LYPD1 antibody YWO.49.H6. In some instances, the second binding domain that binds to LYPD1 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 272;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 273; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 32;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 33;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 34;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 35; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 36, such as SP34v52, may contain a second binding domain that binds to LY6G6D.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 32;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 33;

- 128 040364 (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 34;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 35; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 36, such as SP34v52, may contain a second binding domain that binds to PMEL17.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 32;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 33;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 34;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 35; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 36, such as SP34v52, may contain a second binding domain that binds to LY6E.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 32;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 33;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 34;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 35; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 36, such as SP34v52, may contain a second binding domain that binds to CD19.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 32;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 33;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 34;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 35; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 36, such as SP34v52, may contain a second binding domain that binds to CD33.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 32;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 33;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 34;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 35; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 36, such as SP34v52, may contain a second binding domain that binds to CD22.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 32;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 33;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 34;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 35; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 36, such as SP34v52, may contain a second binding domain that binds to CD79A.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 32;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 33;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 34;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 35; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 36, such as SP34v52, may contain a second binding domain that binds to CD79B.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 32;

- 129 040364 (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 33;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 34;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 35; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 36, such as SP34v52, may contain a second binding domain that binds to EDAR.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 32;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 33;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 34;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 35; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 36, such as SP34v52, may contain a second binding domain that binds to GFRA1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 32;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 33;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 34;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 35; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 36, such as SP34v52, may contain a second binding domain that binds to MRP4.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 32;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 33;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 34;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 35; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 36, such as SP34v52, may contain a second binding domain that binds to RET.

The second binding domain that binds to RET may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 614;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 615;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 616;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 617; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 618, such as those containing the anti-RET antibody 41205.v6.

In some instances, the second binding domain that binds to RET may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 629;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 630; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 32;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 33;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 34;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 35; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 36, such as SP34v52, may contain a second binding domain that binds to Steap1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31;

- 130 040364 (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 32;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 33;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 34;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 35; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 36, such as SP34v52, may contain a second binding domain that binds to TenB2.

Alternatively, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 37;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 38;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 39;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 40;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 41; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 42, such as 41D9a, may contain a second binding domain that binds to CD20.

The second binding domain that binds to CD20 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 158;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 159;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 160;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 161; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 162, such as those containing the anti-CD20 antibody 2H7.v16 (described in US Pat. No. 7,799,900). In some instances, the second binding domain that binds to CD20 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 266;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 267; or (c) a VH domain according to (a) and a VL domain according to (b), for example, such that contains the anti-CD20 antibody 2H7.v16 (described in US patent No. 7799900).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 37;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 38;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 39;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 40;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 41; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 42, such as 41D9a, may contain a second binding domain that binds to FcRH5.

The second binding domain that binds to FcRH5 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 164;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 165;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 166;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 168, such as those containing the anti-FcRH5 antibody 1G7.

In some instances, the second binding domain that binds to FcRH5 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 268;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 269; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody containing a first binding domain containing

- 131 040364 at least one, two, three, four, five or six hypervariable regions (HVR) selected from (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 37;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 38;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 39;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 40;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 41; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 42, such as 41D9a, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 170;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 171;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 172;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 173; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 174, such as those containing the hu4D5 anti-HER2 antibody.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 270;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 271; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 37;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 38;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 39;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 40;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 41; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 42, such as 41D9a, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 582;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 583;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 584;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 585; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 586, such as those containing the anti-HER2 antibody 2C4.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 593;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 594; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 37;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 38;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 39;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 40;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 41; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 42, such as 41D9a, may contain a second binding domain that binds to HER2.

- 132 040364

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 588;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 589;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 590;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 591; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 592, such as those containing the anti-HER2 antibody 7C2.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 595;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 596; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 37;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 38;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 39;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 40;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 41; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 42, such as 41D9a, may contain a second binding domain that binds to LYPD1.

The second binding domain that binds to LYPD1 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 176;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 177;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 178;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 180, such as those containing the anti-LYPD1 antibody YWO.49.H6.

In some instances, the second binding domain that binds to LYPD1 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 272;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 273; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 37;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 38;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 39;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 40;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 41; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 42, such as 41D9a, may contain a second binding domain that binds to LY6G6D.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 37;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 38;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 39;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 40;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 41; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 42,

- 133 040364 such as 41D9a may contain a second binding domain that binds to PMEL17.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 37;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 38;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 39;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 40;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 41; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 42, such as 41D9a, may contain a second binding domain that binds to LY6E.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 37;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 38;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 39;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 40;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 41; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 42, such as 41D9a, may contain a second binding domain that binds to CD19.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 37;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 38;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 39;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 40;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 41; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 42, such as 41D9a, may contain a second binding domain that binds to CD33.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 37;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 38;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 39;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 40;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 41; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 42, such as 41D9a, may contain a second binding domain that binds to CD22.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 37;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 38;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 39;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 40;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 41; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 42, such as 41D9a, may contain a second binding domain that binds to CD79A.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 37;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 38;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 39;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 40;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 41; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 42, such as 41D9a, may contain a second binding domain that binds to CD79B.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 37;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 38;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 39;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 40;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 41; And

- 134 040364 (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 42, such as 41D9a, may contain a second binding domain that binds to EDAR.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 37;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 38;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 39;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 40;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 41; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 42, such as 41D9a, may contain a second binding domain that binds to GFRA1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 37;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 38;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 39;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 40;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 41; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 42, such as 41D9a, may contain a second binding domain that binds to MRP4.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 37;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 38;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 39;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 40;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 41; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 42, such as 41D9a, may contain a second binding domain that binds to RET.

The second binding domain that binds to RET may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 614;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 615;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 616;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 617; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 618, such as those containing the anti-RET antibody 41205.v6.

In some instances, the second binding domain that binds to RET may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 629;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 630; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 37;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 38;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 39;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 40;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 41; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 42, such as 41D9a, may contain a second binding domain that binds to Steap1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 37;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 38;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 39;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 40;

- 135 040364 (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 41; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 42, such as 41D9a, may contain a second binding domain that binds to TenB2.

Alternatively, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, such as 13A3, may contain a second binding domain that binds to CD20.

The second binding domain that binds to CD20 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 158;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 159;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 160;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 161; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 162, such as those containing the anti-CD20 antibody 2H7.v16 (described in US Pat. No. 7,799,900).

In some instances, the second binding domain that binds to CD20 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 266;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 267; or (c) a VH domain according to (a) and a VL domain according to (b), for example, such that contains the anti-CD20 antibody 2H7.v16 (described in US patent No. 7799900).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, such as 13A3, may contain a second binding domain that binds to FcRH5.

The second binding domain that binds to FcRH5 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 164;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 165;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 166;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 168, such as those containing the anti-FcRH5 antibody 1G7.

In some instances, the second binding domain that binds to FcRH5 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 268;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 269; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43;

- 136 040364 (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, such as 13A3, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 170;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 171;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 172;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 173; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 174, such as those containing the hu4D5 anti-HER2 antibody.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 270;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 271; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, such as 13A3, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 582;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 583;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 584;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 585; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 586, such as those containing the anti-HER2 antibody 2C4.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 593;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 594; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, such as 13A3, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, contain at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from

- 137 040364 (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 587;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 588;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 589;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 590;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 591; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 592, such as those containing the anti-HER2 antibody 7C2.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 595;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 596; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, such as 13A3, may contain a second binding domain that binds to LYPD1.

The second binding domain that binds to LYPD1 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 176;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 177;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 178;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 180, such as those containing the anti-LYPD1 antibody YWO.49.H6.

In some instances, the second binding domain that binds to LYPD1 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 272;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 273; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, such as 13A3, may contain a second binding domain that binds to LY6G6D.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, such as 13A3, may contain a second binding domain that binds to PMEL17.

In some cases, an anti-CD3 antibody containing a first binding domain containing

- 138 040364 at least one, two, three, four, five or six hypervariable regions (HVR) selected from (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 43;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, such as 13A3, may contain a second binding domain that binds to LY6E.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, such as 13A3, may contain a second binding domain that binds to CD19.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, such as 13A3, may contain a second binding domain that binds to CD33.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, such as 13A3, may contain a second binding domain that binds to CD22.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, such as 13A3, may contain a second binding domain that binds to CD79A.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, such as 13A3, may contain a second binding domain that binds to CD79B.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, such as 13A3, may contain a second binding domain that binds to EDAR.

- 139 040364

In some cases, an aHTu-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, such as 13A3, may contain a second binding domain that binds to GFRA1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, such as 13A3, may contain a second binding domain that binds to MRP4.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, such as 13A3, may contain a second binding domain that binds to RET.

The second binding domain that binds to RET may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 614;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 615;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 616;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 617; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 618, such as those containing the anti-RET antibody 41205.v6.

In some instances, the second binding domain that binds to RET may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 629;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 630; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, such as 13A3, may contain a second binding domain that binds to Steap1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 48,

- 140 040364 such as 13A3 may contain a second binding domain that binds to TenB2.

Alternatively, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, such as 13A3.v2, may contain a second binding domain that binds to CD20.

The second binding domain that binds to CD20 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 158;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 159;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 160;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 161; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 162, such as those containing the anti-CD20 antibody 2H7.v16 (described in US Pat. No. 7,799,900).

In some instances, the second binding domain that binds to CD20 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 266;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 267; or (c) a VH domain according to (a) and a VL domain according to (b), for example, such that contains the anti-CD20 antibody 2H7.v16 (described in US patent No. 7799900).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, such as 13A3.v2, may contain a second binding domain that binds to FcRH5.

The second binding domain that binds to FcRH5 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 164;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 165;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 166;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 168, such as those containing the anti-FcRH5 antibody 1G7.

In some instances, the second binding domain that binds to FcRH5 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 268;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 269; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

- 141 040364 (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, such as 13A3.v2, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 170;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 171;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 172;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 173; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 174, such as those containing the hu4D5 anti-HER2 antibody.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 270;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 271; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, such as 13A3.v2, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 582;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 583;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 584;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 585; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 586, such as those containing the anti-HER2 antibody 2C4.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 593;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 594; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, such as 13A3.v2, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 588;

- 142 040364 (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 589;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 590;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 591; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 592, such as those containing the anti-HER2 antibody, 7C2.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 595;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 596; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, such as 13A3.v2, may contain a second binding domain that binds to LYPD1.

The second binding domain that binds to LYPD1 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 176;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 177;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 178;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 180, such as those containing the anti-LYPD1 antibody YWO.49.H6.

In some instances, the second binding domain that binds to LYPD1 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 272;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 273; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, such as 13A3.v2, may contain a second binding domain that binds to LY6G6D.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, such as 13A3.v2, may contain a second binding domain that binds to PMEL17.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43;

- 143 040364 (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, such as 13A3.v2, may contain a second binding domain that binds to LY6E.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, such as 13A3.v2, may contain a second binding domain that binds to CD19.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, such as 13A3.v2, may contain a second binding domain that binds to CD33.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, such as 13A3.v2, may contain a second binding domain that binds to CD22.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, such as 13A3.v2, may contain a second binding domain that binds to CD79A.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, such as 13A3.v2, may contain a second binding domain that binds to CD79B.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, such as 13A3.v2, may contain a second binding domain that binds to EDAR.

In some instances, an anti-CD3 antibody comprising a first binding domain containing at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from

- 144 040364 (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 43;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, such as 13A3.v2, may contain a second binding domain that binds to GFRA1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, such as 13A3.v2, may contain a second binding domain that binds to MRP4.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, such as 13A3.v2, may contain a second binding domain that binds to RET.

The second binding domain that binds to RET may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 614;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 615;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 616;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 617; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 618, such as those containing the anti-RET antibody 41205.v6.

In some instances, the second binding domain that binds to RET may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 629;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 630; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, such as 13A3.v2, may contain a second binding domain that binds to Steap1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 44;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 45;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 46;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 47; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 48, such as 13A3.v2, may contain a second binding domain that binds to TenB2.

In another case, an anti-CD3 antibody containing a first binding domain containing

- 145 040364 at least one, two, three, four, five or six hypervariable regions (HVR) selected from (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 49;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 50;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 51;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 52;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 53; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 54, such as 30A1, may contain a second binding domain that binds to CD20.

The second binding domain that binds to CD20 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 158;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 159;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 160;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 161; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 162, such as those containing the anti-CD20 antibody 2H7.v16 (described in US Pat. No. 7,799,900).

In some instances, the second binding domain that binds to CD20 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 266;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 267; or (c) a VH domain according to (a) and a VL domain according to (b), for example, such that contains the anti-CD20 antibody 2H7.v16 (described in US patent No. 7799900).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 49;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 50;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 51;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 52;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 53; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 54, such as 30A1, may contain a second binding domain that binds to FcRH5.

The second binding domain that binds to FcRH5 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 164;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 165;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 166;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 168, such as those containing the anti-FcRH5 antibody 1G7.

In some instances, the second binding domain that binds to FcRH5 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 268;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 269; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 49;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 50;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 51;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 52;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 53; And

- 146 040364 (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 54, such as 30A1, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 170;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 171;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 172;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 173; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 174, such as those containing the hu4D5 anti-HER2 antibody.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 270;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 271; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 49;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 50;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 51;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 52;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 53; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 54, such as 30A1, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 582;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 583;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 584;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 585; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 586, such as those containing the anti-HER2 antibody 2C4.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 593;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 594; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 49;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 50;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 51;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 52;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 53; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 54, such as 30A1, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 588;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 589;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 590;

- 147 040364 (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 591; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 592, such as those containing the anti-HER2 antibody 7C2.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 595;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 596; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 49;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 50;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 51;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 52;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 53; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 54, such as 30A1, may contain a second binding domain that binds to LYPD1.

The second binding domain that binds to LYPD1 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 176;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 177;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 178;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 180, such as those containing the anti-LYPD1 antibody YWO.49.H6.

In some instances, the second binding domain that binds to LYPD1 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 272;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 273; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 49;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 50;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 51;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 52;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 53; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 54, such as 30A1, may contain a second binding domain that binds to LY6G6D.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 49;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 50;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 51;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 52;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 53; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 54, such as 30A1, may contain a second binding domain that binds to PMEL17.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 49;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 50;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 51;

- 148 040364 (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 52;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 53; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 54, such as 30A1, may contain a second binding domain that binds to LY6E.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 49;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 50;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 51;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 52;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 53; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 54, such as 30A1, may contain a second binding domain that binds to CD19.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 49;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 50;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 51;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 52;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 53; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 54, such as 30A1, may contain a second binding domain that binds to CD33.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 49;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 50;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 51;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 52;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 53; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 54, such as 30A1, may contain a second binding domain that binds to CD22.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 49;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 50;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 51;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 52;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 53; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 54, such as 30A1, may contain a second binding domain that binds to CD79A.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 49;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 50;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 51;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 52;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 53; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 54, such as 30A1, may contain a second binding domain that binds to CD79B.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 49;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 50;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 51;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 52;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 53; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 54, such as 30A1, may contain a second binding domain that binds to EDAR.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 49;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 50;

- 149 040364 (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 51;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 52;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 53; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 54, such as 30A1, may contain a second binding domain that binds to GFRA1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 49;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 50;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 51;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 52;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 53; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 54, such as 30A1, may contain a second binding domain that binds to MRP4.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 49;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 50;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 51;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 52;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 53; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 54, such as 30A1, may contain a second binding domain that binds to RET.

The second binding domain that binds to RET may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 614;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 615;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 616;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 617; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 618, such as those containing the anti-RET antibody 41205.v6.

In some instances, the second binding domain that binds to RET may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 629;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 630; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 49;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 50;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 51;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 52;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 53; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 54, such as 30A1, may contain a second binding domain that binds to Steap1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 49;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 50;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 51;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 52;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 53; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 54, such as 30A1, may contain a second binding domain that binds to TenB2.

Alternatively, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55;

- 150 040364 (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 56;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 57;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 58;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 59; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 60, such as 30A1.v2, may contain a second binding domain that binds to CD20.

The second binding domain that binds to CD20 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 158;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 159;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 160;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 161; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 162, such as those containing the anti-CD20 antibody 2H7.v16 (described in US Pat. No. 7,799,900).

In some instances, the second binding domain that binds to CD20 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 266;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 267; or (c) a VH domain according to (a) and a VL domain according to (b), for example, such that contains the anti-CD20 antibody 2H7.v16 (described in US patent No. 7799900).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 56;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 57;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 58;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 59; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 60, such as 30A1.v2, may contain a second binding domain that binds to FcRH5.

The second binding domain that binds to FcRH5 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 164;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 165;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 166;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 168, such as those containing the anti-FcRH5 antibody 1G7.

In some instances, the second binding domain that binds to FcRH5 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 268;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 269; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 56;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 57;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 58;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 59; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 60, such as 30A1.v2, may contain a second binding domain that binds to HER2.

- 151 040364

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 170;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 171;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 172;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 173; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 174, such as those containing the hu4D5 anti-HER2 antibody.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 270;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 271; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 56;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 57;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 58;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 59; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 60, such as 30A1.v2, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 582;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 583;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 584;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 585; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 586, such as those containing the anti-HER2 antibody 2C4.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 593;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 594; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 56;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 57;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 58;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 59; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 60, such as 30A1.v2, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 588;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 589;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 590;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592,

- 152 040364 for example, those containing aHTu-HER2 antibody 7C2.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 595;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 596; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 56;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 57;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 58;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 59; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 60, such as 30A1.v2, may contain a second binding domain that binds to LYPD1.

The second binding domain that binds to LYPD1 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 176;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 177;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 178;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 180, such as those containing the anti-LYPD1 antibody YWO.49.H6.

In some instances, the second binding domain that binds to LYPD1 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 272;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 273; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 56;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 57;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 58;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 59; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 60, such as 30A1.v2, may contain a second binding domain that binds to LY6G6D.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 56;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 57;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 58;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 59; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 60, such as 30A1.v2, may contain a second binding domain that binds to PMEL17.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 56;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 57;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 58;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 59; And

- 153 040364 (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 60, such as 30A1.v2, may contain a second binding domain that binds to LY6E.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 56;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 57;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 58;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 59; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 60, such as 30A1.v2, may contain a second binding domain that binds to CD19.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 56;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 57;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 58;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 59; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 60, such as 30A1.v2, may contain a second binding domain that binds to CD33.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 56;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 57;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 58;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 59; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 60, such as 30A1.v2, may contain a second binding domain that binds to CD22.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 56;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 57;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 58;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 59; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 60, such as 30A1.v2, may contain a second binding domain that binds to CD79A.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 56;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 57;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 58;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 59; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 60, such as 30A1.v2, may contain a second binding domain that binds to CD79B.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 56;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 57;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 58;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 59; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 60, such as 30A1.v2, may contain a second binding domain that binds to EDAR.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 56;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 57;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 58;

- 154 040364 (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 59; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 60, such as 30A1.v2, may contain a second binding domain that binds to GFRA1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 56;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 57;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 58;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 59; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 60, such as 30A1.v2, may contain a second binding domain that binds to MRP4.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 56;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 57;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 58;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 59; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 60, such as 30A1.v2, may contain a second binding domain that binds to RET.

The second binding domain that binds to RET may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 614;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 615;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 616;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 617; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 618, such as those containing the anti-RET antibody 41205.v6.

In some instances, the second binding domain that binds to RET may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 629;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 630; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 56;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 57;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 58;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 59; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 60, such as 30A1.v2, may contain a second binding domain that binds to Steap1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 56;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 57;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 58;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 59; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 60, such as 30A1.v2, may contain a second binding domain that binds to TenB2.

Alternatively, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 62;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 63;

- 155 040364 (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 64;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 65; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 66, such as h21A9, may contain a second binding domain that binds to CD20.

The second binding domain that binds to CD20 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 158;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 159;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 160;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 161; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 162, such as those containing the anti-CD20 antibody 2H7.v16 (described in US Pat. No. 7,799,900).

In some instances, the second binding domain that binds to CD20 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 266;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 267; or (c) a VH domain according to (a) and a VL domain according to (b), for example, such that contains the anti-CD20 antibody 2H7.v16 (described in US patent No. 7799900).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 62;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 63;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 64;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 65; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 66, such as h21A9, may contain a second binding domain that binds to FcRH5.

The second binding domain that binds to FcRH5 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 164;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 165;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 166;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 168, such as those containing the anti-FcRH5 antibody 1G7.

In some instances, the second binding domain that binds to FcRH5 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 268;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 269; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 62;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 63;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 64;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 65; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 66, such as h21A9, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, contain at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from

- 156 040364 (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 169;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 170;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 171;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 172;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 173; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 174, such as those containing the hu4D5 anti-HER2 antibody.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 270;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 271; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 62;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 63;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 64;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 65; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 66, such as h21A9, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 582;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 583;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 584;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 585; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 586, such as those containing the anti-HER2 antibody 2C4.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 593;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 594; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 62;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 63;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 64;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 65; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 66, such as h21A9, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 588;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 589;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 590;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 591; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 592, such as those containing the anti-HER2 antibody 7C2.

In some cases, the second binding domain that binds to HER2 may, for example,

- 157 040364 contain (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (for example, at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) with , or the sequence of SEQ ID NO: 595;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 596; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 62;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 63;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 64;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 65; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 66, such as h21A9, may contain a second binding domain that binds to LYPD1.

The second binding domain that binds to LYPD1 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 176;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 177;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 178;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 180, such as those containing the anti-LYPD1 antibody YWO.49.H6.

In some instances, the second binding domain that binds to LYPD1 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 272;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 273; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 62;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 63;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 64;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 65; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 66, such as h21A9, may contain a second binding domain that binds to LY6G6D.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 62;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 63;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 64;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 65; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 66, such as h21A9, may contain a second binding domain that binds to PMEL17.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 62;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 63;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 64;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 65; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 66, such as h21A9, may contain a second binding domain that binds to LY6E.

- 158 040364

In some cases, an aHTu-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 62;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 63;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 64;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 65; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 66, such as h21A9, may contain a second binding domain that binds to CD19.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 62;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 63;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 64;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 65; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 66, such as h21A9, may contain a second binding domain that binds to CD33.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 62;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 63;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 64;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 65; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 66, such as h21A9, may contain a second binding domain that binds to CD22.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 62;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 63;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 64;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 65; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 66, such as h21A9, may contain a second binding domain that binds to CD79A.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 62;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 63;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 64;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 65; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 66, such as h21A9, may contain a second binding domain that binds to CD79B.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 62;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 63;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 64;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 65; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 66, such as h21A9, may contain a second binding domain that binds to EDAR.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 62;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 63;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 64;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 65; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66,

- 159 040364 such as h21A9 may contain a second binding domain that binds to GFRA1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 62;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 63;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 64;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 65; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 66, such as h21A9, may contain a second binding domain that binds to MRP4.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 62;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 63;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 64;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 65; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 66, such as h21A9, may contain a second binding domain that binds to RET.

The second binding domain that binds to RET may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 614;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 615;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 616;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 617; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 618, such as those containing the anti-RET antibody 41205.v6.

In some instances, the second binding domain that binds to RET may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 629;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 630; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 62;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 63;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 64;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 65; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 66, such as h21A9, may contain a second binding domain that binds to Steap1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 62;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 63;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 64;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 65; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 66, such as h21A9, may contain a second binding domain that binds to TenB2.

Alternatively, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 68;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 69;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 70;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 71; And

- 160 040364 (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 72, such as 21B2, may contain a second binding domain that binds to CD20.

The second binding domain that binds to CD20 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 158;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 159;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 160;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 161; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 162, such as those containing the anti-CD20 antibody 2H7.v16 (described in US Pat. No. 7,799,900).

In some instances, the second binding domain that binds to CD20 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 266;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 267; or (c) a VH domain according to (a) and a VL domain according to (b), for example, such that contains the anti-CD20 antibody 2H7.v16 (described in US patent No. 7799900).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 68;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 69;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 70;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 71; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 72, such as 21B2, may contain a second binding domain that binds to FcRH5.

The second binding domain that binds to FcRH5 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 164;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 165;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 166;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 168, such as those containing the anti-FcRH5 antibody 1G7.

In some instances, the second binding domain that binds to FcRH5 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 268;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 269; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 68;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 69;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 70;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 71; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 72, such as 21B2, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 170;

- 161 040364 (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 171;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 172;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 173; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 174, such as those containing the hu4D5 anti-HER2 antibody.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 270;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 271; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 68;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 69;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 70;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 71; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 72, such as 21B2, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 582;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 583;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 584;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 585; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 586, such as those containing the anti-HER2 antibody 2C4.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 593;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 594; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 68;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 69;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 70;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 71; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 72, such as 21B2, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 588;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 589;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 590;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 591; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 592, such as those containing the anti-HER2 antibody 7C2.

In some cases, the second binding domain that binds to HER2 may, for example, contain (a) a VH domain containing an amino acid sequence having at least 90%

- 162 040364 sequence identity (for example, at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 595;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 596; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 68;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 69;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 70;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 71; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 72, such as 21B2, may contain a second binding domain that binds to LYPD1.

The second binding domain that binds to LYPD1 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 176;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 177;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 178;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 180, such as those containing the anti-LYPD1 antibody YWO.49.H6.

In some instances, the second binding domain that binds to LYPD1 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 272;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 273; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 68;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 69;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 70;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 71; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 72, such as 21B2, may contain a second binding domain that binds to LY6G6D.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 68;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 69;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 70;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 71; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 72, such as 21B2, may contain a second binding domain that binds to PMEL17.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 68;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 69;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 70;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 71; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 72, such as 21B2, may contain a second binding domain that binds to LY6E.

In some cases, an anti-CD3 antibody comprising a first binding domain containing at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from

- 163 040364 (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 67;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 68;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 69;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 70;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 71; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 72, such as 21B2, may contain a second binding domain that binds to CD19.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 68;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 69;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 70;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 71; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 72, such as 21B2, may contain a second binding domain that binds to CD33.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 68;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 69;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 70;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 71; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 72, such as 21B2, may contain a second binding domain that binds to CD22.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 68;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 69;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 70;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 71; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 72, such as 21B2, may contain a second binding domain that binds to CD79A.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 68;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 69;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 70;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 71; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 72, such as 21B2, may contain a second binding domain that binds to CD79B.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 68;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 69;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 70;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 71; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 72, such as 21B2, may contain a second binding domain that binds to EDAR.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 68;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 69;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 70;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 71; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 72, such as 21B2, may contain a second binding domain that binds to GFRA1.

In some cases, an anti-CD3 antibody containing a first binding domain containing

- 164 040364 at least one, two, three, four, five or six hypervariable regions (HVR) selected from (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 67;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 68;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 69;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 70;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 71; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 72, such as 21B2, may contain a second binding domain that binds to MRP4.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 68;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 69;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 70;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 71; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 72, such as 21B2, may contain a second binding domain that binds to RET.

The second binding domain that binds to RET may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 614;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 615;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 616;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 617; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 618, such as those containing the anti-RET antibody 41205.v6.

In some instances, the second binding domain that binds to RET may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 629;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 630; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 68;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 69;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 70;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 71; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 72, such as 21B2, may contain a second binding domain that binds to Steap1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 68;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 69;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 70;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 71; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 72, such as 21B2, may contain a second binding domain that binds to TenB2.

Alternatively, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 74;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 75;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 76;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 77; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 78, such as 125A1, may contain a second binding domain that binds to CD20.

- 165 040364

The second binding domain that binds to CD20 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 158;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 159;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 160;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 161; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 162, such as those containing the anti-CD20 antibody 2H7.v16 (described in US Pat. No. 7,799,900).

In some instances, the second binding domain that binds to CD20 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 266;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 267; or (c) a VH domain according to (a) and a VL domain according to (b), for example, such that contains the anti-CD20 antibody 2H7.v16 (described in US patent No. 7799900).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 74;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 75;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 76;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 77; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 78, such as 125A1, may contain a second binding domain that binds to FcRH5.

The second binding domain that binds to FcRH5 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 164;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 165;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 166;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 168, such as those containing the anti-FcRH5 antibody 1G7.

In some instances, the second binding domain that binds to FcRH5 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 268;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 269; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 74;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 75;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 76;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 77; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 78, such as 125A1, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 170;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 171;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 172;

- 166 040364 (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 173; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 174, such as those containing the hu4D5 anti-HER2 antibody.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 270;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 271; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 74;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 75;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 76;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 77; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 78, such as 125A1, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 582;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 583;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 584;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 585; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 586, such as those containing the anti-HER2 antibody 2C4.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 593;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 594; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 74;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 75;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 76;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 77; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 78, such as 125A1, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 588;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 589;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 590;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 591; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 592, such as those containing the anti-HER2 antibody 7C2.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 595;

- 167 040364 (b) a VL domain containing an amino acid sequence having at least 90% sequence identity (for example, at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or the sequence of SEQ ID NO: 596; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 74;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 75;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 76;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 77; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 78, such as 125A1, may contain a second binding domain that binds to LYPD1.

The second binding domain that binds to LYPD1 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 176;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 177;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 178;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 179; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 180, such as those containing the anti-LYPD1 antibody YWO.49.H6.

In some instances, the second binding domain that binds to LYPD1 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 272;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 273; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 74;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 75;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 76;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 77; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 78, such as 125A1, may contain a second binding domain that binds to LY6G6D.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 74;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 75;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 76;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 77; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 78, such as 125A1, may contain a second binding domain that binds to PMEL17.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 74;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 75;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 76;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 77; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 78, such as 125A1, may contain a second binding domain that binds to LY6E.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 74;

- 168 040364 (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 75;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 76;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 77; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 78, such as 125A1, may contain a second binding domain that binds to CD19.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 74;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 75;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 76;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 77; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 78, such as 125A1, may contain a second binding domain that binds to CD33.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 74;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 75;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 76;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 77; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 78, such as 125A1, may contain a second binding domain that binds to CD22.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 74;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 75;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 76;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 77; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 78, such as 125A1, may contain a second binding domain that binds to CD79A.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 74;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 75;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 76;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 77; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 78, such as 125A1, may contain a second binding domain that binds to CD79B.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 74;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 75;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 76;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 77; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 78, such as 125A1, may contain a second binding domain that binds to EDAR.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 74;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 75;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 76;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 77; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 78, such as 125A1, may contain a second binding domain that binds to GFRA1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73;

- 169 040364 (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 74;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 75;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 76;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 77; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 78, such as 125A1, may contain a second binding domain that binds to MRP4.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 74;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 75;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 76;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 77; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 78, such as 125A1, may contain a second binding domain that binds to RET.

The second binding domain that binds to RET may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 614;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 615;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 616;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 617; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 618, such as those containing the anti-RET antibody 41205.v6.

In some instances, the second binding domain that binds to RET may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 629;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 630; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 74;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 75;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 76;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 77; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 78, such as 125A1, may contain a second binding domain that binds to Steap1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 74;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 75;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 76;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 77; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 78, such as 125A1, may contain a second binding domain that binds to TenB2.

Alternatively, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 80;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 81;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 82;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 83; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 84, such as 72H6, may contain a second binding domain that binds to CD20.

The second binding domain that binds to CD20 may, for example, contain at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from

- 170 040364 (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 157;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 158;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 159;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 160;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 161; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 162, such as those containing the anti-CD20 antibody 2H7.v16 (described in US Pat. No. 7,799,900).

In some instances, the second binding domain that binds to CD20 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 266;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 267; or (c) a VH domain according to (a) and a VL domain according to (b), for example, such that contains the anti-CD20 antibody 2H7.v16 (described in US patent No. 7799900).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 80;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 81;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 82;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 83; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 84, such as 72H6, may contain a second binding domain that binds to FcRH5.

The second binding domain that binds to FcRH5 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 164;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 165;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 166;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 168, such as those containing the anti-FcRH5 antibody 1G7.

In some instances, the second binding domain that binds to FcRH5 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 268;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 269; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 80;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 81;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 82;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 83; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 84, such as 72H6, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 170;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 171;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 172;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 173; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 174,

- 171 040364 for example, those containing aHTu-HER2 antibody hu4D5.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 270;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 271; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 80;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 81;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 82;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 83; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 84, such as 72H6, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 582;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 583;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 584;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 585; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 586, such as those containing the anti-HER2 antibody 2C4.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 593;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 594; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 80;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 81;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 82;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 83; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 84, such as 72H6, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 588;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 589;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 590;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 591; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 592, such as those containing the anti-HER2 antibody 7C2.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 595;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99%

- 172 040364 sequence identity) c, or the sequence of SEQ ID NO: 596; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 80;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 81;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 82;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 83; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 84, such as 72H6, may contain a second binding domain that binds to LYPD1.

The second binding domain that binds to LYPD1 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 176;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 177;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 178;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 180, such as those containing the anti-LYPD1 antibody YWO.49.H6.

In some instances, the second binding domain that binds to LYPD1 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 272;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 273; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 80;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 81;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 82;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 83; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 84, such as 72H6, may contain a second binding domain that binds to LY6G6D.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 80;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 81;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 82;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 83; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 84, such as 72H6, may contain a second binding domain that binds to PMEL17.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 80;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 81;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 82;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 83; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 84, such as 72H6, may contain a second binding domain that binds to LY6E.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 80;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 81;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 82;

- 173 040364 (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 83; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 84, such as 72H6, may contain a second binding domain that binds to CD19.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 80;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 81;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 82;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 83; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 84, such as 72H6, may contain a second binding domain that binds to CD33.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 80;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 81;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 82;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 83; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 84, such as 72H6, may contain a second binding domain that binds to CD22.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 80;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 81;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 82;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 83; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 84, such as 72H6, may contain a second binding domain that binds to CD79A.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 80;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 81;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 82;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 83; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 84, such as 72H6, may contain a second binding domain that binds to CD79B.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 80;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 81;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 82;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 83; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 84, such as 72H6, may contain a second binding domain that binds to EDAR.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 80;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 81;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 82;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 83; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 84, such as 72H6, may contain a second binding domain that binds to GFRA1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 80;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 81;

- 174 040364 (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 82;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 83; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 84, such as 72H6, may contain a second binding domain that binds to MRP4.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 80;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 81;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 82;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 83; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 84, such as 72H6, may contain a second binding domain that binds to RET.

The second binding domain that binds to RET may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 614;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 615;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 616;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 617; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 618, such as those containing the anti-RET antibody 41205.v6.

In some instances, the second binding domain that binds to RET may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 629;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 630; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 80;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 81;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 82;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 83; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 84, such as 72H6, may contain a second binding domain that binds to Steap1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 80;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 81;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 82;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 83; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 84, such as 72H6, may contain a second binding domain that binds to TenB2.

Alternatively, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 86;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 87;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 88;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 89; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 90, such as 19B1, may contain a second binding domain that binds to CD20.

The second binding domain that binds to CD20 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 158;

- 175 040364 (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 159;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 160;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 161; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 162, such as those containing the anti-CD20 antibody 2H7.v16 (described in US Pat. No. 7,799,900).

In some instances, the second binding domain that binds to CD20 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 266;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 267; or (c) a VH domain according to (a) and a VL domain according to (b), for example, such that contains the anti-CD20 antibody 2H7.v16 (described in US patent No. 7799900).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 86;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 87;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 88;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 89; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 90, such as 19B1, may contain a second binding domain that binds to FcRH5.

The second binding domain that binds to FcRH5 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 164;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 165;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 166;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 168, such as those containing the anti-FcRH5 antibody 1G7.

In some instances, the second binding domain that binds to FcRH5 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 268;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 269; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 86;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 87;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 88;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 89; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 90, such as 19B1, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 170;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 171;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 172;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 173; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 174, such as those containing the hu4D5 anti-HER2 antibody.

In some cases, the second binding domain that binds to HER2 may, for example,

- 176 040364 contain (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (for example, at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) with , or the sequence of SEQ ID NO: 270;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 271; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 86;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 87;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 88;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 89; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 90, such as 19B1, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 582;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 583;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 584;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 585; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 586, such as those containing the anti-HER2 antibody 2C4.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 593;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 594; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 86;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 87;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 88;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 89; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 90, such as 19B1, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 588;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 589;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 590;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 591; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 592, such as those containing the anti-HER2 antibody 7C2.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 595;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 596; or (c) a VH domain according to (a) and a VL domain according to (b).

- 177 040364

In some cases, an aHTu-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 86;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 87;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 88;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 89; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 90, such as 19B1, may contain a second binding domain that binds to LYPD1.

The second binding domain that binds to LYPD1 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 176;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 177;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 178;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 180, such as those containing the anti-LYPD1 antibody YWO.49.H6.

In some instances, the second binding domain that binds to LYPD1 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 272;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 273; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 86;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 87;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 88;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 89; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 90, such as 19B1, may contain a second binding domain that binds to LY6G6D.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 86;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 87;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 88;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 89; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 90, such as 19B1, may contain a second binding domain that binds to PMEL17.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 86;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 87;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 88;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 89; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 90, such as 19B1, may contain a second binding domain that binds to LY6E.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 86;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 87;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 88;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 89; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 90,

- 178 040364 such as 19B1 may contain a second binding domain that binds to CD19.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 86;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 87;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 88;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 89; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 90, such as 19B1, may contain a second binding domain that binds to CD33.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 86;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 87;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 88;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 89; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 90, such as 19B1, may contain a second binding domain that binds to CD22.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 86;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 87;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 88;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 89; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 90, such as 19B1, may contain a second binding domain that binds to CD79A.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 86;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 87;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 88;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 89; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 90, such as 19B1, may contain a second binding domain that binds to CD79B.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 86;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 87;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 88;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 89; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 90, such as 19B1, may contain a second binding domain that binds to EDAR.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 86;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 87;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 88;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 89; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 90, such as 19B1, may contain a second binding domain that binds to GFRA1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 86;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 87;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 88;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 89; And

- 179 040364 (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 90, such as 19B1, may contain a second binding domain that binds to MRP4.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 86;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 87;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 88;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 89; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 90, such as 19B1, may contain a second binding domain that binds to RET.

The second binding domain that binds to RET may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 614;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 615;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 616;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 617; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 618, such as those containing the anti-RET antibody 41205.v6.

In some instances, the second binding domain that binds to RET may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 629;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 630; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 86;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 87;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 88;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 89; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 90, such as 19B1, may contain a second binding domain that binds to Steap1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 86;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 87;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 88;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 89; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 90, such as 19B1, may contain a second binding domain that binds to TenB2.

Alternatively, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 91;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 92;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 93;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 94;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 95; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 96, such as 71H7, may contain a second binding domain that binds to CD20.

The second binding domain that binds to CD20 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 158;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 159;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 160;

- 180 040364 (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 161; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 162, such as those containing the anti-CD20 antibody 2H7.v16 (described in US Pat. No. 7,799,900).

In some instances, the second binding domain that binds to CD20 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 266;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 267; or (c) a VH domain according to (a) and a VL domain according to (b), for example, such that contains the anti-CD20 antibody 2H7.v16 (described in US patent No. 7799900).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 91;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 92;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 93;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 94;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 95; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 96, such as 71H7, may contain a second binding domain that binds to FcRH5.

The second binding domain that binds to FcRH5 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 164;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 165;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 166;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 168, such as those containing the anti-FcRH5 antibody 1G7.

In some instances, the second binding domain that binds to FcRH5 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 268;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 269; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 91;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 92;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 93;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 94;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 95; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 96, such as 71H7, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 170;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 171;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 172;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 173; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 174, such as those containing the hu4D5 anti-HER2 antibody.

In some cases, the second binding domain that binds to HER2 may, for example, contain (a) a VH domain containing an amino acid sequence having at least 90%

- 181 040364 sequence identity (eg, at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or the sequence of SEQ ID NO: 270;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 271; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 91;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 92;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 93;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 94;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 95; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 96, such as 71H7, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 582;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 583;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 584;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 585; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 586, such as those containing the anti-HER2 antibody 2C4.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 593;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 594; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 91;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 92;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 93;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 94;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 95; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 96, such as 71H7, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 588;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 589;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 590;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 591; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 592, such as those containing the anti-HER2 antibody 7C2.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 595;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 596; or (c) a VH domain according to (a) and a VL domain according to (b).

In some instances, an anti-CD3 antibody comprising a first binding domain containing at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from

- 182 040364 (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 91;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 92;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 93;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 94;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 95; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 96, such as 71H7, may contain a second binding domain that binds to LYPD1.

The second binding domain that binds to LYPD1 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 176;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 177;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 178;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 180, such as those containing the anti-LYPD1 antibody YWO.49.H6.

In some instances, the second binding domain that binds to LYPD1 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 272;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 273; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 91;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 92;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 93;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 94;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 95; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 96, such as 71H7, may contain a second binding domain that binds to LY6G6D.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 91;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 92;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 93;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 94;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 95; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 96, such as 71H7, may contain a second binding domain that binds to PMEL17.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 91;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 92;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 93;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 94;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 95; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 96, such as 71H7, may contain a second binding domain that binds to LY6E.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 91;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 92;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 93;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 94;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 95; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 96, such as 71H7, may contain a second binding domain that binds to CD19.

In some cases, an anti-CD3 antibody containing a first binding domain containing

- 183 040364 at least one, two, three, four, five or six hypervariable regions (HVR) selected from (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 91;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 92;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 93;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 94;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 95; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 96, such as 71H7, may contain a second binding domain that binds to CD33.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 91;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 92;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 93;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 94;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 95; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 96, such as 71H7, may contain a second binding domain that binds to CD22.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 91;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 92;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 93;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 94;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 95; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 96, such as 71H7, may contain a second binding domain that binds to CD79A.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 91;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 92;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 93;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 94;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 95; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 96, such as 71H7, may contain a second binding domain that binds to CD79B.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 91;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 92;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 93;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 94;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 95; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 96, such as 71H7, may contain a second binding domain that binds to EDAR.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 91;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 92;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 93;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 94;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 95; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 96, such as 71H7, may contain a second binding domain that binds to GFRA1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 91;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 92;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 93;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 94;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 95; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 96, such as 71H7, may contain a second binding domain that binds to MRP4.

- 184 040364

In some cases, an aHTu-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 91;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 92;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 93;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 94;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 95; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 96, such as 71H7, may contain a second binding domain that binds to RET.

The second binding domain that binds to RET may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 614;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 615;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 616;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 617; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 618, such as those containing the anti-RET antibody 41205.v6.

In some instances, the second binding domain that binds to RET may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 629;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 630; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 91;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 92;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 93;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 94;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 95; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 96, such as 71H7, may contain a second binding domain that binds to Steap1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 91;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 92;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 93;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 94;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 95; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 96, such as 71H7, may contain a second binding domain that binds to TenB2.

Alternatively, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 97;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 98;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 99;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 100;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 101; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 102, such as 14C7, may contain a second binding domain that binds to CD20.

The second binding domain that binds to CD20 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 158;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 159;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 160;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 161; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 162,

- 185 040364 for example, those containing aHTu-CD20 antibody 2H7.v16 (described in US patent No. 7799900).

In some instances, the second binding domain that binds to CD20 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 266;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 267; or (c) a VH domain according to (a) and a VL domain according to (b), for example, such that contains the anti-CD20 antibody 2H7.v16 (described in US patent No. 7799900).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 97;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 98;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 99;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 100;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 101; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 102, such as 14C7, may contain a second binding domain that binds to FcRH5.

The second binding domain that binds to FcRH5 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 164;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 165;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 166;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 168, such as those containing the anti-FcRH5 antibody 1G7.

In some instances, the second binding domain that binds to FcRH5 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 268;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 269; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 97;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 98;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 99;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 100;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 101; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 102, such as 14C7, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 170;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 171;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 172;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 173; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 174, such as those containing the hu4D5 anti-HER2 antibody.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 270;

- 186 040364 (b) a VL domain containing an amino acid sequence having at least 90% sequence identity (for example, at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) with, or the sequence of SEQ ID NO: 271; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 97;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 98;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 99;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 100;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 101; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 102, such as 14C7, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 582;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 583;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 584;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 585; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 586, such as those containing the anti-HER2 antibody 2C4.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 593;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 594; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 97;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 98;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 99;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 100;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 101; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 102, such as 14C7, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 588;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 589;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 590;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 591; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 592, such as those containing the anti-HER2 antibody 7C2.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 595;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 596; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 97;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 98;

- 187 040364 (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 99;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 100;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 101; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 102, such as 14C7, may contain a second binding domain that binds to LYPD1.

The second binding domain that binds to LYPD1 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 176;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 177;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 178;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 180, such as those containing the anti-LYPD1 antibody YWO.49.H6.

In some instances, the second binding domain that binds to LYPD1 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 272;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 273; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 97;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 98;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 99;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 100;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 101; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 102, such as 14C7, may contain a second binding domain that binds to LY6G6D.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 97;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 98;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 99;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 100;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 101; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 102, such as 14C7, may contain a second binding domain that binds to PMEL17.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 97;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 98;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 99;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 100;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 101; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 102, such as 14C7, may contain a second binding domain that binds to LY6E.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 97;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 98;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 99;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 100;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 101; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 102, such as 14C7, may contain a second binding domain that binds to CD19.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 97;

- 188 040364 (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 98;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 99;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 100;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 101; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 102, such as 14C7, may contain a second binding domain that binds to CD33.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 97;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 98;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 99;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 100;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 101; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 102, such as 14C7, may contain a second binding domain that binds to CD22.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 97;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 98;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 99;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 100;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 101; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 102, such as 14C7, may contain a second binding domain that binds to CD79A.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 97;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 98;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 99;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 100;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 101; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 102, such as 14C7, may contain a second binding domain that binds to CD79B.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 97;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 98;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 99;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 100;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 101; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 102, such as 14C7, may contain a second binding domain that binds to EDAR.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 97;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 98;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 99;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 100;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 101; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 102, such as 14C7, may contain a second binding domain that binds to GFRA1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 97;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 98;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 99;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 100;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 101; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 102, such as 14C7, may contain a second binding domain that binds to MRP4.

In some instances, an anti-CD3 antibody comprising a first binding domain containing at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from

- 189 040364 (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 97;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 98;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 99;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 100;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 101; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 102, such as 14C7, may contain a second binding domain that binds to RET.

The second binding domain that binds to RET may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 614;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 615;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 616;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 617; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 618, such as those containing the anti-RET antibody 41205.v6.

In some instances, the second binding domain that binds to RET may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 629;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 630; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 97;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 98;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 99;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 100;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 101; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 102, such as 14C7, may contain a second binding domain that binds to Steap1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 97;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 98;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 99;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 100;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 101; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 102, such as 14C7, may contain a second binding domain that binds to TenB2.

Alternatively, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 104;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 105;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 106;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 107; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 108, such as 127B3, may contain a second binding domain that binds to CD20.

The second binding domain that binds to CD20 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 158;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 159;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 160;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 161; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 162, such as those containing the anti-CD20 antibody 2H7.v16 (described in US Pat. No. 7,799,900).

- 190 040364

In some instances, the second binding domain that binds to CD20 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 266;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 267; or (c) a VH domain according to (a) and a VL domain according to (b), for example, such that contains the anti-CD20 antibody 2H7.v16 (described in US patent No. 7799900).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 104;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 105;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 106;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 107; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 108, such as 127B3, may contain a second binding domain that binds to FcRH5.

The second binding domain that binds to FcRH5 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 164;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 165;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 166;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 168, such as those containing the anti-FcRH5 antibody 1G7.

In some instances, the second binding domain that binds to FcRH5 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 268;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 269; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 104;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 105;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 106;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 107; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 108, such as 127B3, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 170;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 171;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 172;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 173; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 174, such as those containing the hu4D5 anti-HER2 antibody.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 270;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99%

- 191 040364 sequence identity) c, or the sequence of SEQ ID NO: 271; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 104;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 105;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 106;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 107; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 108, such as 127B3, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 582;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 583;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 584;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 585; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 586, such as those containing the anti-HER2 antibody 2C4.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 593;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 594; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 104;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 105;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 106;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 107; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 108, such as 127B3, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 588;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 589;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 590;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 591; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 592, such as those containing the anti-HER2 antibody 7C2.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 595;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 596; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 104;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 105;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 106;

- 192 040364 (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 107; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 108, such as 127B3, may contain a second binding domain that binds to LYPD1.

The second binding domain that binds to LYPD1 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 176;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 177;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 178;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 180, such as those containing the anti-LYPD1 antibody YWO.49.H6.

In some instances, the second binding domain that binds to LYPD1 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 272;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 273; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 104;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 105;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 106;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 107; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 108, such as 127B3, may contain a second binding domain that binds to LY6G6D.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 104;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 105;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 106;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 107; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 108, such as 127B3, may contain a second binding domain that binds to PMEL17.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 104;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 105;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 106;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 107; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 108, such as 127B3, may contain a second binding domain that binds to LY6E.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 104;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 105;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 106;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 107; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 108, such as 127B3, may contain a second binding domain that binds to CD19.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 104;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 105;

- 193 040364 (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 106;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 107; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 108, such as 127B3, may contain a second binding domain that binds to CD33.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 104;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 105;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 106;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 107; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 108, such as 127B3, may contain a second binding domain that binds to CD22.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 104;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 105;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 106;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 107; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 108, such as 127B3, may contain a second binding domain that binds to CD79A.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 104;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 105;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 106;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 107; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 108, such as 127B3, may contain a second binding domain that binds to CD79B.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 104;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 105;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 106;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 107; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 108, such as 127B3, may contain a second binding domain that binds to EDAR.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 104;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 105;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 106;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 107; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 108, such as 127B3, may contain a second binding domain that binds to GFRA1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 104;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 105;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 106;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 107; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 108, such as 127B3, may contain a second binding domain that binds to MRP4.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 104;

- 194 040364 (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 105;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 106;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 107; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 108, such as 127B3, may contain a second binding domain that binds to RET.

The second binding domain that binds to RET may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 614;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 615;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 616;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 617; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 618, such as those containing the anti-RET antibody 41205.v6.

In some instances, the second binding domain that binds to RET may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 629;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 630; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 104;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 105;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 106;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 107; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 108, such as 127B3, may contain a second binding domain that binds to Steap1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 104;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 105;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 106;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 107; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 108, such as 127B3, may contain a second binding domain that binds to TenB2.

Alternatively, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 110;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 111;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 112;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 113; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 114, such as 18F12, may contain a second binding domain that binds to CD20.

The second binding domain that binds to CD20 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 158;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 159;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 160;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 161; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 162, such as those containing the anti-CD20 antibody 2H7.v16 (described in US Pat. No. 7,799,900).

In some cases, the second binding domain that binds to CD20 may, for example, contain

- 195 040364 (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (for example, at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) with, or the sequence of SEQ ID NO: 266;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 267; or (c) a VH domain according to (a) and a VL domain according to (b), for example, such that contains the anti-CD20 antibody 2H7.v16 (described in US patent No. 7799900).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 110;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 111;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 112;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 113; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 114, such as 18F12, may contain a second binding domain that binds to FcRH5. The second binding domain that binds to FcRH5 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 164;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 165;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 166;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 168, such as those containing the anti-FcRH5 antibody 1G7.

In some instances, the second binding domain that binds to FcRH5 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 268;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 269; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 110;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 111;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 112;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 113; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 114, such as 18F12, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 170;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 171;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 172;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 173; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 174, such as those containing the hu4D5 anti-HER2 antibody.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 270;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 271; or (c) a VH domain according to (a) and a VL domain according to (b).

- 196 040364

In some cases, an aHTu-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 110;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 111;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 112;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 113; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 114, such as 18F12, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 582;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 583;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 584;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 585; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 586, such as those containing the anti-HER2 antibody 2C4.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 593;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 594; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 110;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 111;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 112;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 113; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 114, such as 18F12, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 588;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 589;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 590;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 591; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 592, such as those containing the anti-HER2 antibody 7C2.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 595;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 596; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 110;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 111;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 112;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 113; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 114,

- 197 040364 such as 18F12 may contain a second binding domain that binds to LYPD1.

The second binding domain that binds to LYPD1 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 176;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 177;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 178;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 180, such as those containing the anti-LYPD1 antibody YWO.49.H6.

In some instances, the second binding domain that binds to LYPD1 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 272;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 273; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 110;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 111;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 112;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 113; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 114, such as 18F12, may contain a second binding domain that binds to LY6G6D.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 110;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 111;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 112;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 113; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 114, such as 18F12, may contain a second binding domain that binds to PMEL17.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 110;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 111;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 112;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 113; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 114, such as 18F12, may contain a second binding domain that binds to LY6E.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 110;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 111;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 112;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 113; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 114, such as 18F12, may contain a second binding domain that binds to CD19.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 110;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 111;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 112;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 113; And

- 198 040364 (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 114, such as 18F12, may contain a second binding domain that binds to CD33.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 110;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 111;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 112;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 113; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 114, such as 18F12, may contain a second binding domain that binds to CD22.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 110;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 111;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 112;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 113; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 114, such as 18F12, may contain a second binding domain that binds to CD79A.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 110;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 111;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 112;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 113; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 114, such as 18F12, may contain a second binding domain that binds to CD79B.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 110;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 111;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 112;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 113; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 114, such as 18F12, may contain a second binding domain that binds to EDAR.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 110;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 111;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 112;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 113; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 114, such as 18F12, may contain a second binding domain that binds to GFRA1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 110;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 111;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 112;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 113; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 114, such as 18F12, may contain a second binding domain that binds to MRP4.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 110;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 111;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 112;

- 199 040364 (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 113; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 114, such as 18F12, may contain a second binding domain that binds to RET.

The second binding domain that binds to RET may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 614;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 615;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 616;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 617; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 618, such as those containing the anti-RET antibody 41205.v6.

In some instances, the second binding domain that binds to RET may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 629;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 630; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 110;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 111;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 112;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 113; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 114, such as 18F12, may contain a second binding domain that binds to Steap1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 110;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 111;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 112;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 113; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 114, such as 18F12, may contain a second binding domain that binds to TenB2.

Alternatively, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 116;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 117;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 118;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 119; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 120, such as 27H5-1, may contain a second binding domain that binds to CD20.

The second binding domain that binds to CD20 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 158;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 159;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 160;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 161; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 162, such as those containing the anti-CD20 antibody 2H7.v16 (described in US Pat. No. 7,799,900).

In some instances, the second binding domain that binds to CD20 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99%

- 200 040364 sequence identity) c, or the sequence of SEQ ID NO: 266;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 267; or (c) a VH domain according to (a) and a VL domain according to (b), for example, such that contains the anti-CD20 antibody 2H7.v16 (described in US patent No. 7799900).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 116;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 117;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 118;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 119; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 120, such as 27H5-1, may contain a second binding domain that binds to FcRH5.

The second binding domain that binds to FcRH5 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 164;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 165;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 166;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 168, such as those containing the anti-FcRH5 antibody 1G7.

In some instances, the second binding domain that binds to FcRH5 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 268;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 269; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 116;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 117;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 118;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 119; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 120, such as 27H5-1, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 170;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 171;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 172;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 173; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 174, such as those containing the hu4D5 anti-HER2 antibody.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 270;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 271; or (c) a VH domain according to (a) and a VL domain according to (b).

In some instances, an anti-CD3 antibody comprising a first binding domain containing at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from

- 201 040364 (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 115;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 116;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 117;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 118;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 119; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 120, such as 27H5-1, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 582;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 583;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 584;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 585; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 586, such as those containing the anti-HER2 antibody 2C4.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 593;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 594; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 116;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 117;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 118;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 119; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 120, such as 27H5-1, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 588;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 589;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 590;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 591; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 592, such as those containing the anti-HER2 antibody 7C2.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 595;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 596; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 116;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 117;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 118;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 119; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 120, such as 27H5-1, may contain a second binding domain that binds to LYPD1.

The second binding domain that binds to LYPD1 may, for example, contain at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 containing the amino acid sequence SEQ ID NO: 175;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 176;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 177;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 178;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 180, such as those containing the anti-LYPD1 antibody YWO.49.H6.

In some instances, the second binding domain that binds to LYPD1 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 272;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 273; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 116;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 117;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 118;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 119; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 120, such as 27H5-1, may contain a second binding domain that binds to LY6G6D.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 116;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 117;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 118;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 119; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 120, such as 27H5-1, may contain a second binding domain that binds to PMEL17.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 116;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 117;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 118;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 119; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 120, such as 27H5-1, may contain a second binding domain that binds to LY6E.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 116;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 117;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 118;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 119; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 120, such as 27H5-1, may contain a second binding domain that binds to CD19.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 116;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 117;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 118;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 119; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 120, such as 27H5-1, may contain a second binding domain that binds to CD33.

- 203 040364

In some cases, an aHTu-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 116;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 117;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 118;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 119; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 120, such as 27H5-1, may contain a second binding domain that binds to CD22.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 116;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 117;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 118;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 119; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 120, such as 27H5-1, may contain a second binding domain that binds to CD79A.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 116;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 117;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 118;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 119; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 120, such as 27H5-1, may contain a second binding domain that binds to CD79B.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 116;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 117;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 118;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 119; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 120, such as 27H5-1, may contain a second binding domain that binds to EDAR.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 116;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 117;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 118;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 119; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 120, such as 27H5-1, may contain a second binding domain that binds to GFRA1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 116;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 117;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 118;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 119; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 120, such as 27H5-1, may contain a second binding domain that binds to MRP4.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 116;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 117;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 118;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 119; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 120,

- 204 040364 such as 27H5-1 may contain a second binding domain that binds to RET.

The second binding domain that binds to RET may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 614;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 615;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 616;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 617; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 618, such as those containing the anti-RET antibody 41205.v6.

In some instances, the second binding domain that binds to RET may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 629;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 630; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 116;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 117;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 118;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 119; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 120, such as 27H5-1, may contain a second binding domain that binds to Steap1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 116;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 117;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 118;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 119; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 120, such as 27H5-1, may contain a second binding domain that binds to TenB2.

Alternatively, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 122;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 123;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 124;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 125; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 126, such as 39B7, may contain a second binding domain that binds to CD20.

The second binding domain that binds to CD20 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 158;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 159;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 160;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 161; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 162, such as those containing the anti-CD20 antibody 2H7.v16 (described in US Pat. No. 7,799,900).

In some instances, the second binding domain that binds to CD20 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 266;

(b) a VL domain containing an amino acid sequence having at least 90%

- 205 040364 sequence identity (eg, at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or the sequence of SEQ ID NO: 267; or (c) a VH domain according to (a) and a VL domain according to (b), for example, such that contains the anti-CD20 antibody 2H7.v16 (described in US patent No. 7799900).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 122;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 123;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 124;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 125; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 126, such as 39B7, may contain a second binding domain that binds to FcRH5.

The second binding domain that binds to FcRH5 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 164;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 165;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 166;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 168, such as those containing the anti-FcRH5 antibody 1G7.

In some instances, the second binding domain that binds to FcRH5 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 268;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 269; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 122;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 123;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 124;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 125; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 126, such as 39B7, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 170;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 171;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 172;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 173; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 174, such as those containing the hu4D5 anti-HER2 antibody.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 270;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 271; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 122;

- 206 040364 (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 123;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 124;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 125; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 126, such as 39B7, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 582;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 583;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 584;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 585; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 586, such as those containing the anti-HER2 antibody 2C4.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 593;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 594; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 122;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 123;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 124;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 125; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 126, such as 39B7, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 588;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 589;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 590;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 591; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 592, such as those containing the anti-HER2 antibody 7C2.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 595;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 596; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 122;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 123;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 124;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 125; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 126, such as 39B7, may contain a second binding domain that binds to LYPD1.

The second binding domain that binds to LYPD1 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175;

- 207 040364 (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 176;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 177;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 178;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 180, such as those containing the anti-LYPD1 antibody YWO.49.H6.

In some instances, the second binding domain that binds to LYPD1 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 272;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 273; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 122;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 123;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 124;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 125; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 126, such as 39B7, may contain a second binding domain that binds to LY6G6D.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 122;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 123;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 124;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 125; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 126, such as 39B7, may contain a second binding domain that binds to PMEL17.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 122;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 123;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 124;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 125; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 126, such as 39B7, may contain a second binding domain that binds to LY6E.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 122;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 123;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 124;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 125; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 126, such as 39B7, may contain a second binding domain that binds to CD19.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 122;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 123;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 124;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 125; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 126, such as 39B7, may contain a second binding domain that binds to CD33.

In some instances, an anti-CD3 antibody comprising a first binding domain containing at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from

- 208 040364 (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 121;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 122;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 123;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 124;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 125; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 126, such as 39B7, may contain a second binding domain that binds to CD22.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 122;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 123;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 124;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 125; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 126, such as 39B7, may contain a second binding domain that binds to CD79A.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 122;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 123;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 124;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 125; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 126, such as 39B7, may contain a second binding domain that binds to CD79B.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 122;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 123;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 124;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 125; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 126, such as 39B7, may contain a second binding domain that binds to EDAR.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 122;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 123;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 124;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 125; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 126, such as 39B7, may contain a second binding domain that binds to GFRA1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 122;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 123;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 124;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 125; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 126, such as 39B7, may contain a second binding domain that binds to MRP4.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 122;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 123;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 124;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 125; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 126, such as 39B7, may contain a second binding domain that binds to RET.

The second binding domain that binds to the RET may, for example, contain at least

- 209 040364 at least one, two, three, four, five or six hypervariable regions (HVR) selected from (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 613;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 614;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 615;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 616;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 617; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 618, such as those containing the anti-RET antibody 41205.v6.

In some instances, the second binding domain that binds to RET may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 629;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 630; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 122;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 123;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 124;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 125; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 126, such as 39B7, may contain a second binding domain that binds to Steap1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 122;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 123;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 124;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 125; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 126, such as 39B7, may contain a second binding domain that binds to TenB2.

Alternatively, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 128;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 129;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 130;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 131; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 132, such as 40D2, may contain a second binding domain that binds to CD20.

The second binding domain that binds to CD20 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 158;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 159;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 160;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 161; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 162, such as those containing the anti-CD20 antibody 2H7.v16 (described in US Pat. No. 7,799,900).

In some instances, the second binding domain that binds to CD20 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 266;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 267; or

- 210 040364 (c) a VH domain according to (a) and a VL domain according to (b), for example, those containing aHTu-CD20 antibody 2H7.v16 (described in US patent No. 7799900).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 128;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 129;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 130;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 131; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 132, such as 40D2, may contain a second binding domain that binds to FcRH5.

The second binding domain that binds to FcRH5 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 164;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 165;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 166;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 168, such as those containing the anti-FcRH5 antibody 1G7.

In some instances, the second binding domain that binds to FcRH5 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 268;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 269; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 128;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 129;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 130;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 131; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 132, such as 40D2, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 170;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 171;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 172;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 173; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 174, such as those containing the hu4D5 anti-HER2 antibody.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 270;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 271; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 128;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 129;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 130;

- 211 040364 (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 131; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 132, such as 40D2, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 582;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 583;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 584;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 585; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 586, such as those containing the anti-HER2 antibody 2C4.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 593;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 594; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 128;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 129;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 130;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 131; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 132, such as 40D2, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 588;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 589;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 590;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 591; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 592, such as those containing the anti-HER2 antibody 7C2.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 595;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 596; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 128;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 129;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 130;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 131; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 132, such as 40D2, may contain a second binding domain that binds to LYPD1.

The second binding domain that binds to LYPD1 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 176;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 177;

- 212 040364 (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 178;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 180, such as those containing the anti-LYPD1 antibody YWO.49.H6.

In some instances, the second binding domain that binds to LYPD1 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 272;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 273; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 128;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 129;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 130;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 131; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 132, such as 40D2, may contain a second binding domain that binds to LY6G6D.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 128;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 129;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 130;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 131; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 132, such as 40D2, may contain a second binding domain that binds to PMEL17.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 128;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 129;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 130;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 131; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 132, such as 40D2, may contain a second binding domain that binds to LY6E.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 128;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 129;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 130;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 131; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 132, such as 40D2, may contain a second binding domain that binds to CD19.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 128;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 129;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 130;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 131; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 132, such as 40D2, may contain a second binding domain that binds to CD33.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 128;

- 213 040364 (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 129;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 130;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 131; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 132, such as 40D2, may contain a second binding domain that binds to CD22.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 128;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 129;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 130;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 131; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 132, such as 40D2, may contain a second binding domain that binds to CD79A.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 128;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 129;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 130;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 131; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 132, such as 40D2, may contain a second binding domain that binds to CD79B.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 128;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 129;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 130;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 131; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 132, such as 40D2, may contain a second binding domain that binds to EDAR.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 128;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 129;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 130;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 131; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 132, such as 40D2, may contain a second binding domain that binds to GFRA1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 128;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 129;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 130;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 131; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 132, such as 40D2, may contain a second binding domain that binds to MRP4.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 128;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 129;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 130;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 131; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 132, such as 40D2, may contain a second binding domain that binds to RET.

The second binding domain that binds to RET may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613;

- 214 040364 (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 614;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 615;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 616;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 617; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 618, such as those containing the anti-RET antibody 41205.v6.

In some instances, the second binding domain that binds to RET may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 629;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 630; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 128;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 129;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 130;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 131; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 132, such as 40D2, may contain a second binding domain that binds to Steap1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 128;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 129;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 130;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 131; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 132, such as 40D2, may contain a second binding domain that binds to TenB2.

Alternatively, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 631;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 632;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 633;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 634;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 635; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 636, such as 43H8, may contain a second binding domain that binds to CD20.

The second binding domain that binds to CD20 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 158;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 159;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 160;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 161; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 162, such as those containing the anti-CD20 antibody 2H7.v16 (described in US Pat. No. 7,799,900).

In some instances, the second binding domain that binds to CD20 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 266;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 267; or (c) a VH domain according to (a) and a VL domain according to (b), for example, such that contains the anti-CD20 antibody 2H7.v16 (described in US patent No. 7799900).

- 215 040364

In some cases, an aHTu-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 631;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 632;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 633;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 634;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 635; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 636, such as 43H8, may contain a second binding domain that binds to FcRH5.

The second binding domain that binds to FcRH5 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 164;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 165;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 166;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 168, such as those containing the anti-FcRH5 antibody 1G7.

In some instances, the second binding domain that binds to FcRH5 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 268;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 269; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 631;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 632;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 633;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 634;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 635; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 636, such as 43H8, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 170;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 171;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 172;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 173; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 174, such as those containing the hu4D5 anti-HER2 antibody.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 270;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 271; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 631;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 632;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 633;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 634;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 635; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 636,

- 216 040364 such as 43H8 may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 582;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 583;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 584;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 585; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 586, such as those containing the anti-HER2 antibody 2C4.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 593;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 594; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 631;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 632;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 633;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 634;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 635; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 636, such as 43H8, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 588;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 589;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 590;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 591; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 592, such as those containing the anti-HER2 antibody 7C2.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 595;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 596; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 631;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 632;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 633;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 634;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 635; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 636, such as 43H8, may contain a second binding domain that binds to LYPD1.

The second binding domain that binds to LYPD1 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 176;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 177;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 178;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 179; And

- 217 040364 (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 180, such as those containing the anti-LYPD1 antibody YWO.49.H6.

In some instances, the second binding domain that binds to LYPD1 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 272;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 273; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 631;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 632;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 633;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 634;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 635; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 636, such as 43H8, may contain a second binding domain that binds to LY6G6D.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 631;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 632;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 633;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 634;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 635; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 636, such as 43H8, may contain a second binding domain that binds to PMEL17.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 631;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 632;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 633;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 634;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 635; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 636, such as 43H8, may contain a second binding domain that binds to LY6E.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 631;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 632;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 633;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 634;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 635; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 636, such as 43H8, may contain a second binding domain that binds to CD19.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 631;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 632;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 633;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 634;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 635; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 636, such as 43H8, may contain a second binding domain that binds to CD33.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 631;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 632;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 633;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 634;

- 218 040364 (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 635; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 636, such as 43H8, may contain a second binding domain that binds to CD22.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 631;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 632;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 633;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 634;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 635; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 636, such as 43H8, may contain a second binding domain that binds to CD79A.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 631;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 632;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 633;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 634;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 635; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 636, such as 43H8, may contain a second binding domain that binds to CD79B.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 631;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 632;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 633;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 634;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 635; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 636, such as 43H8, may contain a second binding domain that binds to EDAR.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 631;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 632;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 633;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 634;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 635; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 636, such as 43H8, may contain a second binding domain that binds to GFRA1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 631;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 632;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 633;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 634;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 635; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 636, such as 43H8, may contain a second binding domain that binds to MRP4.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 631;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 632;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 633;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 634;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 635; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 636, such as 43H8, may contain a second binding domain that binds to RET.

The second binding domain that binds to RET may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 614;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 615;

- 219 040364 (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 616;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 617; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 618, such as those containing the anti-RET antibody 41205.v6.

In some instances, the second binding domain that binds to RET may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 629;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 630; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 631;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 632;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 633;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 634;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 635; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 636, such as 43H8, may contain a second binding domain that binds to Steap1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 631;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 632;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 633;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 634;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 635; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 636, such as 43H8, may contain a second binding domain that binds to TenB2.

Alternatively, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 134;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 135;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 136;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 137; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 138, such as 79B7, may contain a second binding domain that binds to CD20.

The second binding domain that binds to CD20 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 158;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 159;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 160;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 161; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 162, such as those containing the anti-CD20 antibody 2H7.v16 (described in US Pat. No. 7,799,900).

In some instances, the second binding domain that binds to CD20 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 266;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 267; or (c) a VH domain according to (a) and a VL domain according to (b), for example, such that contains the anti-CD20 antibody 2H7.v16 (described in US patent No. 7799900).

In some instances, an anti-CD3 antibody comprising a first binding domain containing at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from

- 220 040364 (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 133;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 134;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 135;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 136;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 137; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 138, such as 79B7, may contain a second binding domain that binds to FcRH5.

The second binding domain that binds to FcRH5 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 164;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 165;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 166;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 168, such as those containing the anti-FcRH5 antibody 1G7.

In some instances, the second binding domain that binds to FcRH5 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 268;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 269; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 134;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 135;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 136;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 137; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 138, such as 79B7, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 170;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 171;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 172;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 173; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 174, such as those containing the hu4D5 anti-HER2 antibody.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 270;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 271; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 134;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 135;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 136;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 137; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 138, such as 79B7, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, contain at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 containing the amino acid sequence SEQ ID NO: 581;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 582;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 583;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 584;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 585; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 586, such as those containing the anti-HER2 antibody 2C4.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 593;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 594; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 134;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 135;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 136;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 137; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 138, such as 79B7, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 588;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 589;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 590;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 591; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 592, such as those containing the anti-HER2 antibody 7C2.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 595;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 596; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 134;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 135;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 136;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 137; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 138, such as 79B7, may contain a second binding domain that binds to LYPD1.

The second binding domain that binds to LYPD1 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 176;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 177;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 178;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 180, such as those containing the anti-LYPD1 antibody YWO.49.H6.

- 222 040364

In some instances, the second binding domain that binds to LYPD1 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 272;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 273; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 134;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 135;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 136;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 137; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 138, such as 79B7, may contain a second binding domain that binds to LY6G6D.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 134;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 135;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 136;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 137; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 138, such as 79B7, may contain a second binding domain that binds to PMEL17.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 134;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 135;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 136;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 137; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 138, such as 79B7, may contain a second binding domain that binds to LY6E.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 134;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 135;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 136;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 137; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 138, such as 79B7, may contain a second binding domain that binds to CD19.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 134;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 135;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 136;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 137; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 138, such as 79B7, may contain a second binding domain that binds to CD33.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 134;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 135;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 136;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 138,

- 223 040364 such as 79B7 may contain a second binding domain that binds to CD22.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 134;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 135;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 136;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 137; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 138, such as 79B7, may contain a second binding domain that binds to CD79A.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 134;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 135;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 136;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 137; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 138, such as 79B7, may contain a second binding domain that binds to CD79B.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 134;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 135;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 136;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 137; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 138, such as 79B7, may contain a second binding domain that binds to EDAR.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 134;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 135;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 136;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 137; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 138, such as 79B7, may contain a second binding domain that binds to GFRA1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 134;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 135;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 136;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 137; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 138, such as 79B7, may contain a second binding domain that binds to MRP4.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 134;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 135;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 136;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 137; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 138, such as 79B7, may contain a second binding domain that binds to RET.

The second binding domain that binds to RET may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 614;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 615;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 616;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 617; And

- 224 040364 (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 618, such as those containing anti-RET antibody 41205.v6.

In some instances, the second binding domain that binds to RET may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 629;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 630; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 134;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 135;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 136;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 137; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 138, such as 79B7, may contain a second binding domain that binds to Steap1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 134;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 135;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 136;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 137; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 138, such as 79B7, may contain a second binding domain that binds to TenB2.

Alternatively, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 140;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 141;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 142;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 143; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 144, such as 95A2, may contain a second binding domain that binds to CD20.

The second binding domain that binds to CD20 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 158;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 159;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 160;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 161; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 162, such as those containing the anti-CD20 antibody 2H7.v16 (described in US Pat. No. 7,799,900).

In some instances, the second binding domain that binds to CD20 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 266;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 267; or (c) a VH domain according to (a) and a VL domain according to (b), for example, such that contains the anti-CD20 antibody 2H7.v16 (described in US patent No. 7799900).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 140;

- 225 040364 (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 141;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 142;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 143; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 144, such as 95A2, may contain a second binding domain that binds to FcRH5.

The second binding domain that binds to FcRH5 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 164;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 165;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 166;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 168, such as those containing the anti-FcRH5 antibody 1G7. In some instances, the second binding domain that binds to FcRH5 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 268;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 269; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 140;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 141;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 142;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 143; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 144, such as 95A2, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 170;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 171;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 172;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 173; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 174, such as those containing the hu4D5 anti-HER2 antibody.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 270;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 271; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 140;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 141;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 142;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 143; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 144, such as 95A2, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 582;

- 226 040364 (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 583;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 584;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 585; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 586, such as those containing the anti-HER2 antibody 2C4.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 593;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 594; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 140;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 141;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 142;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 143; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 144, such as 95A2, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 588;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 589;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 590;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 591; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 592, such as those containing the anti-HER2 antibody 7C2.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 595;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 596; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 140;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 141;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 142;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 143; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 144, such as 95A2, may contain a second binding domain that binds to LYPD1.

The second binding domain that binds to LYPD1 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 176;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 177;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 178;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 180, such as those containing the anti-LYPD1 antibody YWO.49.H6.

In some cases, the second binding domain that binds to LYPD1 may, for example, contain (a) a VH domain containing an amino acid sequence having at least 90%

- 227 040364 sequence identity (for example, at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 272;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 273; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 140;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 141;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 142;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 143; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 144, such as 95A2, may contain a second binding domain that binds to LY6G6D.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 140;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 141;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 142;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 143; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 144, such as 95A2, may contain a second binding domain that binds to PMEL17.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 140;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 141;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 142;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 143; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 144, such as 95A2, may contain a second binding domain that binds to LY6E.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 140;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 141;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 142;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 143; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 144, such as 95A2, may contain a second binding domain that binds to CD19.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 140;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 141;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 142;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 143; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 144, such as 95A2, may contain a second binding domain that binds to CD33.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 140;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 141;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 142;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 143; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 144, such as 95A2, may contain a second binding domain that binds to CD22.

In some instances, an anti-CD3 antibody comprising a first binding domain containing at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from

- 228 040364 (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 139;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 140;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 141;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 142;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 143; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 144, such as 95A2, may contain a second binding domain that binds to CD79A.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 140;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 141;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 142;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 143; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 144, such as 95A2, may contain a second binding domain that binds to CD79B.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 140;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 141;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 142;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 143; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 144, such as 95A2, may contain a second binding domain that binds to EDAR.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 140;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 141;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 142;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 143; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 144, such as 95A2, may contain a second binding domain that binds to GFRA1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 140;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 141;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 142;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 143; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 144, such as 95A2, may contain a second binding domain that binds to MRP4.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 140;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 141;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 142;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 143; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 144, such as 95A2, may contain a second binding domain that binds to RET.

The second binding domain that binds to RET may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 614;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 615;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 616;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 617; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 618, such as those containing the anti-RET antibody 41205.v6.

In some cases, the second binding domain that binds to the RET may, for example,

- 229 040364 contain (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (for example, at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) with , or the sequence of SEQ ID NO: 629;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 630; or (c) VH domain according to (a) and VL domain according to (b)

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 140;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 141;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 142;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 143; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 144, such as 95A2, may contain a second binding domain that binds to Steap1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 140;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 141;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 142;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 143; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 144, such as 95A2, may contain a second binding domain that binds to TenB2.

Alternatively, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 146;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 147;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 148;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 149; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 150, such as 118G9, may contain a second binding domain that binds to CD20.

The second binding domain that binds to CD20 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 158;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 159;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 160;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 161; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 162, such as those containing the anti-CD20 antibody 2H7.v16 (described in US Pat. No. 7,799,900).

In some instances, the second binding domain that binds to CD20 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 266;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 267; or (c) a VH domain according to (a) and a VL domain according to (b), for example, such that contains the anti-CD20 antibody 2H7.v16 (described in US patent No. 7799900).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 146;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 147;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 148;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 149; And

- 230 040364 (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 150, such as 118G9, may contain a second binding domain that binds to FcRH5.

The second binding domain that binds to FcRH5 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 164;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 165;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 166;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 168, such as those containing the anti-FcRH5 antibody 1G7.

In some instances, the second binding domain that binds to FcRH5 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 268;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 269; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 146;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 147;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 148;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 149; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 150, such as 118G9, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 170;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 171;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 172;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 173; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 174, such as those containing the hu4D5 anti-HER2 antibody.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 270;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 271; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 146;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 147;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 148;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 149; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 150, such as 118G9, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 582;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 583;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 584;

- 231 040364 (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 585; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 586, such as those containing the anti-HER2 antibody 2C4.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 593;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 594; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 146;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 147;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 148;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 149; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 150, such as 118G9, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 588;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 589;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 590;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 591; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 592, such as those containing the anti-HER2 antibody 7C2.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 595;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 596; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 146;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 147;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 148;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 149; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 150, such as 118G9, may contain a second binding domain that binds to LYPD1.

The second binding domain that binds to LYPD1 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 176;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 177;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 178;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 180, such as those containing the anti-LYPD1 antibody YWO.49.H6.

In some instances, the second binding domain that binds to LYPD1 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 272;

- 232 040364 (b) a VL domain containing an amino acid sequence having at least 90% sequence identity (for example, at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) with, or the sequence of SEQ ID NO: 273; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 146;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 147;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 148;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 149; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 150, such as 118G9, may contain a second binding domain that binds to LY6G6D.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 146;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 147;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 148;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 149; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 150, such as 118G9, may contain a second binding domain that binds to PMEL17.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 146;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 147;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 148;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 149; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 150, such as 118G9, may contain a second binding domain that binds to LY6E.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 146;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 147;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 148;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 149; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 150, such as 118G9, may contain a second binding domain that binds to CD19.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 146;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 147;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 148;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 149; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 150, such as 118G9, may contain a second binding domain that binds to CD33.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 146;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 147;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 148;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 149; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 150, such as 118G9, may contain a second binding domain that binds to CD22.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 146;

- 233 040364 (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 147;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 148;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 149; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 150, such as 118G9, may contain a second binding domain that binds to CD79A.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 146;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 147;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 148;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 149; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 150, such as 118G9, may contain a second binding domain that binds to CD79B.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 146;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 147;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 148;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 149; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 150, such as 118G9, may contain a second binding domain that binds to EDAR.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 146;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 147;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 148;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 149; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 150, such as 118G9, may contain a second binding domain that binds to GFRA1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 146;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 147;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 148;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 149; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 150, such as 118G9, may contain a second binding domain that binds to MRP4.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 146;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 147;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 148;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 149; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 150, such as 118G9, may contain a second binding domain that binds to RET.

The second binding domain that binds to RET may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 614;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 615;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 616;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 617; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 618, such as those containing the anti-RET antibody 41205.v6.

In some cases, the second binding domain that binds to RET may, for example, contain (a) a VH domain containing an amino acid sequence having at least 90%

- 234 040364 sequence identity (eg, at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or the sequence of SEQ ID NO: 629;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 630; or (c) VH domain according to (a) and VL domain according to (b)

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 146;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 147;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 148;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 149; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 150, such as 118G9, may contain a second binding domain that binds to Steap1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 146;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 147;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 148;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 149; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 150, such as 118G9, may contain a second binding domain that binds to TenB2.

Alternatively, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 152;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 153;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 154;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 155; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 156, such as Rab17, may contain a second binding domain that binds to CD20.

The second binding domain that binds to CD20 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 158;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 159;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 160;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 161; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 162, such as those containing the anti-CD20 antibody 2H7.v16 (described in US Pat. No. 7,799,900).

In some instances, the second binding domain that binds to CD20 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 266;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 267; or (c) a VH domain according to (a) and a VL domain according to (b), for example, such that contains the anti-CD20 antibody 2H7.v16 (described in US patent No. 7799900).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 152;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 153;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 154;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 155; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 156, such as Rab17, may contain a second binding domain that binds to FcRH5.

- 235 040364

The second binding domain that binds to FcRH5 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 164;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 165;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 166;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 168, such as those containing the anti-FcRH5 antibody 1G7.

In some instances, the second binding domain that binds to FcRH5 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 268;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 269; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 152;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 153;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 154;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 155; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 156, such as Rab17, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 170;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 171;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 172;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 173; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 174, such as those containing the hu4D5 anti-HER2 antibody.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 270;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 271; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 152;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 153;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 154;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 155; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 156, such as Rab17, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 582;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 583;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 584;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 585; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 586,

- 236 040364 for example, those containing aHTu-HER2 antibody 2C4.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 593;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 594; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 152;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 153;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 154;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 155; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 156, such as Rab17, may contain a second binding domain that binds to HER2.

The second binding domain that binds to HER2 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 588;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 589;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 590;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 591; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 592, such as those containing the anti-HER2 antibody 7C2.

In some cases, the second binding domain that binds to HER2 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 595;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) c, or a SEQ sequence ID NO: 596; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 152;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 153;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 154;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 155; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 156, such as Rab17, may contain a second binding domain that binds to LYPD1.

The second binding domain that binds to LYPD1 may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 176;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 177;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 178;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 180, such as those containing the anti-LYPD1 antibody YWO.49.H6.

In some instances, the second binding domain that binds to LYPD1 may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 272;

(b) a VL domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95, 96, 97, 98, or 99%

- 237 040364 sequence identity) c, or the sequence of SEQ ID NO: 273; or (c) a VH domain according to (a) and a VL domain according to (b).

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 152;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 153;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 154;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 155; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 156, such as Rab17, may contain a second binding domain that binds to LY6G6D.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 152;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 153;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 154;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 155; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 156, such as Rab17, may contain a second binding domain that binds to PMEL17.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 152;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 153;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 154;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 155; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 156, such as Rab17, may contain a second binding domain that binds to LY6E.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 152;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 153;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 154;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 155; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 156, such as Rab17, may contain a second binding domain that binds to CD19.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 152;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 153;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 154;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 155; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 156, such as Rab17, may contain a second binding domain that binds to CD33.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 152;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 153;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 154;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 155; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 156, such as Rab17, may contain a second binding domain that binds to CD22.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 152;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 153;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 154;

- 238 040364 (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 155; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 156, such as Rab17, may contain a second binding domain that binds to CD79A.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 152;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 153;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 154;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 155; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 156, such as Rab17, may contain a second binding domain that binds to CD79B.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 152;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 153;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 154;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 155; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 156, such as Rab17, may contain a second binding domain that binds to EDAR.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 152;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 153;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 154;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 155; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 156, such as Rab17, may contain a second binding domain that binds to GFRA1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 152;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 153;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 154;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 155; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 156, such as Rab17, may contain a second binding domain that binds to MRP4.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 152;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 153;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 154;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 155; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 156, such as Rab17, may contain a second binding domain that binds to RET.

The second binding domain that binds to RET may, for example, comprise at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 614;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 615;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 616;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 617; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 618, such as those containing the anti-RET antibody 41205.v6.

In some instances, the second binding domain that binds to RET may, for example, comprise (a) a VH domain containing an amino acid sequence having at least 90% sequence identity (e.g., at least 91, 92, 93, 94, 95 , 96, 97, 98 or 99% sequence identity) c, or the sequence of SEQ ID NO: 629;

- 239 040364 (b) a VL domain containing an amino acid sequence having at least 90% sequence identity (for example, at least 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity) with, or the sequence of SEQ ID NO: 630; or (c) VH domain according to (a) and VL domain according to (b)

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 152;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 153;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 154;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 155; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 156, such as Rab17, may contain a second binding domain that binds to Steap1.

In some cases, an anti-CD3 antibody comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 152;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 153;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 154;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 155; and (f) an HVR-L3 containing the amino acid sequence of SEQ ID NO: 156, such as Rab17, may contain a second binding domain that binds to TenB2.

In some embodiments of the invention, bispecific antibodies can also be used to localize cytotoxic agents in cells that express a tumor antigen, such as those shown in table. 1 tumor antigen (eg, CD20, FcRH5, HER2, LYPD1, LY6G6D, PMEL17, LY6E, CD19, CD33, CD22, CD79A, CD79B, EDAR, GFRA1, MRP4, RET, Steap1, or TenB2). Also, bispecific antibodies can be obtained as full length antibodies or antibody fragments.

Methods for producing multispecific antibodies include, but are not limited to, recombinant co-expression of two immunoglobulin heavy chain-light chain pairs having different specificities (see Milstein, Cuello, Nature, 305:537 (1983)); W093/08829; and Traunecker et al., EMBO J., 10:3655 (1991)), and a ridge-to-bottom design method (see, for example, US Pat. No. 5,731,168). The ridge-to-cavity multispecific antibody construction method can be used to obtain a first arm containing a ridge and a second arm containing a pit where the ridge of the first arm can bind. The protrusion of the multispecific antibodies of the invention may be an anti-CD3 arm in one embodiment. Alternatively, the protrusion of the multispecific antibodies of the invention may be an anti-target/antigen arm in one embodiment. The trough of the multispecific antibodies of the invention may be an anti-CD3 arm in one embodiment. Alternatively, the trough of the multispecific antibodies of the invention may be an anti-target/antigen arm in one embodiment. Multispecific antibodies can also be constructed using the immunoglobulin crossover method (also known as Fab domain exchange or CrossMab format) (see, for example, WO 2009/080253; Schaefer et al., Proc. Natl. Acad. Sci., USA, 108 :11187-11192 (2011)). Multispecific antibodies can also be obtained by design using the effect of electrostatic interaction to obtain Fc-heterodimeric antibody molecules (WO 2009/089004 A1); cross-linking two or more antibodies or fragments (see, for example, US patent No. 4676980; and Brennan et al., Science, 229:81 (1985)); the use of hazel zippers to obtain bispecific antibodies (see, for example, Kostelny et al., J. Immunol., 148(5):1547-1553 (1992)); the use of diabody technology to generate bispecific antibody fragments (see, for example, Hollinger et al., Proc. Natl. Acad. Sci., USA, 90:6444-6448 (1993)); and the use of single chain Fv (sFv) dimers (see, for example, Gruber et al., J. Immunol., 152:5368 (1994)); and making trispecific antibodies as described, for example, in Tutt et al., J. Immunol., 147:60 (1991).

Engineered antibodies with three or more functional antigen-binding sites, including octopus antibodies, are also included here (see, for example, US 2006/0025576A1).

Antibodies or antibody fragments can also include dual-acting FAbs or DAFs containing an antigen-binding site that binds to CD3 as well as to a different antigen (eg, a second biological molecule) (see, for example, US 2008/0069820).

7. Antibody variants.

In certain embodiments of the invention, amino acid sequence variants of anti-CD3 antibodies of the invention are provided (e.g., bispecific anti-CD3 antibodies of the invention that bind to CD3 and a second biological molecule, e.g.

- 240 040364 cell surface antigen, for example a tumor antigen, such as TDB antibodies according to the invention or variants thereof). For example, there may be a need to improve the binding affinity and/or other biological properties of an antibody. Variants of the amino acid sequences of the antibody can be obtained by making appropriate modifications to the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletions from and/or insertion into and/or substitutions of residues in the amino acid sequence of the antibody. Any combination of deletions, insertions, and substitutions can be made to obtain the final construct, provided that the final construct has the desired characteristics, eg, antigen binding.

a. Substitution, insertion and deletion variants.

In certain embodiments of the invention, antibody variants containing one or more amino acid substitutions are provided. Sites of interest for displacement mutagenesis include HVR and FR. Conservative substitutions are given in table. 2 under the heading preferred replacements. More significant changes are given in table. 2 under the heading exemplary substitutions and, as further described below, with respect to classes of amino acid side chains. Amino acid substitutions can be made to the antibody of interest and the resulting products screened for desired activity, eg, maintaining/improving antigen binding, reducing immunogenicity, or improving ADCC or CDC.

table 2

Exemplary and Preferred Amino Acid Substitutions

Opening balance Typical replacements Preferred substitutions Ala (A) Val; Leu; lie Val Arg(R) Lys; gln; Asn Lys Asn(N) gln; His; Asp, Lys; Arg Gln Asp(D) Glu; Asn Glu Cys(C) Ser; Ala Ser Gln(Q) asn; Glu Asn Glu(E) asp; Gln asp Gly(G) Ala Ala His(H) asn; gln; Lys; Arg Arg He(I) Leu; Val; met; Ala; Ph; Norleucine Leu Leu(L) Norleucine; lie; Val; met; Ala; Phe lie Lys (K) Arg; gln; Asn Arg Met(M) Leu; Ph; lie Leu Phe(F) trp; Leu; Val; lie; Ala; Tyr Tyr Pro (P) Ala Ala Ser(S) Thr Thr Thr(T) Val; Ser Ser TRP(W) Tyr; Phe Tyr Tyr(Y) trp; Ph; Thr; Ser Phe Val(V) lie; Leu; met; Ph; Ala; Norleucine Leu

- 241 040364

Amino acids can be divided into the following groups according to the general properties of the side chains:

(1) hydrophobic: Norleucine, Met, Ala, Val, Leu, Ile;

(2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gln;

(3) acidic: Asp, Glu;

(4) main: His, Lys, Arg;

(5) residues that affect chain orientation: Gly, Pro;

(6) aromatic: Trp, Tyr, Phe.

Non-conservative substitutions involve replacing a member of one of these classes with another class.

One type of replacement variants includes replacing one or more hypervariable region residues of the parent antibody (eg, a humanized or human antibody). In general, the resulting variants selected for further study will have modifications (e.g., improvements) in certain biological properties (e.g., increased affinity, reduced immunogenicity) compared to the parent antibody and/or will largely retain certain biological properties of the parent antibody. antibodies. An exemplary replacement variant is an affinity matured antibody, which can traditionally be generated, for example, using phage display maturation techniques such as those described herein. Briefly, one or more HVR residues are mutated and variant antibodies are displayed on the surface of phage and screened for a particular biological activity (eg, binding affinity).

Changes (eg substitutions) can be made in the HVR, eg to improve the affinity of the antibody. Such changes can be made at HVR hotspots, i.e. residues encoded by codons that have undergone a high frequency mutation during the somatic maturation process (see, for example, Chowdhury, Methods Mol. Biol., 207:179-196 (2008)), and/or residues that as a result, the variant VH or VL is tested for binding affinity. Affinity maturation by construction and reselection from secondary libraries has been described, for example, in Hoogenboom et al., Methods in Molecular Biology, 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, ( 2001)) In some embodiments of affinity maturation, the variable regions selected for maturation are varied by any of a variety of methods (eg, reduced precision PCR, strand shuffling, and oligonucleotide-guided mutagenesis). Then a secondary library is created. The library is then screened to identify antibody variants with the desired affinity. Another method of diversification involves HVR-directed approaches, in which several HVR residues are randomized (eg, 4-6 residues at a time). HVR residues involved in antigen binding can be separately detected, for example, using alanine-scanning mutagenesis or modeling. In particular, CDR-H3 and CDR-L3 are often targeted.

In certain embodiments of the invention, substitutions, insertions, or deletions may be in one or more HVRs, as long as such changes do not significantly reduce the ability of the antibody to bind the antigen. For example, conservative substitutions (eg, conservative substitutions provided herein) can be made in HVR that do not significantly reduce binding affinity. Such changes may, for example, be beyond the contact residues of the antigen in the HVR. In certain embodiments of the variant VH and VL sequences provided above, each of the HVRs is either unchanged or contains no more than one, two, or three amino acid substitutions.

A convenient method for identifying antibody residues or regions that can be targets for mutagenesis is called alanine scanning mutagenesis, described by Cunningham, Wells (1989), Science, 244:1081-1085. In this method, a residue or group of target residues (eg, charged residues such as arg, asp, his, lys, and glu) is identified and replaced with a neutral or negatively charged amino acid (eg, alanine or polyalanine) to determine if this has an effect on the interaction of an antibody with an antigen. Additional substitutions can be made at amino acid locations showing functional sensitivity to the original substitutions. Alternatively or additionally, the crystal structure of the antigen-antibody complex is used to identify points of contact between the antibody and antigen. Such contact residues and neighboring residues may be targeted or removed as candidates for replacement. Variants can be screened to determine if they have the desired properties.

Amino acid inserts include amino- and/or carboxy-terminal fusions ranging in length from one residue to polypeptides containing one hundred or more residues, as well as insertions of one or more amino acid residues within a sequence. Examples of end inserts include an antibody with an N-terminal methionyl residue. Other insertion variants of an antibody molecule include fusion of the N- or C-terminus of the antibody with an enzyme (eg, for ADEPT) or a polypeptide that increases the serum half-life of the antibody.

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b. glycosylated variants.

In certain embodiments, anti-CD3 antibodies of the invention (e.g., bispecific anti-CD3 antibodies of the invention that bind to CD3 and a second biological molecule, e.g., a cell surface antigen, e.g., a tumor antigen, such as TDB antibodies of the invention or variants thereof ) can be modified to increase or decrease the degree of glycosylation of the antibody. The addition or removal of glycosylation sites in an anti-CD3 antibody of the invention can conventionally be accomplished by altering the amino acid sequence so as to create or remove one or more glycosylation sites.

If the antibody contains an Fc region, the carbohydrate attached to it can be changed. Native antibodies produced by mammalian cells typically contain a branched, 2-antennary oligosaccharide that is generally N-linked to the Asn297 CH2 domain of the Fc region. See, for example, Wright et al., TIBTECH, 15:26-32 (1997). The oligosaccharide may contain various carbohydrates, such as mannose, N-acetylglucosamine (GlcNAc), galactose and sialic acid, as well as fucose attached to GlcNAc in the stem of the 2-antennary structure of the oligosaccharide. In some embodiments of the invention, modifications can be made to the oligosaccharide in an antibody of the invention in order to create antibody variants with certain improved properties.

In one embodiment, anti-CD3 antibody variants are provided having a carbohydrate structure lacking fucose attached (directly or indirectly) to an Fc region. For example, the amount of fucose in such an antibody may be 1 to 80%, 1 to 65%, 5 to 65%, or 20 to 40%. The amount of fucose is determined by calculating the average amount of fucose in the Asn297 sugar chain relative to the total number of glycostructures attached to Asn 297 (e.g., complex, hybrid, or mannose-rich structures) according to MALDI-TOF mass spectrometry, as described, for example, in WO 2008/077546. Asn297 refers to the asparagine residue located at position 297 in the Fc region (according to the EU numbering of Fc region residues); while Asn297 can also be located about ±3 amino acids upstream or downstream of position 297, i.e. between positions 294 and 300 due to minor sequence variations in the antibodies. Such fucosylated variants may have improved ADCC function. See, for example, US Patent Publications No. US 2003/0157108 (Presta, L.); US 2004/0093621 (Kyowa Hakko Kogyo Co., Ltd). Examples of publications related to defucosylated or fucose-deficient antibody variants include US 2003/0157108; WO2000/61739; WO 2001/29246; US 2003/0115614; US 2002/0164328; US 2004/0093621; US 2004/0132140; US 2004/0110704; US 2004/0110282; US 2004/0109865; WO2003/085119; WO2003/084570; WO2005/035586; W02005/035778; WO2005/053742; WO2002/031140; Okazaki et al., J. Mol. Biol., 336:1239-1249 (2004); Yamane-Ohnuki et al., Biotech. Bioeng. 87:614 (2004). Examples of cell lines capable of producing defucosylated antibodies include CHO Lec13 cells deficient in protein fucosylation (Ripka et al., Arch. Biochem. Biophys., 249:533-545 (1986); US Patent Application No. US 2003/0157108 A1, Presta, L; and WO 2004/056312 A1, Adams et al., in particular in example 11) and gene knockout cell lines such as alpha-1,6-fucosyltransferase gene knockout CHO cells, FUT8 (see, for example, Yamane-Ohnuki et al., Biotech Bioeng., 87:614 (2004), Kanda, Y. et al., Biotechnol. Bioeng., 94(4):680-688 (2006), and WO 2003/ 085107).

Additionally, anti-CD3 bisected oligosaccharides are provided, for example, in which the 2-antennary oligosaccharide attached to the Fc region of the antibody is separated by GlcNAc. Such antibody variants may have reduced levels of fucosylation and/or improved ADCC function. Examples of such antibody variants are described, for example, in WO 2003/011878 (Jean-Mairet et al.); US patent No. 6602684 (Umana et al.); and US 2005/0123546 (Umana et al.). Also provided are variants of antibodies with at least one galactose residue in the oligosaccharide attached to the Fc region. Such antibody variants may have improved CSC function. Such antibody variants are described, for example, in WO 1997/30087 (Patel et al); WO 1998/58964 (Raju, S.); and WO 1999/22764 (Raju, S.).

c. Fc region variants.

In certain embodiments, one or more amino acid modifications can be made to the Fc region of an anti-CD3 antibody of the invention (e.g., an anti-CD3 bispecific antibody of the invention that binds to CD3 and a second biological molecule, such as a cell surface antigen, such as a tumor antigen , such as a TDB antibody according to the invention or a variant thereof), thus obtaining a variant Fc region (see, for example, US 2012/0251531). A variant Fc region may comprise a human Fc region sequence (eg, an IgG1, IgG2, IgG3, or IgG4 human Fc region) containing an amino acid modification (eg, substitution) at one or more amino acid positions.

In certain embodiments, the invention provides a variant of an anti-CD3 antibody that has some, but not all, effector functions that make it a suitable candidate for applications where the in vivo half-life of the antibody is important, and some effector functions (such as complement dependent and ADCC) are not necessary or harmful. An in vitro and/or in vivo cytotoxicity assay can be performed,

- 243 040364 to confirm the decrease/depletion of CDC and ADCC activity. For example, an Fc receptor (FcR) binding assay can be performed to ensure that the antibody lacks FcγR binding (and therefore likely lacks ADCC activity) but retains FcRn binding capacity. The primary cells for mediating ADCC, NK cells, only express FcyRIII, while monocytes express FcyRI, FcyRII, and FcyRIII. Information on FcR expression in hematopoietic cells is summarized in Table 1. 3 on p. 464 at Ravetch, Kinet, Annu. Rev. Immunol. 9:457-492 (1991). Non-limiting examples of in vitro assay methods for evaluating ADCC activity of a molecule of interest are described in US Pat. (1986)); and Hellstrom, I. et al., Proc. Nat'l Acad. Sci. USA 82:1499-1502 (1985); 5821337 (see Bruggemann, M. et al., J. Exp. Med., 166:1351-1361 (1987)). Alternatively, non-radioactive assay methods can be used (see, for example, ACTI™ non-radioactive cytotoxicity assay method for flow cytometry (CellTechnology, Inc. Mountain View, CA); and CytoTox 96® non-radioactive cytotoxicity assay method (Promega, Madison, WI). Effector cells useful in such assays include peripheral blood mononuclear cells (PBMC) and natural killer (NK) cells.Alternatively or additionally, ADCC activity of the molecule of interest can be assessed in vivo, for example, in an animal model, as disclosed in Clynes et al., Proc. Nat'l Acad. Sci., USA, 95:652-656 (1998) A C1q binding assay can also be performed to confirm that the antibody is unable to bind C1q and therefore lacks CSC activity. ., for example, ELISA for C1q and C3c binding in WO 2006/029879 and WO 2005/100402 To evaluate complement activation, a CSC assay can be performed (see, for example, Gazzano-Santoro et al., J. Immunol. Methods, 202:163 (1996); Cragg, M.S. et al., Blood., 101:1045-1052 (2003); and Cragg, M.S., Glennie M.J., Blood., 103:2738-2743 (2004)). FcRn binding and in vivo clearance/half-life can also be determined by methods known in the art (see, for example, Petkova, S. B. et al., Int'l. Immunol., 18(12):1759-1769 (2006) ).

Antibodies with reduced effector function include those containing substitutions for one or more Fc region residues 238, 265, 269, 270,297, 327, and 329 (US Pat. Nos. 6,737,056 and 8,219,149). Such Fc mutants include Fc mutants with substitutions at two or more amino acid positions 265, 269, 270, 297 and 327, including the so-called DANA Fc mutant with residues 265 and 297 replaced by alanine (U.S. Patent Nos. 7,332,581 and 8,219,149).

In certain embodiments, the proline at position 329 of the wild-type human Fc region in the antibody is replaced by a glycine or arginine, or an amino acid residue large enough to disrupt the proline sandwich at the Fc/Fc-gamma receptor interface that is formed between proline 329 of the Fc and tryptophan residues Trp 87 and Trp 110 from FcgRIII (Sondermann et al., Nature 406, 267-273 (July 20, 2000)). In certain embodiments of the invention, the antibody contains at least one additional amino acid substitution. In one embodiment, the additional amino acid substitution is S228P, E233P, L234A, L235A, L235E, N297A, N297D, or P331S, and in another embodiment, at least one additional amino acid substitution is L234A and L235A of the human IgG1 Fc region, or S228P and L235E human IgG4 Fc regions (see, for example, US 2012/0251531) and in another embodiment of the invention, at least one additional amino acid substitution is L234A and L235A, and P329GFc regions of human IgG1.

Certain antibody variants with improved or reduced binding to FcRs have been described (see, for example, US Pat. No. 6,737,056; WO 2004/056312; and Shields et al., J. Biol. Chem., 9(2):6591-6604 (2001 )).

In certain embodiments, the antibody variant comprises an Fc region with one or more amino acid substitutions that improve ADCC, such as substitutions at positions 298, 333, and/or 334 of the Fc region (EU residue numbering).

In some embodiments of the invention, changes are made to the Fc region that result in a change (i.e., improvement or weakening) of C1q binding and/or complement-dependent cytotoxicity (CDC), for example, as described in US patent No. 6194551; W099/51642; and Idusogie et al., J. Immunol., 164:4178-4184 (2000).

Antibodies with increased half-life and improved binding to the neonatal Fc receptor (FcRn), which is responsible for the transfer of maternal IgG into the embryo (Guyer et al., J. Immunol., 117:587 (1976); and Kim et al., J Immunol., 24:249 (1994)), described in US 2005/0014934 A1 (Hinton et al.). These antibodies contain an Fc region with one or more substitutions therein that improve the binding of the Fc region to FcRn. Such Fc variants include those with substitutions at one or more Fc region residues 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424, or 434, for example, by substituting the 434 Fc region residue (US Pat. No. 7,371,826).

See also Duncan & Winter, Nature, 322:738-40 (1988); US patent No. 5648260; US patent No. 5624821; and WO 94/29351 for other examples of Fc region variants.

In some aspects, an anti-CD3 antibody (eg, a bispecific anti-CD3 antibody) contains an Fc region containing the N297G mutation. In some embodiments, anti-CD3

- 244 040364 an antibody containing the N297G mutation contains an aHTu-CD3 arm containing a first binding domain containing the following six HVRs:

(a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 1;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 2;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 3;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 4;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 5; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 6;

and an anti-CD20 arm containing a second binding domain containing the following six HVRs:

(a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 157;

(b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 158;

(c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 159;

(d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 160;

(e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 161; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 162.

In some embodiments, an anti-CD3 antibody containing the N297G mutation comprises an anti-CD3 arm comprising a first binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 184; and (b) a VL domain containing the amino acid sequence of SEQ ID NO: 185, and an anti-CD20 arm containing a second binding domain containing (a) a VH domain containing the amino acid sequence of SEQ ID NO: 266; and (b) a VL domain containing the amino acid sequence of SEQ ID NO: 267.

In some embodiments, an anti-CD3 antibody containing the N297G mutation contains one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from the first CH1 domain (CH11), the first CH2 domain (CH21), the first domain CH3 (CH31), second CH1 domain (CH1 ₂ ), second CH2 domain (CH22), and second CH3 domain (CH32). In some instances, at least one of the one or more heavy chain constant domains is conjugated to another heavy chain constant domain. In some cases, each of the CH31 and CH32 domains contains a ridge or a pit, with the ridge or pit in the CH31 domain being compatible with the pit or ridge in the CH32 domain, respectively. In some cases, the CH31 and CH32 domains join at the interface between said ridge and valley. In some cases, each of the CH21 and CH22 domains contains a ridge or a pit, with the ridge or pit in the CH21 domain being compatible with the pit or ridge in the CH22 domain, respectively. In other cases, the CH21 and CH22 domains join at the interface between said ridge and valley. In some cases, the anti-CD3 antibody is an IgG1 antibody.

In other embodiments, an anti-CD3 antibody containing the N297G mutation comprises an anti-CD3 arm comprising a first binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 184; and (b) a VL domain containing the amino acid sequence of SEQ ID NO: 185, and an anti-CD20 arm containing a second binding domain containing (a) a VH domain containing the amino acid sequence of SEQ ID NO: 266; and (b) a VL domain containing the amino acid sequence of SEQ ID NO: 267, wherein (a) the anti-CD3 arm contains the T366S, L368A, Y407V, and N297G substitution mutations, and (b) the anti-CD20 arm contains the T366W and N297G substitution mutations .

d. Cysteine-engineered antibody variants.

In certain embodiments of the invention, there may be a need to create cysteine-engineered antibodies, such as thioMAbs, in which one or more antibody residues are replaced by cysteine residues. In specific embodiments of the invention, the substituted residues are located in accessible regions of the antibody. The replacement of these residues with cysteine places reactive thiol groups at accessible sites on the antibody, which can be used to conjugate the antibody to other components, such as drug components or linker drug components, to create an immunoconjugate, as further described herein. In certain embodiments, any one or more of the following residues may be substituted with cysteine: V205 (Kabat numbering) light chain; A118 (EU numbering) heavy chain; and S400 (EU numbering) heavy chain Fc region. Cysteine-engineered antibodies can be prepared as described, for example, in US Pat. No. 7,521,541.

e. Derivatives of antibodies.

In certain embodiments, an anti-CD3 antibody of the invention provided herein (e.g., a bispecific anti-CD3 antibody of the invention that binds to CD3 and a second biological molecule, e.g., a cell surface antigen, e.g., a tumor antigen, such as The TDB antibody of the invention or a variant thereof) may be further modified to contain additional non-protein components which are known in the art and readily available. Components suitable for antibody derivatization include, but are not limited to, water-soluble polymers. Non-limiting examples of water-soluble polymers include, but are not limited to, polyethylene glycol (PEG), ethylene glycol/propylene glycol copolymers, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly-1,3-dioxolane, poly-1,3,6-trioxane, ethylene copolymer /maleic anhydride, polyaminoacids (homopolymers or random copolymers) and dextran or poly(p-vinylpyrrolidone)polyethylene glycol, propylene glycol homopolymers, polypropylene oxide/ethylene oxide copolymers, polyoxyethylene polyols (eg glycerol), polyvinyl alcohol and mixtures thereof. Propionaldehyde polyethylene glycol may be advantageous in production due to its stability in water. The polymer may be of any molecular weight and may be branched or unbranched. The number of polymers attached to an antibody may vary, and if more than one polymer is attached, they may be the same or different molecules. In general, the number and/or type of polymers used for derivatization can be determined based on factors including, but not limited to, the specific properties or functions of the antibody to be improved, whether the antibody derivative will be used in therapy under certain conditions, etc. d.

In another embodiment, the invention provides conjugates of an antibody and a non-protein component that can be selectively heated by irradiation. In one embodiment, the non-protein component is a carbon nanotube (Kam et al., Proc. Natl. Acad. Sci., USA, 102:11600-11605 (2005)). The radiation can be of any wavelength and includes, but is not limited to, wavelengths that do not harm normal cells but that heat the non-protein component to a temperature at which cells close to the antibody-non-protein component die.

B. Recombinant methods and compositions.

Ahtu-CD3 antibodies of the invention (e.g., bispecific anti-CD3 antibodies of the invention that bind to CD3 and a second biological molecule, e.g., a cell surface antigen, e.g., a tumor antigen, such as TDB antibodies of the invention or variants thereof) can be generated using recombinant methods and compositions, eg, as described in US Pat. No. 4,816,567. In one embodiment, the invention provides an isolated nucleic acid encoding an anti-CD3 antibody as described herein. Such a nucleic acid may encode an amino acid sequence containing the VL and/or an amino acid sequence containing the VH of an antibody (eg, an antibody light and/or heavy chain). In a further embodiment of the invention, one or more vectors (eg, expression vectors) containing such a nucleic acid are provided. In an additional embodiment, the invention provides a host cell containing such a nucleic acid. In one such embodiment, the host cell contains (eg, has been transformed with) (1) a vector containing a nucleic acid that encodes an amino acid sequence containing an antibody VL and an amino acid sequence containing an antibody VH; or (2) a first vector containing a nucleic acid that encodes an amino acid sequence containing the VL of an antibody and a second vector containing a nucleic acid that encodes an amino acid sequence containing the VH of an antibody.

In one embodiment, the host cell is a eukaryotic cell, such as a Chinese Hamster Ovary (CHO) cell or a lymphoid cell (eg, a Y0, NS0, Sp20 cell). In one embodiment, the invention provides a method for producing an anti-CD3 antibody, comprising culturing a host cell containing a nucleic acid encoding the antibody as proposed above, under conditions suitable for expression of the antibody, and optionally isolating the antibody from the host cell (or culture medium containing host cells).

For recombinant production of an anti-CD3 antibody, a nucleic acid encoding an antibody, eg as described above, is isolated and inserted into one or more vectors for further cloning and/or expression in a host cell. Such a nucleic acid can be readily isolated and sequenced using conventional procedures (eg, using oligonucleotide probes that are capable of specifically binding to genes encoding antibody heavy and light chains).

Suitable host cells for cloning and expression of antibody-encoding vectors include prokaryotic and eukaryotic cells described herein. For example, antibodies can be produced in bacteria, in particular when there is no need for glycosylation and Fc effector function. For information on the expression of antibody fragments and polypeptides in bacteria, see, for example, US Pat. 2003), pp. 245-254, which describes antibody expression in E. coli). Once expressed, the antibody can be isolated from the bacterial cell suspension

- 246 040364 in the soluble fraction and further purified.

In addition to prokaryotes, suitable hosts for cloning and expression of antibody-encoding vectors are eukaryotic microbes such as filamentous fungi or yeasts, including fungal and yeast strains with humanized glycosylation pathways, resulting in an antibody with a partially or fully human glycosylation profile. See Gerngross, Nat. Biotech., 22:1409-1414 (2004); and Li et al., Nat. Biotech. 24:210-215 (2006).

Suitable host cells for expression of the glycosylated antibody are also obtained from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant and insect cells. Many baculovirus strains have been identified that can be used in combination with insect cells, in particular for transfection of Spodoptera frugiperda cells.

Plant cell cultures have also been used as hosts. See, for example, US Pat. Nos. 5,959,177; 6,040,498; 6,420,548;

Vertebrate cells can also be used as hosts. For example, mammalian cell lines that have been adapted to grow in suspension can be used. Other examples of suitable mammalian host cell lines are the CV1 monkey kidney line transformed by SV40 (COS-7); human embryonic kidney line (cells 293 or 293, described, for example, in Graham et al., J. Gen Virol. 36:59 (1977)); newborn hamster kidney (BHK) cells; mouse sertoli cells (TM4 cells described, for example, in Mather, Biol. Reprod., 23:243-251 (1980)); monkey kidney cells (CV1); African green monkey kidney cells (VERO-76); human cervical carcinoma (HELA) cells; canine kidney cells (MDCK); gray rat liver cells (BRL 3A); human lung cells (W138); human liver cells (Hep G2); mouse mammary tumor (MMT 060562); TRI cells as described, for example, in Mather et al., Annals NY Acad. Sci. 383:44-68 (1982); MRC 5 cells; and FS4 cells. Other suitable mammalian host cell lines include Chinese Hamster Ovary (CHO) cells, including DHFR ^- CHO cells (Urlaub et al., Proc. Natl. Acad. Sci., USA, 77:4216 (1980)); and myeloma cell lines such as Y0, NS0 and Sp2/0. For a review of some mammalian host cell lines suitable for antibody production, see, for example, Yazaki, Wu, Methods in Molecular Biology, vol. 248 (BKC Lo, ed., Humana Press, Totowa, NJ), p. 255-268 (2003).

C. Methods of analysis.

For anti-CD3 antibodies of the invention provided herein (e.g., bispecific anti-CD3 antibodies of the invention that bind to CD3 and a second biological molecule, such as a cell surface antigen, such as a tumor antigen, such as TDB antibodies of the invention or variants thereof ) can be detected, screened or characterized by their physical/chemical properties and/or biological activities by various assay methods known in the art.

1. Methods of analysis of binding and other methods of analysis.

In one aspect, an anti-CD3 antibody of the invention is tested for its antigen-binding activity by known methods such as ELISA, Western blotting, and the like.

In another aspect, competitive assay methods can be used to detect an antibody that competes with an anti-CD3 antibody of the invention for binding to CD3.

In a typical competition assay, immobilized CD3 is incubated in a solution containing a first labeled antibody that binds to CD3 and a second unlabeled antibody that is tested for its ability to compete with the first antibody for binding to CD3. The second antibody may be present in the hybridoma supernatant. As a control, immobilized CD3 is incubated in a solution containing the first labeled antibody but not containing the second unlabeled antibody. After incubation under conditions that allow binding of the first antibody to CD3, the excess of unbound antibody is removed and the amount of label associated with immobilized CD3 is measured. If the amount of label associated with immobilized CD3 is significantly reduced in the test sample compared to the control sample, this indicates that the second antibody is competing with the first antibody for binding to CD3. See, for example, Harlow, Lane (1988), Antibodies: A Laboratory Manual., ch. 14 (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY).

2. Methods of activity analysis.

In one aspect, assay methods are provided for detecting anti-CD3 antibodies with biological activity. Biological activity may include, for example, binding to CD3 (eg CD3 on the surface of a T cell) or a fragment of its peptide in vivo, in vitro or ex vivo. In the case of a multispecific (e.g., bispecific) anti-CD3 antibody of the invention (e.g., a TDB antibody containing one anti-CD3 arm and one arm that recognizes a second biological molecule, such as a cell surface antigen, such as a tumor antigen), the biological activity may also include, for example, effector cell activation (e.g., T cell activation (e.g., CD8+ and/or CD4+ T cells)), increase in effector cell population (i.e., increase in T cells), decrease in target cell population ( i.e. a decrease in the population of cells expressing a second biological molecule on their surface) and / or a target

- 247 040364 cell destruction. Antibodies having such biological activity in vivo and/or in vitro are proposed. In certain embodiments, an antibody of the invention is tested for such biological activity as detailed in the examples below.

In some embodiments of the invention, the activity includes the ability to provide destruction of B cells and/or activation of cytotoxic T cells. In certain embodiments, a B cell-targeted anti-CD3 antibody of the invention (such as -CD20 TDB) is tested for such killing of B cells and/or activation of the cytotoxic effect of T cell biological activity by any of the methods described herein, especially in the examples. In some embodiments of any of these assays, PBMC activity can be isolated from whole blood from a healthy donor by Ficoll separation. In particular, human blood can be drawn into heparinized syringes and PBMC isolated using Leucosep and Ficoll Paque Plus. If necessary, separation of CD4+ T cells and CD8+ T cells can be performed using Miltenyi kits according to the manufacturer's instructions.

Alternatively, cells can be washed in RPMI containing 10% PBS supplemented with GlutaMax, penicillin, and streptomycin and ~0.2 million suspended cells added to a 96-well U-bottomed plate. Cells can be cultured in RPMI1640 supplemented with 10% PBS at 37° C. in a humidified standard cell culture incubator. For the BJAB kill assay, 20,000 BJAB cells can be incubated with effector cells, human PBMCs (huPBMC) or purified T cells at the indicated ratio for each assay, in the presence of various concentrations of TDB antibodies for 24 hours. α-cells 200,000 human PBMCs can be incubated with various concentrations of TDB antibodies for 24 hours.

After culturing, cells can be washed with FACS buffer (0.5% BSA, 0.05% Na azide in PBS). Cells can then be stained in FACS buffer, washed with FACS buffer and suspended in 100 µl of FACS buffer containing 1 µg/ml propidium iodide. Data can be acquired with a FACSCalibur flow cytometer and analyzed with a FlowJo. Live B cells can be isolated as PI-CD19+ or PI-CD20+ B cells by FACS, and absolute cell counts can be obtained with FITC beads added to the reaction mixture as an internal counting control. Percentage (%) cell killing can be calculated based on untreated TDB controls. Activated T cells can be detected by surface expression of CD69 and CD25 using anti-CD69-FITC and anti-CD25-PE.

D. Immunoconjugates.

The invention also provides immunoconjugates comprising an anti-CD3 antibody conjugated to one or more cytotoxic agents such as chemotherapeutic agents or drugs, growth inhibitory agents, toxins (e.g. protein toxins, enzymatically active bacterial, fungal, plant or animal toxins). origin or their fragments) or radioactive isotopes.

In one embodiment, the immunoconjugate is an antibody-drug conjugate (ADC) wherein the antibody is conjugated to one or more drugs, including, but not limited to, maytansinoid (see US Pat. IN 1); auristatin, such as the drugs monomethylauristatin DE and DF (MMAE and MMAF) (see US Pat. Nos. 5,635,483, 5,780,588, and 7,498,298); dolastatin; calicheamicin or derivatives thereof (See US Pat. Cancer Res., 58:2925-2928 (1998)); anthracycline such as daunomycin or doxorubicin (see Kratz et al., Current Med. Chem., 13:477-523 (2006); Jeffrey et al., Bioorganic & Med. Chem. Letters, 16:358-362 (2006) ; Torgov et al., Bioconj. Chem., 16:717-721 (2005); Nagy et al., Proc. Natl. Acad. Sci., USA, 97:829-834 (2000); Dubowchik et al., Bioorg. & Med. Chem. Letters, 12:1529-1532 (2002), King et al., J. Med. Chem., 45:4336-4343 (2002), and U.S. Patent No. 6,630,579); methotrexate; vindesine; a taxane such as docetaxel, paclitaxel, larotaxel, tezetaxel and orthotaxel; trichothecin; and CC1065.

In another embodiment, the immunoconjugate comprises an anti-CD3 antibody described herein conjugated to an enzymatically active toxin or fragment thereof, including, but not limited to, diphtheria A chain, diphtheria toxin non-binding active fragments, exotoxin A chain (from Pseudomonas aeruginosa) , ricin A chain, abrin A chain, modesin A chain, alpha-sarcin, Aleurites fordii proteins, diantin proteins, Phytolaca americana proteins (PAPI, PAPII and PAP-S), momordica charanta inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin , mitogellin, restrictocin, fenomycin, enomycin and tricothecenes.

In another embodiment, the immunoconjugate comprises an anti-CD3 antibody described herein conjugated to a radioactive atom to form a radioconjugate. Numerous radioactive isotopes are available for the production of radioconjugates. Their examples include At ²¹¹ , I ¹³¹ , I ¹²⁵ , Y ⁹⁰ , Re ¹⁸⁶ , Re ¹⁸⁸ , Sm ¹⁵³ , Bi ²¹² , P ³² , Pb ²¹² and Lu radioactive isotopes. If the radioconjugate is used for detection, it may contain a radioactive atom for scintigraphic

- 248 040364 studies, such as tc99m or I123, or a spin label for nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging, mri), such as iodine-123, iodine-131, indium-111, fluoro- 19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese or iron.

Antibody-cytotoxic agent conjugates can be prepared using a variety of bifunctional protein binding agents such as K-succinimidyl-3-(2-pyridyldithio)propionate (SPDP), succinimidyl-4-(K-maleimidomethyl)cyclohexane-1-carboxylate (SMCC ), iminothiolane (IT), bifunctional imidoester derivatives (such as dimethyl adipimidate HCl), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis(p-azidobenzoyl)-hexanediamine), bis-diazonium derivatives (such as bis(p-diazonium benzoyl)-ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene) . For example, the ricin immunotoxin can be prepared as described in Vitetta et al., Science 238:1098 (1987). Carbon-14 labeled 1-isothiocyanatobenzyl-3methyldiethylene triaminepentaacetic acid (MX-DTPA) is a typical chelating agent for conjugation of a radionucleotide to an antibody. See WO 94/11026. The linker may be a cleavable linker that facilitates the release of the cytotoxic drug into the cell. For example, an acid labile linker, a peptidase sensitive linker, a photolabile linker, a dimethyl linker, or a disulfide containing linker can be used (Chan et al., Cancer Res., 52:127-131 (1992); US Pat. No. 5,208,020).

Immunoconjugates or ADCs expressly means, but is not limited to, conjugates made with cross-linking reagents, including but not limited to BMPS, EMCS, GMBS, HBVS, LC-SMCC, MBS, MPBH, SBAP, SIA, SIAB, SMCC, SMPB, SMPH, sulfo-EMCS, sulfo-GMBS, sulfo-KMUS, sulfo-MBS, sulfo-SIAB, sulfo-SMCC and sulfo-SMPB, as well as SVSB (succinimidyl-(4-vinyl sulfone)benzoate), which are commercially available (eg, from Pierce Biotechnology, Inc., Rockford, IL., USA).

E. Methods and compositions for diagnosis and detection.

In certain embodiments, any of the anti-CD3 antibodies of the invention (e.g., bispecific anti-CD3 antibodies of the invention that bind to CD3 and a second biological molecule, such as a cell surface antigen, such as a tumor antigen, such as TDB antibodies of the invention, or their variants) is applicable to detect the presence of CD3 in a biological sample. As used herein, the term detection includes quantitative or qualitative detection. In certain embodiments of the invention, the biological sample includes a cell or tissue.

In one embodiment, an anti-CD3 antibody is provided for use in a diagnostic or detection method. In a further aspect, a method is provided for detecting the presence of CD3 in a biological sample. In certain embodiments, the method includes contacting a biological sample with an anti-CD3 antibody described herein under conditions that allow the anti-CD3 antibody to bind to CD3 and determine if a complex has formed between the anti-CD3 antibody and CD3. Such a method may be an in vitro or in vivo method.

In certain embodiments of the invention, labeled anti-CD3 antibodies are provided. Labels include, but are not limited to, labels or components that are detected directly (such as fluorescent, chromophoric, electron dense, chemiluminescent, and radioactive labels) as well as components such as enzymes or ligands that are indirectly detected, such as through an enzymatic reaction or molecular interaction. Typical labels include, but are not limited to, ^32P , ^14C , ^125I , 3H and ^131I radioisotopes, fluorophores such as rare earth chelates or fluorescein and its derivatives, rhodamine and its derivatives, dansyl, umbelliferone, luciferases such as firefly luciferase and bacterial luciferase (U.S. Pat. No. 4,737,456), luciferin, 2,3-dihydrophthalazinediones, horseradish peroxidase (HRP), alkaline phosphatase, β-galactosidase, glucoamylase, lysozyme, saccharide oxidases such as glucose oxidase, galactose oxidase and glucose-6phosphate dehydrogenase, heterocyclic oxidases, such as uricase and xanthine oxidase coupled to an enzyme that uses hydrogen peroxide to oxidize a dye precursor such as HRP, lactoperoxidase or microperoxidase, biotin/avidin, spin labels, bacteriophage labels, stable free radicals, and the like.

F. Pharmaceutical formulations.

Pharmaceutical formulations of an anti-CD3 antibody of the invention (e.g., a bispecific anti-CD3 antibody of the invention that binds to CD3 and a second biological molecule, e.g., a cell surface antigen, e.g., a tumor antigen, such as a TDB antibody of the invention or variants thereof) are prepared by mixing such an antibody having the required degree of purification, with one or more optional pharmaceutically acceptable carriers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. ed. (1980)), in the form of lyophilized formulations or aqueous solutions. Pharmaceutically acceptable carriers are generally non-toxic to recipients at the dosages and concentrations employed and include, but are not limited to, buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethionine chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight polypeptides (less than about 10 residues); proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates, including glucose, mannose or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium; metal complexes (eg Zn-protein complexes); and/or non-ionic surfactants such as polyethylene glycol (PEG). Exemplary pharmaceutically acceptable carriers further include interstitial drug dispersing agents such as soluble neutrally active hyaluronidase proteins (sHASEGP), e.g. human soluble hyaluronidase PH-20 proteins such as rHuPH20 (HYLENEX®, Baxter International, Inc.). Some exemplary sHASEGPs and their uses, including rHuPH20, are described in US Patent Publication Nos. 2005/0260186 and 2006/0104968. In one aspect, sHASEGP is combined with one or more glycosaminoglycanases, such as chondroitinases.

Exemplary lyophilized antibody formulations are described in US Pat. No. 6,267,958. Aqueous antibody formulations include those described in US Pat. No. 6,171,586 and WO 2006/044908, the latter formulations including a histidine acetate buffer.

The composition according to this document may also contain more than one active ingredient, if necessary in the case of a particular indication, which is being treated, preferably those that have complementary activities and do not adversely affect each other. For example, there may be a need for an additional therapeutic agent (eg, a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, and/or an antihormonal agent, such as those listed above). Such active ingredients are preferably in combination in amounts that are effective for the intended purpose.

The active ingredients can be placed in microcapsules obtained, for example, by coacervation or interfacial polymerization, for example, microcapsules of hydroxymethylcellulose or gelatin and microcapsules of poly(methyl methacrylate), respectively; in colloidal drug delivery systems (eg, liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or macroemulsions. Such methods are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. ed. (1980).

Sustained release formulations can be prepared. Suitable examples of sustained release formulations include semi-permeable matrices of solid hydrophobic polymers containing the antibody, the matrices being in molded articles such as films or microcapsules.

Formulations intended for in vivo use are generally sterile. Sterility can easily be achieved, for example, by filtration through sterile filter membranes.

G. Therapeutic Methods and Compositions.

Any of the anti-CD3 antibodies of the invention (e.g., the bispecific anti-CD3 antibodies of the invention that bind to CD3 and a second biological molecule, such as a cell surface antigen, such as a tumor antigen, such as the TDB antibodies of the invention or variants thereof) may be used. in therapeutic ways.

In one aspect, an anti-CD3 antibody is provided for use as a drug. In additional aspects, an anti-CD3 antibody is provided for use in treating or slowing the progression of a cell proliferative disorder (eg, cancer) or an autoimmune disorder (eg, arthritis). In certain embodiments, an anti-CD3 antibody is provided for use in a method of treatment. In certain embodiments, an anti-CD3 antibody is provided for use in a method of treating an individual having a cell proliferative disorder or an autoimmune disorder, comprising administering to the individual an effective amount of the anti-CD3 antibody. In one such embodiment, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent, for example, as described below. In further embodiments, an anti-CD3 antibody is provided for use in enhancing immune function in an individual having a cell proliferative disorder or an autoimmune disorder. In certain embodiments, an anti-CD3 antibody is provided for use in a method of enhancing immune function in an individual having a cell proliferative disorder or an autoimmune disorder, comprising administering to the individual an effective amount of an anti-CD3 antibody to activate effector cells (e.g., T cells, e.g. , CD8+ and/or CD4+ T cells), expansion (increase) in the population of effector cells, decrease in the population of target cells (e.g., cells,

- 250 040364 expressing a second biological molecule recognized by an aHTu-CD3 antibody of the invention, such as a bispecific TDB antibody of the invention) and/or killing target cells (eg tumor target cells). The individual in accordance with any of the above embodiments of the invention may be a human.

In a further aspect, the invention provides the use of an anti-CD3 antibody in the manufacture or formulation of a medicament. In one embodiment, the drug is for the treatment of a cell proliferative disorder (eg, cancer) or an autoimmune disorder (eg, arthritis). In a further embodiment of the invention, the drug is for use in a method of treating a cell proliferative disorder or an autoimmune disorder, comprising administering to an individual having a cell proliferative disorder or an autoimmune disorder an effective amount of the drug. In one such embodiment, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent, for example, as described below. In an additional embodiment of the invention, the drug is intended to activate effector cells (for example, T cells, for example, CD8+ and/or CD4+ T cells), expand (increase) the population of effector cells, decrease the population of target cells (for example, cells expressing the second a biological molecule recognized by an anti-CD3 antibody of the invention, such as a TDB bispecific antibody of the invention) and/or killing target cells (eg, tumor target cells) in an individual. In a further embodiment, the drug is for use in a method of enhancing immune function in an individual having a cell proliferative disorder or an autoimmune disorder, comprising administering to the individual an effective amount of the drug to activate effector cells (e.g., T cells, e.g., CD8+ T cells and/ or CD4+), expansion (increase) in the population of effector cells, decrease in the population of target cells (for example, cells expressing a second biological molecule recognized by an anti-CD3 antibody of the invention, such as a TDB bispecific antibody of the invention), and/or killing cells targets (eg tumor target cells). The individual in accordance with any of the above embodiments of the invention may be a human.

In a further aspect, the invention provides a method for treating a cell proliferative disorder (eg, cancer) or an autoimmune disorder (eg, arthritis). In one embodiment, the method includes administering to an individual having such a cell proliferative disorder or autoimmune disorder an effective amount of an anti-CD3 antibody. In one such embodiment, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent, for example, as described below. The individual in accordance with any of the above embodiments of the invention may be a human.

In a further aspect, the invention provides a method for enhancing immune function in an individual having a cell proliferative disorder or an autoimmune disorder. In one embodiment, the method includes administering to an individual an effective amount of an anti-CD3 antibody to activate effector cells (e.g., T cells, e.g., CD8+ and/or CD4+ T cells), expand (increase) the population of effector cells, decrease the population of target cells (e.g., , cells expressing a second biological molecule recognized by an anti-CD3 antibody of the invention, such as a TDB bispecific antibody of the invention) and/or killing target cells (eg tumor target cells). In one embodiment of the invention, the individual is a human.

In a further aspect, the invention provides a method of treating a hematologic cancer, such as B cell cancer (e.g., mature B cell lymphoma), by administering an effective amount of an anti-CD3 antibody of the invention, such as a bispecific TDB antibody of the invention, such as a B-cell-targeting TDB such as CD20-TDB containing an anti-CD3 arm and an anti-CD20 arm. In a further aspect of an embodiment of the invention, the mature B cell lymphoma is non-Hodgkin's lymphoma (NHL). In a further aspect of the embodiment, NHL is selected from the group consisting of DLBCL from germinal center B cell-like cells (GCC), DLBCL from activated B-cell like cells (AVC), follicular lymphoma (FL), mantle cell lymphoma (MCL) , acute myeloid leukemia (AML), chronic lymphoid leukemia (CLL), marginal zone lymphoma (LMZ), small lymphocyte lymphoma (LML), lymphoplasmacytic lymphoma (LL), Waldenström's macroglobulinemia (MB), central nervous system (LCNS) lymphoma, Burkitt's lymphoma (BL), B-cell prolymphocytic leukemia, splenic marginal zone lymphoma, hairy cell leukemia, unclassifiable splenic lymphoma/leukemia, diffuse red pulp splenic B-cell lymphoma, hairy cell leukemia variant, Waldenström's macroglobulinemia, heavy chain diseases , heavy chain disease α, heavy chain disease γ, heavy chain disease μ, plasma cell

- 251 040364 myeloma, bone solitary plasmacytoma, extraosseous plasmacytoma, extranodal marginal zone lymphoma from mucosal lymphoid tissue (MALT-lymphomas), nodal marginal zone lymphoma, nodal marginal zone lymphoma of children, childhood follicular lymphoma, primary cutaneous follicular center cell lymphoma, B-cell large cell lymphoma with a predominance of T-cells / histiocytes, primary DLBCL of the CNS, primary cutaneous leg-type DLBCL, EBV-positive DLBCL of the elderly, DLBCL associated with chronic inflammation, Hodgkin's disease, primary mediastinal (thymic) B-cell large cell lymphoma, intravascular large B-cell lymphoma, KAL-positive large B-cell lymphoma, plasmablastic lymphoma, HHV-8-associated multifocal Castleman's B-cell lymphoma, primary effusion lymphoma: unclassifiable B-cell lymphoma, with signs diffuse large B-cell lymphoma and Burkitt's lymphoma; and unclassifiable B-cell lymphoma with features of diffuse large B-cell lymphoma and classical Hodgkin's lymphoma. In a preferred embodiment of the invention, said method comprises the treatment of cancer, including DLBCL from germinal center B cell-like cells (GGC), DLBCL from activated B-cell like cells (AVC), follicular lymphoma (FL), mantle cell lymphoma (MCL) , acute myeloid leukemia (AML), chronic lymphoid leukemia (CLL), marginal zone lymphoma (MLZ), small lymphocyte lymphoma (LML), lymphoplasmacytic lymphoma (LL), Waldenström macroglobulinemia (MB), central nervous system (LCNS) lymphoma, or Burkitt's lymphoma (LB).

In one embodiment, the method comprises administering to an individual having such a hematologic cancer (e.g., B cell cancer, e.g., B cell lymphoma) an effective amount of an anti-CD3 antibody of the invention, such as a TDB bispecific antibody such as CD20-TDB containing a CD20-targeted arm and a CD3-targeted arm. In other embodiments of the invention, CD20 TDB is administered together with one or more additional therapeutic agents. In one embodiment, the therapeutic agent is an antibody that targets CD20. In one embodiment, CD20 TDB is administered together with one or more CD20-targeting antibodies selected from a chimeric anti-CD20 monoclonal antibody, rituximab (Rituxan®), or an anti-CD20 monoclonal antibody, obinutuzumab (Gaziva®). In one embodiment, CD20 TDB is administered with rituximab. In one embodiment, CD20 TDB is co-administered with obinutuzumab. In one embodiment, CD20 TDB is co-administered with obinutuzumab and rituximab.

In one additional embodiment, an anti-CD3 antibody of the invention (eg, CD20 TDB) with or without an anti-CD20 monoclonal antibody is administered with an additional therapeutic agent and/or an antibody/drug conjugate (ADC). In one embodiment, CD20 TDB is administered along with one or more additional chemotherapeutic agents selected from cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP). In one embodiment, CD20 TDB is administered with ADC. In one embodiment, CD20 TDB is administered with CHOP, with vincristine replaced with ADC. In one embodiment, CD20 TDB is administered together with an ADC selected from an anti-CD79b antibody-drug conjugate (such as an anti-CD79b-MC-vc-PAB-MMAE conjugate or an anti-CD79b antibody-drug described in any of the US Patent 8088378 and/or US 2014/0030280 or polatuzumab vedotin), an anti-CD19 antibody-drug conjugate, an anti-CD22 antibody-drug conjugate, an anti-CD45 antibody-drug conjugate, and an anti-CD32 antibody-drug conjugate.

In one other embodiment of the invention, the therapeutic agent is a biological modifier. In one embodiment, CD20 TDB is administered together with one or more biological modifiers selected from a BCL-2 inhibitor (such as GDC-0199/ABT-199), lenalidomide (Revlimid®), a PI3K-delta inhibitor (such as idelicib (Zydelig ®)), an antagonist that binds to a component of the PD-1 signaling pathway, an agonist, e.g. an agonistic antibody directed against the activation of a costimulatory molecule, e.g. 4-1BB or ILA), CD27 (e.g. CDX-1127), HVEM or CD127, antagonist, e.g. antagonistic antibody directed against an inhibitory co-stimulatory molecule, e.g. CTLA-4 (also known as CD152), PD-1, TIM-3 , BTLA, VISTA, LAG-3, B7-H3, B7-H4, IdO (e.g., 1-methyl-O-tryptophan (also known as 1-D-MT)), TIGIT, MICA/B, GITR (e.g., TRX518) or arginase, ipilimumab (also known as MDX-010, MDX-101 or Yervoy®), tremelimumab (also known as known as ticilimumab or CP-675,206), urelumab (also known as BMS-663513), MGA271, an anti-TGF beta antagonist such as metelimumab (also known as CAT-192), fresolimumab (also known as GC1008), LY2157299k and adoptive transfer of T cells (eg, cytotoxic T cells or CTL) expressing a chimeric antigen receptor (XAR), such as adoptive

- 252 040364 transfer of T cells containing a dominant negative TGF receptor beta, for example a dominant negative TGF receptor beta type II.

In one embodiment, CD20 TDB is administered together with rituximab and one or more chemotherapeutic agents. In one such embodiment, CD20 TDB is administered along with rituximab and CHOP. In one embodiment, CD20 TDB is administered with rituximab and ADC. In one embodiment, CD20 TDB is administered along with rituximab and CHOP, with vincristine replaced with ADC. In one embodiment, the CD20 TDB is administered together with an ADC selected from an anti-CD79b antibody drug conjugate (such as an anti-CD79b-MC-vc-PAB-MMAE conjugate or an anti-CD79b antibody drug described in any of the US Patent 8088378 and/or US 2014/0030280 or polatuzumab vedotin), an anti-CD19 antibody-drug conjugate, an anti-CD22 antibody-drug conjugate, an anti-CD45 antibody-drug conjugate, and an anti-CD32 antibody-drug conjugate. In one embodiment, CD20 TDB is administered together with rituximab and one or more biological modifiers selected from a BCL-2 inhibitor (such as GDC-0199/ABT-199), lenalidomide (Revlimid®), a PI3K delta inhibitor (such as idelicib (Zydelig®)), an antagonist that binds to a component of the PD-1 signaling pathway, an agonist, e.g., an agonistic antibody directed against the activation of a costimulatory molecule, e.g. TNFRSF9, 4-1BB or ILA), CD27 (e.g. CDX-1127), HVEM or CD127, antagonist e.g. antagonist antibody directed against an inhibitory co-stimulatory molecule e.g. CTLA-4 (also known as CD152), PD-1, TIM -3, BTLA, VISTA, LAG-3, B7-H3, B7-H4, IDO (e.g. 1-methyl-D-tryptophan (also known as 1-D-MT)), TIGIT, MIC A/B, GITR (e.g. TRX518) or arginase, ipilimumab (also known as MDX-010, MDX-101 or Yervoy®), tremelimumab (also known as ticilimumab or CP-675,206), urelumab (also known as BMS-663513), MGA271, an anti-TGF beta antagonist such as metelimumab (also known as CAT-192), fresolimumab (also known as GC1008), LY2157299k and adoptive transfer of T cells (eg, cytotoxic T cells or CTL) expressing a chimeric antigen receptor (XAP), such as adoptive transfer of T cells containing a dominant negative TGF receptor beta, such as a dominant negative TGF receptor beta type II .

In one embodiment, CD20 TDB is administered together with rituximab, one or more chemotherapeutic agents, and one or more biological modifiers selected from a BCL-2 inhibitor (such as GDC-0199/ABT-199), lenalidomide (Revlimid®), a PI3K inhibitor -delta (such as idelalisib (Zydelig®)), an antagonist that binds to a component of the PD-1 signaling pathway, an agonist, e.g., an agonist antibody directed against the activation of a co-stimulatory molecule, e.g. , CD137 (also known as TNFRSF9, 4-1BB, or ILA), CD27 (for example, CDX-1127), HVEM, or CD127, an antagonist, for example, an antagonist antibody directed against an inhibitory co-stimulatory molecule, for example, CTLA-4 (also known as CD152 ), PD-1, TIM-3, BTLA, VISTA, LAG-3, B7-H3, B7-H4, IDO (e.g. 1-methyl-O-tryptophan (also known as 1-D-MT)), TIGIT , MICA/B, GITR (such as TRX518) or arginase, ipilimumab (also known as as MDX-010, MDX-101 or Yervoy®), tremelimumab (also known as ticilimumab or CP-675,206), urelumab (also known as BMS-663513), MGA271, an anti-TGF beta antagonist such as metelimumab (also known as CAT-192), fresolimumab (also known as GC1008), LY2157299k, and adoptive transfer of T cells (eg, cytotoxic T cells or CTL) expressing the chimeric antigen receptor (XAP), such as adoptive transfer of T cells containing the dominant negative TGF receptor beta, for example the dominant negative TGF receptor beta type II.

In one embodiment, CD20 TDB is administered together with rituximab, ADC, and one or more biological modifiers selected from a BCL-2 inhibitor (such as GDC-0199/ABT-199), lenalidomide (Revlimid®), a PI3K delta inhibitor (such such as idelicib (Zydelig®)), an antagonist that binds to a component of the PD-1 signaling pathway, an agonist, e.g. an agonist antibody directed against the activation of a co-stimulatory molecule, e.g. known as TNFRSF9, 4-1BB or ILA), CD27 (e.g. CDX-1127), HVEM or CD127, antagonist e.g. antagonist antibody directed against an inhibitory co-stimulatory molecule e.g. , TIM-3, BTLA, VISTA, LAG-3, B7-H3, B7-H4, IDO (e.g., 1-methyl-Dtryptophan (also known as 1-D-MT)), TIGIT, MIC A/B, GITR (eg TRX518) or arginase, ipilimumab (also known as MDX-010, MDX-101 or Yervoy®), tremelimum aba (also known as ticilimumab or CP-675,206), urelumab (also known as BMS-663513), MGA271, an anti-TGF beta antagonist such as metelimumab (also known as CAT-192), fresolimumab (also known as GC1008), LY2157299k and adoptive transfer of T cells (eg, cytotoxic T cells or CTLs) expressing a chimeric antigen receptor (XAP), e.g.

- 253 040364 adoptive transfer of T cells containing a dominant negative TGF receptor beta, for example a dominant negative TGF receptor beta type II.

In one embodiment, CD20 TDB is administered together with obinutuzumab and one or more chemotherapeutic agents. In one embodiment, CD20 TDB is co-administered with obinutuzumab and CHOP. In one embodiment, CD20 TDB is administered with obinutuzumab and ADC. In one embodiment, CD20 TDB is administered with obinutuzumab and CHOP, with vincristine replaced with ADC. In one embodiment, the CD20 TDB is administered together with an ADC selected from an anti-CD79b antibody-drug conjugate (such as an anti-CD79b-MC-vc-PAB-MMAE conjugate or an anti-CD79b antibody-drug described in any of 8,088,378 and/or US 2014/0030280 or polatuzumab vedotin), an anti-CD19 antibody drug conjugate, an anti-CD22 antibody drug conjugate, an anti-CD45 antibody drug conjugate, and an anti-CD32 antibody drug conjugate. In one embodiment, CD20 TDB is administered together with obinutuzumab and one or more biological modifiers selected from a BCL-2 inhibitor (such as GDC-0199/ABT-199), lenalidomide (Revlimid®), a PI3K delta inhibitor (such as idelicib (Zydelig®)), an antagonist that binds to a component of the PD-1 signaling pathway, an agonist, e.g., an agonistic antibody directed against the activation of a costimulatory molecule, e.g. TNFRSF9, 4-1BB or ILA), CD27 (e.g. CDX-1127), HVEM or CD127, antagonist e.g. antagonist antibody directed against an inhibitory co-stimulatory molecule e.g. CTLA-4 (also known as CD152), PD-1, TIM -3, BTLA, VISTA, LAG-3, B7-H3, B7-H4, IDO (e.g., 1-methyl-Dtryptophan (also known as 1-D-MT)), TIGIT, MICA/B, GITR (e.g., TRX518) or arginase, ipilimumab (also known as MOX-010, MDX-101 or Yervoy®), tremelimumab (also known as ticilimumab or CP-675,206), urelumab (also known as BMS-663513), MGA271, anti-TGF beta antagonist, e.g. metelimumab (also known as CAT-192), fresolimumab (also known as GC1008), LY2157299k and adoptive transfer of T cells (eg, cytotoxic T cells or CTL) expressing a chimeric antigen receptor (XAP), such as adoptive transfer of T cells containing a dominant negative TGF receptor beta, such as a dominant negative TGF receptor beta type II.

In one embodiment, CD20 TDB is administered together with obinutuzumab, ADC, and one or more biological modifiers selected from a BCL-2 inhibitor (such as GDC-0199/ABT-199), lenalidomide (Revlimid®), a PI3K delta inhibitor (such such as idelicib (Zydelig®)), an antagonist that binds to a component of the PD-1 signaling pathway, an agonist, e.g. an agonist antibody directed against the activation of a co-stimulatory molecule, e.g. known as TNFRSF9, 4-1BB or ILA), CD27 (e.g. CDX-1127), HVEM or CD127, antagonist e.g. antagonist antibody directed against an inhibitory co-stimulatory molecule e.g. , TIM-3, BTLA, VISTA, LAG-3, B7-H3, B7-H4, IDO (e.g., 1-methyl-Dtryptophan (also known as 1-D-MT)), TIGIT, MICA/B, GITR ( e.g. TRX518) or arginase, ipilimumab (also known as MDX-010, MDX-101 or Yervoy®), tremelim maba (also known as ticilimumab or CP-675,206), urelumab (also known as BMS-663513), MGA271, an anti-TGF beta antagonist such as metelimumab (also known as CAT-192), fresolimumab (also known as GC1008), LY2157299k and adoptive transfer of T cells (eg, cytotoxic T cells or CTL) expressing a chimeric antigen receptor (XAP), such as adoptive transfer of T cells containing a dominant negative TGF receptor beta, such as a dominant negative TGF receptor beta type II .

In a further aspect of the invention, the additional therapy comprises the use of an anti-CD20 antibody. In one embodiment, the anti-CD20 antibody is rituximab. In one embodiment, the anti-CD20 antibody is a humanized B-Ly1 antibody. In one embodiment, the humanized B-Ly1 antibody is obinutuzumab. In one embodiment, the anti-CD20 antibody is ofatumumab, ublituximab, and/or ibritutomab tiuxetan.

In a further aspect of the invention, the additional therapy comprises the use of an alkylating agent. In one embodiment, the alkylating agent is 4[5-[bis(2-chloroethyl)amino]-1-methylbenzimidazol-2-yl]butanoic acid and salts thereof. In one embodiment of the invention, the alkylating agent is bendamustine.

In a further aspect of the invention, the additional therapy comprises the use of a BCL-2 inhibitor. In one embodiment, the BCL-2 inhibitor is 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-ul)-N -({3-nitro-4-[(tetrahydro2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridine-5-uloxy)benzamide and its salts. In one embodiment, the BCL-2 inhibitor is venetoclax

- 254 040364 (CAS No. 1257044-40-8).

In a further aspect of the invention, the adjunctive therapy comprises the use of a phosphatidylinositol 3-kinase (PI3K) inhibitor. In one embodiment, the PI3K inhibitor inhibits the delta isoform of PI3K (ie, P110δ). In some embodiments, the PI3K inhibitor is 5-fluoro-3-phenyl-2-[(1S)-1-(7H-purin-6-ylamino)propyl]-4(3H)-quinazolinone and salts thereof. In some embodiments, the PI3K inhibitor is idelicib (CAS No. 870281-82-6). In one embodiment, the PI3K inhibitor inhibits alpha-delta isoforms of PI3K. In some embodiments, the PI3K inhibitor is 2-{3-[2-(1-isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo [1,2-d][1,4]oxacepin-9yl]-1H-pyrazol-1-yl}-2-methylpropanamide and salts thereof.

In a further aspect of the invention, the adjunctive therapy comprises the use of a Bruton's tyrosine kinase (BTK) inhibitor. In one embodiment, the BTK inhibitor is 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1 -yl]prop2-en-1-one and its salts. In one embodiment, the BTK inhibitor is ibrutinib (CAS No. 936563-96-1).

In a further aspect of the invention, the adjunctive therapy comprises the use of thalidomide or a derivative thereof. In one embodiment, thalidomide or a derivative thereof is (RS)-3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione and its salts . In one embodiment, thalidomide or a derivative thereof is lenalidomide (CAS No. 191732-72-6).

In a further aspect of the invention, the adjunctive therapy comprises the use of one or more of cyclophosphamide, doxorubicin, vincristine, or prednisolone (CHOP). In one embodiment, the adjunctive therapy comprises the use of an anti-CD20 antibody as described above (eg, GA-101 and/or Rituxan®). Any of the above methods and therapies can be used without limitation for any type of cancer, including, for example, the treatment of B-cell cancer or breast cancer.

In a further aspect, the invention provides a method for treating HER2 positive cancer. In one embodiment, the method comprises administering to an individual having such cancer an effective amount of an anti-HER2 antibody of the invention, such as a TDB bispecific antibody with a HER2-targeted arm and a CD3-targeted arm. In a preferred embodiment of the invention, HER2-TDB has an acceptable toxicity profile when administered to a patient at an effective dose. In one embodiment, the HER2-TDB CD3 arm with an acceptable toxicity profile is a low affinity CD3 arm. In one embodiment, the CD3 arm of HER2-TDB with an acceptable toxicity profile is 40G5c.

In a preferred embodiment, the HER2 positive cancer is HER2 positive breast cancer or HER2 positive stomach cancer. In one embodiment, HER2 TDB is administered along with one or more additional therapeutic agents that target the HER pathway. In one embodiment, the therapeutic agent that targets the HER pathway is selected from an EGFR inhibitor, a HER2 inhibitor, a HER3 inhibitor, and/or a HER4 inhibitor. In one embodiment, HER2 TDB is administered together with one or more additional therapeutic agents selected from trastuzumab (Herceptin®), T-DM1 (Kadcyla®) and pertuzumab (Perjeta®). In one embodiment, HER2 TDB is administered with trastuzumab. In one embodiment of the invention, HER2 TDB is administered together with T-DM1. In one embodiment, HER2 TDB is administered with pertuzumab. In one embodiment, HER2 TDB is co-administered with trastuzumab and pertuzumab. In one embodiment, HER2 TDB is administered together with T-DM1 and pertuzumab.

In a further aspect, the invention provides pharmaceutical compositions comprising any of the anti-CD3 antibodies provided herein, for example, for use in any of the therapeutic methods described above. In one embodiment, the pharmaceutical composition comprises any of the anti-CD3 antibodies provided herein and a pharmaceutically acceptable carrier. In another embodiment of the invention, the pharmaceutical composition contains any of the anti-CD3 antibodies provided herein and at least one additional therapeutic agent, for example, as described herein.

The antibodies of the invention may be used in therapy alone or in combination with other agents. For example, an antibody of the invention may be co-administered with at least one additional therapeutic agent. In certain embodiments, the additional therapeutic agent is a chemotherapeutic agent, a growth inhibitory agent, a cytotoxic agent, a radiotherapy agent, an antiangiogenic agent, an apoptotic agent, an antitubulin agent, or another agent such as an antagonist of the epidermal growth factor receptor (EGFR) (eg, tyrosine kinase inhibitor), HER1/EGFR inhibitor (eg, erlotinib (Tarceva™), platelet-derived growth factor inhibitor (eg, Glivec™

- 255 040364 (imatinib mesylate)), COX-2 inhibitor (e.g. celecoxib), interferon, cytokine, antibody other than an anti-CD3 antibody of the invention, such as an antibody that binds to one or more of the following ErbB2, ErbB3 targets , ErbB4, PDGFR-beta, BlyS, APRIL, BCMA VEGF, or VEGF receptor(s), TRAIL/Apo2, PD-1, PD-L1, PD-L2, or other bioactive or organic chemical agent.

In some embodiments of the invention, a method is provided wherein the additional therapeutic agent is a glucocorticoid. In one embodiment, the glucocorticoid is dexamethasone.

Combination therapies described above include combined administration (when two or more therapeutic agents are included in the same or different preparations) and separate administration, in which case the administration of an antibody of the invention may be before, simultaneously with and/or after administration of an additional therapeutic agent or agents. In one embodiment, administration of the anti-CD3 antibody and administration of an additional therapeutic agent may be separated by about one month, or about one, two, or three weeks, or about one, two, three, four, five, or six days. Ahtu-CD3 antibodies of the invention (e.g., bispecific anti-CD3 antibodies of the invention that bind to CD3 and a second biological molecule, e.g., a cell surface antigen, e.g., a tumor antigen, such as TDB antibodies of the invention or variants thereof) can also be used in combinations with radiation therapy.

The antibody of the invention (and/or any additional therapeutic agent) can be administered by any suitable route, including parenteral, intrapulmonary and intranasal, and, if local treatment is required, intralesional administration. Parenteral infusions include intramuscular, intravenous, intra-arterial, intraperitoneal or subcutaneous administration. In some embodiments of the invention, the antibody is administered by subcutaneous injection. In some embodiments, an anti-CD3 antibody administered by subcutaneous injection elicits a less toxic response in a patient than the same anti-CD3 antibody administered by intravenous injection. Dosing may be by any convenient means, for example by injection, such as intravenous or subcutaneous injection, depending in part on whether the administration is transient or continuous. Various dosing regimens are contemplated herein, including, but not limited to, single or multi-timed administration, bolus administration, and pulsed infusion.

The antibodies of the invention should be formulated, dosed and administered in accordance with good medical practice. In this context, factors to consider include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, site of delivery of the agent, route of administration, mode of administration, and other factors known to practitioners. The antibody is optionally formulated with one or more agents currently used to prevent or treat the disorder in question. The effective amount of such other agents depends on the amount of antibody present in the formulation, the type of disorder or treatment, and other factors discussed above. In general, they are used at the dosages and route of administration as described herein, or from about 1% to 99% of the dosages described herein, or at any dosage and by any route that has been empirically/clinically determined to be suitable.

For the prevention or treatment of a disease, the appropriate dosage of an antibody of the invention (whether used alone or in combination with one or more other additional therapeutic agents) will depend on the type of disease being treated, the type of antibody, the severity and dynamics of the disease, whether administered antibody for preventive or therapeutic purposes, previous treatment, the patient's clinical history and response to the antibody, and the prescription of the attending physician. The antibody is conveniently administered to a patient at a single time or over a series of treatments.

As a general guideline, a therapeutically effective amount of an anti-CD3 antibody administered to a human ranges from about 0.01 mg/kg to about 100 mg/kg of the patient's body weight, whether one or more administrations are made. In some embodiments of the invention, the daily use of the antibody is, for example, from about 0.01 mg/kg to about 45 mg/kg, from about 0.01 mg/kg to about 40 mg/kg, from about 0.01 mg/kg up to about 35 mg/kg, from about 0.01 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 25 mg/kg, from about 0.01 mg/kg to about 20 mg/kg kg, from about 0.01 mg/kg to about 15 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.01 mg/kg to about 5 mg/kg, or from about 0 .01 mg/kg to about 1 mg/kg. In one embodiment, an anti-CD3 antibody described herein is administered to a human at a dose of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg. , about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg or about 1400 mg, on day 1 of 21 day cycles. The dose can be administered as a single dose or multiple doses (eg 2 or 3 doses),

- 256 040364 eg infusions. In the case of repeated administrations after several days or more, depending on the condition, treatment is generally continued until the necessary suppression of the symptoms of the disease. One typical dosage of the antibody is in the range of about 0.05 mg/kg to about 10 mg/kg. Thus, one or more doses of about 0.5, 2.0, 4.0, or 10 mg/kg (or any combination thereof) may be administered to a patient. Such doses may be administered at intervals, such as every week or every three weeks (eg, so that the patient receives from about two to about twenty or, for example, about six, doses of anti-CD3 antibody). A higher initial loading dose may be administered followed by one or more lower doses. Progress in this type of therapy is easy to monitor using traditional methods and methods of analysis.

In some embodiments of the invention, the methods may further include additional therapy. Complementary therapy may be radiation therapy, surgery, chemotherapy, gene therapy, DNA therapy, viral therapy, RNA therapy, immunotherapy, bone marrow transplantation, nanotherapy, monoclonal antibody therapy, or a combination of the above. Additional therapy may take the form of adjuvant or neoadjuvant therapy. In some embodiments of the invention, the additional therapy is the administration of a small molecule enzymatic inhibitor or anti-metastatic agent. In some embodiments of the invention, the adjunctive therapy is the administration of agents that limit side effects (eg, agents designed to reduce the occurrence and/or severity of side effects of treatment, such as antiemetic agents, etc.). In some embodiments of the invention, the additional therapy is radiation therapy. In some embodiments of the invention, the additional therapy is surgery. In some embodiments, the complementary therapy is a combination of radiation therapy and surgery. In some embodiments of the invention, the additional therapy is gamma irradiation. In some embodiments of the invention, additional therapy may be a separate administration of one or more of the therapeutic agents described above.

H. Products.

In another aspect of the invention, there is provided an article of manufacture containing materials useful in the treatment, prevention and/or diagnosis of the disorders described above. The product contains a container and a label on it or an insert attached to it. Suitable containers include, for example, bottles, vials, syringes, BB solution bags, etc. Containers can be made from different materials such as glass or plastic. The container contains a composition, alone or in combination with another composition effective in treating, preventing and/or diagnosing a pathological condition, and may have a sterile entry port (for example, the container may be an intravenous solution bag or vial with a stopper pierced by a hypodermic needle for injections). At least one active agent in the composition is an antibody according to the invention. The label or insert indicates that the composition is used to treat the selected pathological condition. In addition, the product may contain (a) the first container containing the composition, while the composition contains an antibody according to the invention; and (b) a second container containing the composition, wherein the composition contains an additional cytotoxic or other therapeutic agent.

The product in this embodiment of the invention may further contain an insert indicating that the compositions can be used to treat a particular pathological condition. Alternatively or additionally, the article of manufacture may further comprise a second (or third) container containing a pharmaceutically acceptable buffer such as bacteriostatic water for injection (BVDI), phosphate buffered saline, Ringer's solution and dextrose solution. It may additionally contain other materials required from a commercial and user point of view, including other buffers, diluents, filters, needles and syringes.

III. Examples.

The following are examples of methods and compositions according to the invention. It will be understood that, given the above general description, many other embodiments may be practiced.

Example 1 Preparation of anti-CD3 antibodies.

CD3ε antigens.

A. Bispecific human and cynomolgus CD3ε+CD3γ fused to mouse IgG2a-Fc (CD3εγ-muFc).

cDNA encoding the extracellular portions of human or cynomolgus CD3ε or CD3y (cyno) was fused at the C-terminus with mouse IgG2a Fc to give CD3-Fc fusion products. cDNAs encoding the extracellular domains of human or cynomolgus CD3ε or CD3y were generated using total RNA from anti-CD3/anti-CD28 activated peripheral blood mononuclear cells (PBMCs). Nor

- 257 040364 Small PBMCs were activated plate-immobilized aHTu-CD3 and aHTu-CD28 in RPMI supplemented with 10% PBS for 72 hours. Total mRNA was isolated using the RNeasy mini kit from Qiagen. cDNA was cloned using gene specific primers by RT-PCR into TOPO vectors using Taq polymerase amplified PCR products following the protocol provided with the TOPO TA cloning kit from Invitrogen. The resulting fragments were introduced into a mammalian expression vector containing a mouse IgG2a Fc domain by restriction-free subcloning using high quality Phusion DNA polymerase (New England Biolabs, Cat # M0530L). The CD3 fragments were amplified so that the overlapping regions contained in the template plasmid oriented them directly downstream of the signal sequence and N-terminally to mouse Fc.

For both constructs, human and cynomolgus monkey, the CD3ε-Fc-containing plasmid was transiently co-expressed with the CD3y-Fc-containing plasmid in mammalian CHO cells. CD3ε/γ heterodimers were purified using Protein A Sepharose (Pharmacia Biotech).

B. N-terminal peptide-KLU (CD3ε-KLU) conjugates.

Peptide fragments were synthesized containing N-terminal human and cynomolgus CD3ε sequences. Fragments intended for immunization were conjugated with keyhole limpet hemocyanin (KHL), a widely used carrier protein to generate an enhanced immune response. The addition of a naturally occurring cysteine at position 28 in the case of human and cynomolgus CD3ε allows conjugation of the maleimide-activated GLU to the thiol-containing C-terminal cysteine.

C. Single stranded CD3ε-26mer-CD3γ (CD3εγ).

cDNAs encoding the extracellular portions of the human CD3ε and CD3y subunits were obtained by PCR. Amino acids 1-97 of human CD3ε and amino acids 1-81 of human CD3y were linked using a flexible 26 amino acid peptide linker to generate the CD3ε26mer-CD3y (CD3εy) construct (FIG. 1). The construct was cloned into a His-tagged expression vector for secretion from E. coli using the alkaline phosphatase promoter and the STIII secretory signal sequence. CD3εy was purified on a Ni column and then allowed to refold. The properly folded CD3εy was then purified using an OKT3 affinity column.

In addition, commercial CD3ε from Creative Biomart, Shirley, New York 11967 (catalog number CD3E-2194H) was purchased for some binding experiments.

Immunizations.

A. Immunization of mice.

BALB/c or C57BL/6 mice were immunized (2 or 10 μg/mouse injection). Antigens dissolved in monophosphoryl lipid A/trehalose dicorinomycolate adjuvant were injected into the paw pad at intervals of 3 to 4 days for a total of 12-15 repeats. Three days after the final pre-fusion injection, lymphocytes were obtained from the spleens and lymph nodes of immunized mice. Isolated mouse lymphocytes were fused with SP2/0-Ag14 myeloma cells (American Type Culture Collection) using a Cyto Pulse CEEF-50 device (Cyto Pulse Sciences). Briefly, after washing twice with Cytofusion Medium C (Part No. LCM-C), isolated spleen cells and SP2/0-Ag14 cells were mixed 1:1 and then suspended at 10 million cells/ml in Cytofusion Medium C, electrofusion was performed according to with manufacturer's recommendations. The fused cells were cultured in ClonaCell-HY Medium C (Cat. No. 03803) overnight at 37°C in a 7% CO ₂ incubator. The following day, the fused cells were centrifuged and then suspended in 10 ml of ClonaCell-HY Medium C and then gently mixed with 90 ml of ClonaCell-HY Medium D based on methylcellulose (Cat. No. 03804) containing HAT components. Cells were seeded on OmniTray plates (Thermo Scientific) and allowed to grow at 37°C in a 7% CO2 incubator. After 6-7 days of incubation, single hybridoma clones were harvested using ClonePix FL (Molecular Devices) and transferred to 96-well cell culture plates (#353075, Becton Dickinson) with 200 µl/well of ClonaCell-HY Medium E (cat. no. 03805). The hybridoma culture medium was changed prior to screening by ELISA.

B. Immunization of rabbits.

Rabbit immunizations were performed using 0.5 mg/injection of human and cynomolgus monkey CFA/IFA CD3ε-GLU every two weeks for a total of 5 injections (d0, d14, d28, d42, d56). Blood was taken on days 52 and 66.

PEG fusion and screening was performed as follows. Clones were screened by ELISA for binding to the N-terminal portion of CD3ε conjugated with thyroglobulin (THY). Also, by ELISA, all positive clones were found to cross-react with cynomolgus monkey CD3ε, and 16 unique clones were selected for subcloning. Total RNA was isolated from frozen cell mass and purified using Qiagen's RNeasy kit following the manufacturer's instructions. First strand cDNA was synthesized using one-step RT-PCR (Qiagen). Rabbit VH and VL domains were further amplified by PCR using the protocol described

- 258 040364 for obtaining rabbit immune libraries (Kontermann, Dubel, Antibody Engineering, 1:115-123,

2010). Moderate degeneracy was designed to represent the conventional rabbit germline immunoglobulin genes.

Antibody screening.

A. Screening for mouse hybridoma.

3 days after medium change, hybridoma supernatants were screened by ELISA for binding to human and cynomolgus CD3ε as described below. All ELISA positive clones were further screened by flow cytometry for binding to human Jurkat T cells, human PBMC, and cynomolgus monkey PBMC (FIGS. 2 and 3). Hybridoma supernatants were purified by protein A affinity chromatography followed by sterile filtration (pore size 0.2 μm, Nalge Nunc International, NY, USA) and stored at 4° C. in PBS. Confirmation of the purified mAbs was performed by ELISA before further testing by functional analysis methods. The mAb isotype was determined using a mouse monoclonal antibody isotyping kit from Roche Diagnostics Corporation.

The amino acid sequences of the light and heavy chain variable domains of anti-CD3 antibodies 13A3, 72H6, and 19B1 are shown in FIG. 4A. In FIG. 4A also defines the HVR sequence boundaries for each of the three antibodies. Fig. 4B, 4C, 5A and 5B illustrate additional light and heavy chain variable domain amino acid sequences of other anti-CD3 antibodies.

B. Screening after immunization of rabbits.

Six unique heavy chain sequences and six unique light chain sequences were cloned from hybridoma cell lines. Fig. 7 illustrates the heavy chain and light chain sequences for one of these antibodies, Rab17. The high degree of sequence similarity led to the decision to focus on 6 pairs of heavy and light chains. 6 The resulting antibodies were expressed as chimeric rabbit/human IgG on a small scale (100 ml 293S culture) and examined for binding to CD3 epsilon by ELISA.

Antibody characterization - T-cell binding and activation affinity analysis.

A. CD3εγ binding analysis by ELISA.

CD3εγ binding analysis by ELISA was performed in 96-well microtiter ELISA plates (Greiner, Germany) coated with N-terminal amino acids human/cynomolgus macaque CD3ε conjugated to THY or human/cynomolgus monkey CD3ε/γ fused to mouse Fc at a concentration of 2 μg/ml in 0.05 M carbonate buffer (pH 9.6), 4°C, overnight. After washing three times with wash buffer (0.05% Tween 20 in PBS), the plates were blocked with 200 µl of BSA ELISA diluent. 100 μl cultured supernatants or diluted purified mAbs were added and incubated for 1 hour at room temperature. Plates were washed three times and incubated with HRP-conjugated goat anti-mouse IgG Fc for 1 h. After washing three times, bound enzyme was detected by adding 100 µl/well of TMB substrate (BioFX Laboratories, MD, USA) for 5 min. Reactions were stopped by adding 100 μl/well stop reagent (BioFX, Laboratories, MD, USA) and color detection was performed at A6 _{30 nm} .

B. Analysis by flow cytometry.

Human Jurkat T cells, human PBMC or cynomolgus PBMC were washed twice with FACS staining buffer (phosphate-buffered saline containing 1% fetal bovine serum) and then suspended in FACS staining buffer to a final concentration of 5x106 cell-ml. 100 µl of cells were added to a 96-well U-bottom tissue culture plate (#353077, Becton Dickinson) and 100 µl of hybridoma supernatants or diluted purified mAbs were added. After 30 min incubation on ice, cells were washed twice with FACS staining buffer and then stained with FITC or allophycocyanin (APC) conjugated goat anti-mouse IgG antibody (No. 1012-11, Southern Biotech) at a 1:300 dilution for 30 min. After washing twice with FACS staining buffer, cells were analyzed by FACSCalibur flow cytometry (BD Biosciences). Data was analyzed using FlowJo software (Tree Star, Inc.).

C. Human T cell activation assay.

Human blood was drawn into heparinized syringes and PBMCs were isolated using Leucosep (Greiner Bio-one, cat. no. 227290P) and Ficoll Paque Plus (GE Healthcare Biosciences, cat. no. 95038-168) according to the manufacturer's recommendations. Cells were washed in RPMI medium containing 10% PBS supplemented with GlutaMax (Gibco, cat. no. 35050-061), penicillin, and streptomycin (Gibco, cat. no. 15140-122), and ~0.2 million suspended cells were added in 96- well plate with a U-shaped bottom. Ahtu-CD3 antibodies were added at concentrations between 10 and 0.01 μg/ml. After culturing for ~20 h, the cells were washed with FACS buffer (0.5% BSA, 0.05% Na azide in PBS). Cells were then stained with anti-CD69-FITC (BD cat. no. 555530), anti-CD25-PE (BD cat. no. 555432), anti-CD4-APC (BD cat. no. 555349), or anti-CD8-APC (BD , cat. no. 555369) in FACS buffer, washed with FACS buffer and suspended in 100 µl

- 259 040364 FACS buffer containing 1 µg/ml propidium iodide. Data were obtained using a FACSCalibur flow cytometer and analyzed using a FlowJo. The degree of T cell activation was determined by comparing the percentage of the CD69+ and CD25+ population in CD4+ or CD8+ T cells.

D. Cynomolgus macaque T-cell activation assay.

The blood of cynomolgus monkeys was collected in heparinized tubes. Red blood cells were lysed twice with ACK red blood cell lysis buffer (0.874% NH ₄ Cl, 0.1% KHCO ₃ , 0.00368 EDTA disodium salt). Cells were washed in RPMI medium containing 10% PBS supplemented with GlutaMax (Gibco, cat. no. 35050-061), penicillin, and streptomycin (Gibco, cat. no. 15140-122), and ~0.2 million suspended cells were added in 96- well plate with a U-shaped bottom. Ahtu-CD3 antibodies were added at a concentration of 10 μg/ml. After culturing for ~20 h, the cells were washed with FACS buffer (0.5% BSA, 0.05% Na azide in PBS). Cells were then stained with anti-CD69-FITC (BD, cat. no. 555530), α anti-CD25-PE (BD, cat. no. 555432), anti-CD4-APC (BD, cat. no. 551980) in FACS buffer, washed with buffer FACS and suspended in 100 µl FACS buffer containing 1 µg/ml propidium iodide. Data were obtained using a FACSCalibur flow cytometer and analyzed using a FlowJo. The degree of T cell activation was determined by comparing the percentage of the CD69+ and CD25+ population in CD4+ T cells.

Generation of anti-CD3 antibody variants.

A. Cloning and sequencing of human/cynomolgus monkey cross-reactive murine CD3εγ hybrid.

Total RNA was isolated from mouse hybridoma cells using the RNeasy kit (Qiagen) and first strand cDNA was synthesized using the Superscript III RT kit (Invitrogen). The antibody genes were amplified by PCR with high fidelity Taq polymerase with a mixture of 5' degenerate primers and 3' Cy-, Ck-, N-specific primers. The PCR products were purified and the heavy and light chain variable regions of the antibody were obtained by sequencing the PCR product. The antibody heavy and light chain variable regions were digested with appropriate restriction enzymes and cloned into the appropriate pRK expression vectors. Mouse antibodies were expressed in 293 cells.

B. Humanization.

The sequences of cross-reactive human/cynomolgus CD3εγ hybridomas were aligned to the most homologous human consensus or germline light and heavy chain variable domains (FIG. 7). A consensus sequence named mu40G5c was derived from the light and heavy chain variable domains of related hybridoma clones (FIG. 7). Hypervariable regions (HVRs) were inserted into light and heavy human acceptor frameworks to produce humanized CDR grafts (see, eg, FIGS. 8A-8F). Humanized variants were evaluated as Fab fragments or as IgG. For grafts, VL domain positions 24-34 (L1), 50-56 (L2), and 89-97 (L3) and VH domain positions 26-35 (H1), 50-65 (H2), and 95-102 (H3) were used. (FIGS. 8A-8F). Additional variants were also generated and tested for binding affinity, which contained various combinations of one or more mouse vernier positions (see, for example, FIGS. 9A-9F). Mouse variable domain residues at selected vernier positions were included in the final humanized sequence based on their ability to improve binding affinity. Monovalent binding affinities for selected humanized antibodies for various CD3ε antigens are shown in FIG. 10. Binding affinities for humanized anti-CD3 antibody variants 38E4 (38E4v1-38E4v9) and 40G5c are shown in FIG. eleven.

C. Mapping of paratopes.

Each residue in HVR-L3 and HVR-H3 from hu38E4 was separately replaced with alanine using Kunkel mutagenesis. In addition, position 95 in HVR-H3 has also been replaced with serine, threonine, or glutamate. Variants with these single point mutations were expressed as Fab in HER293 cells and were previously tested using a single cycle kinetic method on Biacore T100. Selected variants were scaled and purified to carry out the traditional multi-cycle kinetic method. In the case of single cycle kinetics, Biacore Series S CM5 sensor chips were immobilized with anti-human Fab antibodies (human Fab capture kit, GE Healthcare). Each Fab was captured from the culture supernatant and incremental concentrations (ranging from 3 to 250 nM in HBSP buffer) of human CD3εγ were injected sequentially at a flow rate of 30 μl/min during one assay run without resurfacing between injections; each cycle corresponded to 10 min of dissociation. In the case of conventional multi-cycle kinetics, human CD3εγ, cynomolgus CD3εγ, or a 27-mer peptide was immobilized on a Biacore Series S CM5 sensor chip using the Biacore amine conjugation kit. Serial 3-fold dilutions of each Fab variant were injected at a flow rate of 30 μl/min. Each sample was analyzed according to the 3-minute association and 3-minute dissociation protocol. In both methods, Biacore chips were reconstituted using 10 mM glycine (pH 1.7). The binding response was corrected by background subtraction, and a 1:1 Langmuir model with

- 260 040364 simultaneous adjustment to _ass and _diss . The effect of these mutations, summarized in FIG. 12 indicates that the R96 light chain residue and the Y97, R99 and F100b heavy chain residues play an important role in CD3εγ binding.

D. Mapping of CD3 epitopes.

Alanine mutations were introduced into CD3ε ^1-27 -Fc to assess epitope recognition in the case of N-terminal binding of anti-CD3ε antibodies. Each CD3ε ^1-27 -Fc variant was immobilized on Nunc Maxisorp plates overnight in PBS at 2 μg/ml at 4°C. After blocking the plates with 2% milk powder in PBS containing 0.05% Tween 20, 100 μl of 3 nM anti-CD3ε was added to each well for 1 hour and allowed to bind for 1 hour at 25°C. After 6 washes with PBS containing 0.05% Tween 20, antibody binding was detected by adding a secondary antibody to mouse IgG-HRP as illustrated in FIG. 13A.

CD3εγ was subcloned into the M13 phagemid, which contains the C-terminal gD tag followed by an amber stop codon so that it can be presented on phage or expressed in a non-suppressor E. coli strain. This CD3εγ phagemid was used as a template to generate single alanine mutations in CD3ε by Kunkel mutagenesis. Each CD3ε alanine mutant present on the phage was confirmed by DNA sequencing, isolated from a single colony, grown overnight in 2YT/Carb plus KO7 helper phage, and purified by PEG precipitation. The effect of an alanine mutation in CD3εγ on the binding of anti-CD3 antibodies was assessed using phage ELISA. Each anti-CD3 antibody was immobilized on a NUNC maxisorp plate at a concentration of 2 μg/ml in PBS buffer overnight at 4°C. Purified phage supernatant representing the CD3εγ alanine variant (1.0 OD ₄₅₀ ) was added to the plate and allowed to bind at room temperature with shaking for 1 hour. After washing, bound phage was detected using anti-M13-HRP (GE Healthcare cat. no. 45 -001-419). The binding of each CD3εγ alanine variant was compared to that of the wild-type CD3εγ phage (FIG. 13B). For alanine variants that affected anti-CD3 antibody binding, additional studies were performed evaluating binding as a function of phage concentration (FIG. 13C).

To quantify the effect of CD3 alanine mutations on antibody binding, selected CD3 alanine mutants were expressed in a non-suppressor E. coli strain. Secreted CD3εγ variants were captured from the crude periplasmic fraction with the anti-CD3 antibody UCHT1v9. UCHT1v9 was immobilized on the CM5 serios S chip by amine coupling using an anti-human IgG (Fc) capture kit (BR-1008-39) from GE Healthcare. SPR measurements were performed on a Biacore 4000 instrument using kinetic software. To measure monovalent binding affinity, bispecific anti-CD3 antibodies were used in which one arm represented the anti-CD3 to be tested and the other arm recognized an irrelevant antigen. Bispecific anti-CD3 antibodies were run through the immobilized supernatant in a concentration series of two-fold dilutions from 0.39 to 100 nM. The resulting kinetics (FIG. 13D) was measured and evaluated using the Biacore 4000 BIAevaluation software (product code 28-9664-57).

E. Structural mapping of the CD3ε binding site

1. Hu38E4.v1Fab.

Hu38E4.v1 Fab dissolved in 0.15 MNaCl, 25 mM Tris, pH 7.5 at 10 mg/ml, and with a 2-fold molar excess (1 mg) of CD3ε peptide, QDGNEEMGGITQTPYK (SEQ ID NO: 284) ( Fig. 14A), mixed and carried out crystallization studies. Initial screening was performed with a sparse matrix of precipitating agents in a sessile vapor diffusion format. Optimized crystals were grown from a 1:1 mixture with a reservoir solution containing 70% v/v. methylpentadiol and 0.1 M HEPES buffer at pH 7.5. The reservoir was used as a cryoprotectant. The crystals were cooled to cryogenic temperature by rapid immersion in liquid nitrogen.

X-ray diffraction data for a co-crystal of hu38E4.v1 Fab and CD3ε peptide were acquired at the beam axis of the 22ID Advanced Photon Source using a MAR300 CCD detector. The recorded diffraction data were combined and recalculated using the HKL2000 software.

The structure was phased by molecular displacement (MS) using the Phaser software. The M3 search model was the Fab subunit derived from the crystal structure of the HGFA/Fab complex (PDB code: 2R0L). The CD3ε peptide was built into the structure based on the Fo-Fc map. The structure was subsequently adjusted using the REFMAC5 and PHENIX programs, using the maximum similarity of objective functions, anisotropic individual B-factor correlation analysis and least squares correlation analysis to achieve convergence. Data and statistics on adjustment are given in Table. 3A.

- 261 040364

Table FOR

Data Acquisition and Adjustment Statistics for the hu38E4.vl/CD36 Complex

space group R3221 elementary cell a=73.2A, b=73.2A, c=183.7A α=90° β=120° γ=90° Permission 50.0-1.95 A Total number of reflections 42632(4188) ¹ Completeness (%) 100(100) Redundancy 19.7 (8.3) Ι/σ 7.1 (3.0) Rchm ² 0.112(0.812) Resolution range 50- 1.95 A Cchrist ³ / Rcbo6 ⁴ 0.152/0.185 non-hydrogen atoms 3960 water molecules 446 Average B, total 21.97 Average B, protein 20.63 Medium B, water 32.27 s.c.o. bond lengths 0.009 A s.c.o. corners 1.258°

¹ The values in brackets are for the highest resolution surface, which corresponds to 2.02-1.95 A.

² RcHM=E|Ihi-Ih|/ZIhi, where 1^ is the normalized intensity of the i-ro observation of reflection h similar in symmetry, and E is the average value.

³ RKpncn=Eh|F _oh -F _c J/E _h F _oh , where F _0>h and F _c>h are the observed and calculated amplitudes of the structure factor for reflection h.

⁴ The Rcbo6 value calculated for 5% randomly selected reflections is not included in the adjustment.

The crystal structure of the hu38E4.vl complex and the Fab/CD3c peptide was determined at a resolution of 1.9 A. The structure shows that the CD3c peptide makes a slight turn and enters deeply into the recess between the heavy and light chains of the 38E4.vl Fab (FIGS. 14B and 14C). The binding occupies 666 A ² of the solvent-exposed surface area between the peptide and the Fab fragment and involves a complex set of hydrophobic, hydrogen and ionic interactions (FIG. 14D). The N-terminal pyroglutamate (pyroglu) ring is located opposite the heavy chain Tyr33 and forms a hydrogen bond with the heavy chain His35 in HVR-H1. The bulky side chain of the FlOOb residue in HVR-H3 properly orients His35 for pyroglutamate interaction and explains the lack of binding when FlOOb is replaced by alanine, a small side chain residue. In addition, according to the alanine scan results, R96 in CDR-L3 forms a key hydrogen bond with the carboxyl group in pyroglutamate, while Y97 in CDR-H3 forms a hydrogen bond with Me17 of the CD3s peptide (Fig. 14E). Interestingly, although alanine substitution at R99 in CDR-H3 has a strong effect on antigen binding, the structure shows that the side chain is directed away from the CD3c peptide and does not participate in any interactions with the peptide. Instead, R99 forms strong contacts with several residues in CDR-H3, including a hydrogen bond to D101 and hydrophobic packing opposite YlOOa, which further affects the LC vernier residue of Y49 (FIG. 14F). It is likely that these interactions are important for the maintenance and overall ordering of the CDR loops in the 38E4.vl Fab by creating a key central recess between the heavy and light chains, allowing binding of the CD3c peptide.

In FIG. 14G identified all 38E4.vl Fab residues located within 5 A of the CD3c peptide. These antigen-contacting residues are identical for hu38E4.vl and hu40G5c except that the G96 residue in hu38E4.vl is the serine (S96) residue in hu40G5 (see Figure 14H, which illustrates the location of the G96 contact residue in hu38E4.vl) .

Contacts between anti-POPs (38E4.vl) and the CD3cy peptide were calculated based on the alanine scan. Epitopes recognized by anti-POPs 38E4vl are contacts at a distance

-262040364

3.5 angstroms or less, as shown below in the table. 3b. From this analysis, the Gln1 (PCA1, pyroglutamic acid), Asp2, Glu6 and Met7 epitopes from CD3 were found to be important contact-forming residues with the anti-CD3 antibody light chain and heavy chain variable region paratopes.

Table 3B

CD3 contacts for hu38E4.v1/CD3ε complex

Chain Name Peptide Name Distance antibodies Atomic residues Atom CD3 Atomic residues Atomic 96(ARG) NH2 iiiiii /A/ l(PCA) lii | 2.76 /n/ 35(Ht$) NE2 1· eiiiM l(PCA) AND ||th 2.85* N 96(ARG) NH1 N l(PCA) iiiiii ii 11I m 96(ARG) cz C /A/ l(PCA) 0 0 3.24 /n/ 33(TYR) CG C /A/ l(PCA) OE 0 3.27 /L/ 96(ARG) NH2 N /A/ l(PCA) OE 0 3.28 /n/ lOO(TYR) CD1 C /A/ l(PCA) 0 0 3.33 /N/ 33(TYR) CB C /A/ l(PCA) OE 0 3.34 /L/ 96(ARG) NH2 N /A/ l(PCA) CD c 3.35 /n/ 33(TYR) CD2 C /A/ l(PCA) OE 0 3.44 /N/ 50(TRP) CH2 C /A/ l(PCA) N N 3.45 /N/ 33(TYR) CD2 C /A/ l(PCA) CD C 3.47 /N/ 50(TRP) CZ3 C /A/ l(PCA) N N 3.48 D/ 94(LEU) IIIiii /A/ 2(ASP) lie 0 II /N/ 50(TRP) CH2 c /A/ 2(ASP) ODl 0 3.23 /L/ 92(PHE) 0 0 /A/ 2(ASP) CB C 3.44 /n/ lOO(TYR) CE1 c /A/ 2(ASP) 0 0 3.48 D/ 91(SER) ABOUT ό /A/ 3(GLY) IM N 2.88 AND 27(ASN)d ND2 N /A/ 3(GLY) 0 about 1 2.96 D/ 92(PHE) ill /A/ 3(GLY) 1st 1I /L/ 32(TYR) Oh 0 /A/ 3(GLY) 0 0 3.3 /L/ 32(TYR) cz c /A/ 3(GLY) 0 0 3.42 /L/ 32(TYR) CE2 c /A/ 3(GLY) 0 0 3.42 /L/ 91(SER) 0 0 /A/ 3(GLY) CA c 3.49 D/ 92(PHE) /A/ 4(ASN) IM N 2.81 m 27(ARG)f NH1 N !! 4(ASN) ABOUT 111I e/ 92(PHE) 0 0 /A/ 4(ASN) CB c 3.11 /L/ 92(PHE) cz C /A/ 4(ASN) ODl 0 3.43 e/ 32(TYR) Oh 0 /A/ 6(GLU) OE1 0 2.58* m 30(LYS) NZ /A/ 6(GLU) OE2 2.74* No. 27(ARG)f NHl iiiiii ISH 6(GLU) III 2.77 m 27(ASN)d ND2 N /A/ 6(GLU) O 1I m 30(LYS) NZ N /A/ 6(GLU) OEl 0 3.2 m 30(LYS) CD C /A/ 6(GLU) OE1 0 3.35 m 30(LYS) NZ N /A/ 6(GLU) CD c 3.36 /N/ lOO(TYR) CE2 C /A/ 6(GLU) OEl 0 3.4 /n/ 98(SER) CA C /A/ 6(GLU) OE2 0 3.42 /n/ lOO(TYR) Oh 0 /A/ 6(GLU) CB c 3.44 M 32(TYR) cz C /A/ 6(GLU) OEl 0 3.47 /n/ 97(TYR) Oh b /A/ 7(MET) IM N 2.87 D/ 27(ARG)f 1st /A/ 7(MET) III 11th /n/ 97(TYR) Oh 0 /A/ 7(MET) CB c 3.49 M 27(ARG)f CD c /A/ 7(MET) 0 0 3.5

* Represents hydrogen bonding between two side chains.

Shaded cells represent confirmed hydrogen bonding contacts.

The contacts in bold are the hydrogen bonds between the side chains and backbones of the main chain.

2.SP34v52Fab.

SP34v52 Fab was dissolved in 0.25 M NaCl, 25 mM MES, pH 5.5, at a concentration of 10 mg/ml. Elementary

- 263 040364 screening was performed with a sparse matrix (PEGU, Qiagen) in the sessile drop vapor diffusion format. The center of crystallization was in a drop in a tank containing 0.2 M CaCl ₂ , 0.1 M HEPES, pH 7.5 and 30% w/v. PEG 4000. Optimized crystals were grown from a mixture of 2 μl of protein and 2 μl of a reservoir solution containing 20-23% w/v. PEG 3350, 0.1 M HEPES, pH 7.2, 0.1 M CaCl ₂ . The sessile drop vapor diffusion method was used and the final crystallization drop was incubated at 18°C.

Diffraction data for the SP34v52 Fab were acquired on the beam axis of the Stanford Synchrotron 12-2 photon source using the PILATUS detector. The recorded diffraction data was then combined using the XDS program and recalculated using the SCALA program. The structure was phased by molecular displacement (MS) using the Phaser software. The M3 search model was the Fab subunit derived from the crystal structure of the HGFA/Fab complex (PDB code: 2R0L). The CD3ε peptide was built into the structure based on the Fo-F _c map. The structure was subsequently adjusted using the REFMAC5 and PHENIX programs, using the maximum similarity of objective functions, anisotropic individual B-factor correlation analysis and least squares correlation analysis to achieve convergence. Data and statistics on the adjustment are given below in Table. 4.

Table 4 Data Acquisition and Adjustment Statistics for SP34v52___________

Spatial R622 group a \u003d b \u003d 146, ZA, c \u003d 80.1 A elementary cell α=90° β=90° γ=120° Permission 50.0 - 2.50 A Total 18004(170) ¹ reflections Completeness (%) 100(100) Redundancy 19.3 (19.7) Ι/σ 24.0 (3.6) Rchm ² 0.127 (0.896) Resolution range 50 - 2.50 A Cchrist ³ / Rcbo6 ⁴ 0.152/0.185 non-hydrogen atoms 3451 water molecules 123 Average B, total 29.59 Average B, protein 29.81 Medium B, water 22.47 s.c.o. bond lengths 0.007 A s.c.o. corners 1.163°

¹ The values in parentheses are for the highest resolution surface, which corresponds to 2.51-2.50 A.

² Rsim=Σ|I _hi -I _h |/ΣI _hi , where I _hi is the normalized intensity of the i-th observation of reflection h similar in symmetry, and I _h is the average value.

³ Rcrist=Σh|Fo,h-Fc,h|/ΣhFo,h, where Fo,h and Fc,h are the observed and calculated amplitudes of the structure factor for reflection h.

⁴ The Rfree value calculated for 5% randomly selected reflections is not included in the adjustment.

In FIG. 14I-14L compare the crystal structures of hu38E4.v1 and SP34v52 Fab in the same orientation. When the CD3ε peptide was superimposed on the SP34v52 Fab in the same orientation as hu38E4.v1, clean peptide junctions with SP34v52 were observed (FIG. 14L). HVR-H2 residues R50 and R52 from SP34v52, which were not present in hu38E4.v1 or hu40G5c, were found to be important for CD3 binding by SP34v52 (FIG. 14L). These data demonstrate that hu38E4.v1 and hu40G5c bind to CD3 in a manner different from SP34v52.

The crystal structure of hu38E4.v1 in complex with the N-terminal CD3εγ peptide is illustrated in FIG. 14M and 14N. In FIG. 14M is an enlarged view of the key intermolecular interactions involved in contact formation with the sixth residue in CD3εγ. The enlarged image in Fig. 14N illustrates a 3D model of the Fab/CD3 peptide complex in which

- 264 040364 the fifth residue is completely directed away from the site of interaction. The sixth site, as shown, is involved in interactions with Fab and is directed to the active site.

Example 2 Production and selection of T-cell dependent bispecific (TDB) antibodies.

One of the approaches to use the high cytotoxic potential of T cells in the destruction of tumor cells has been the use of T-cell-dependent bispecific (TDB) antibodies. Favorable clinical responses have been reported with molecules such as the B cell-targeted blinatumomab, the CD19/CD3 bispecific antibody BiTE. However, the therapeutic prospects of many forms of bispecific antibodies have been limited by disadvantages, including adverse pharmacokinetics (PK), toxicity, and/or manufacturing problems. Accordingly, we first generated and characterized anti-CD3 TDB antibodies having different combinations of anti-CD3 arms and arms directed against tumor antigens (e.g., anti-CD20, anti-FcRH5, anti-HER2, anti-LYPD1, anti-LY6E , anti-LY6G6D, anti-PMEL17, anti-CD19, anti-CD22, anti-CD33, anti-CD79A, anti-CD79B, anti-EDAR, anti-GFRA1, anti-MRP4, anti-RET, anti-Steap1, anti -TenB2) obtained as full-length antibodies in the ledge-in-trough format. Surprisingly, we found that specific combinations of anti-CD3 arms and arms directed against tumor antigens resulted in TDBs showing favorable activity compared to other TDBs.

TDB antibodies were prepared as full-length antibodies in the ridge-to-cavity format as human IgG1 as previously described (Atwell et al., J. Mol. Biol., 270:26-35, 1997). Antibody halves were expressed in E. coli or Chinese hamster ovary (CHO) cells, purified by protein A affinity chromatography, and the corresponding halves of antibody pairs were annealed in vitro as previously described (Spiess et al., Nat. Biotechnol., 2013). If TDB antibody production was carried out in CHO cells, the antibody could contain an aglycosylation mutation, for example, at the N297 residue (for example, N297G), so that the TDB antibody was a variant with no effector function and was not able to initiate antibody-dependent cell-mediated cytotoxicity (ADCC). Fig. 15 illustrates a scheme for obtaining CD3/CD20 TDB.

After annealing, CD3/CD20 TDB was purified by hydrophobic interaction chromatography (HIC) and analyzed by analytical size exclusion filtration, mass spectrometry and polyacrylamide gel electrophoresis. Purified antibodies produced a single peak (>99% signal) on gel filtration with less than 0.2% aggregates. Mass spectrometry revealed no homodimers. Ahtu-CD20 arms tested in the CD3/CD20 TDB generation included 2H7v16, 2H7v114, 2H7v511 and GA101. Ahtu-CD3 arms investigated in the CD3/CD20 TDB generation included UCHT1v1, UCHT1v9, UCHT1vM1, 72H6, 13A3, 30A1, 41D9a, SP34v52, 40G5c, 38E4v1-38E4v9, 21B2, 125A1 and 21A9. CD3/CD20 TDB was examined for CD3 binding as well as activity as measured in an in vitro B cell killing assay and T cell activation assay.

A. Binding affinity.

Binding affinity for each of the CD3/CD20 TDBs was examined by Biacore or FACS analysis as described above for anti-CD3 antibodies. Briefly, for the Biacore binding assay, human CD3εγ was immobilized on a Biacore Series S CM5 sensor chip using the Biacore amine conjugation kit, and CD3/CD20 TDB or their Fab variants were in the flow fraction. For the FACS binding assay, Bjab cells (in the case of B-cell antigens) or Jurkat cells (in the case of CD3 antigen) were incubated with different concentrations of TDB antibodies at 4°C for 30 min, then the cells were washed and incubated with the 2nd antibody (anti-huIgG-PE; BD Bioscience) for an additional 15 min, after which the cells were washed again and were ready for FACS analysis. Fig. 16 illustrates the results of an in vitro FACS binding assay for CD3/CD20 TDB. The results demonstrate that specific combinations of an anti-CD3 antibody arm and an arm directed against a tumor antigen (eg, anti-CD20 arm) resulted in TDB antibodies with more favorable binding properties. Fig. 17 illustrates monovalent and bivalent binding affinity for these particular CD3/CD20 TDBs. In particular, coupling 2H7v16 to anti-CD3 arms (e.g., UCHT1v9), for example, resulted in CD3/CD20 TDB, which showed surprisingly strong binding to both Bjab and Jurkat cells compared to other CD3/CD20 TDBs tested. containing different anti-CD20 arms. Also investigated the binding affinity of other CD3/CD20 TDB containing 2H7v16 anti-CD20 arm and different-CD3 arms (see Fig. 18-24).

B. In vitro B cell killing and T cell activation assay.

The generated CD3/CD20 TDBs were also investigated for their ability to promote B-cell killing and activation of the cytotoxic effect of T-cells. In these assays, tumor B cell lines (Bjab) were obtained from ATCC, and PBMCs were isolated from whole blood of healthy donors by Ficoll separation. If necessary, separation of CD4+ and CD8+ T cells was performed using Miltenyi kits according to the manufacturer's instructions. Cells were cultured in RPMI1640 supplemented with 10% PBS (Sigma-Aldrich) at 37° C. in a humidified standard cell culture incubator. For the Bjab cell kill assay, 20,000 Bjab cells were incubated with effector cells, human PBMCs (huPBMCs), or purified T cells at the indicated ratio for each assay, in the presence of various concentrations of TDB antibodies for the times indicated for each assay. . For the endogenous B cell kill assay, 200,000 human PBMCs (huPBMCs) were incubated with various concentrations of TDB antibodies for the times indicated for each assay. At the end of each assay, live B cells were isolated as PI-CD19+ or PI-CD20+ B cells by FACS, and absolute cell counts were obtained using FITC beads added to the reaction mixture as an internal counting control. Percentage (%) cell killing was calculated based on untreated TDB controls. Activated T cells were detected by surface expression of CD69 and CD25.

The differing efficiencies of the generated TDB antibodies with bispecificity for CD3 and the second biological molecule (in this case CD20) highlight the critical and unpredictable influence of both antibody arms in generating a generic TDB with high potency (see FIGS. 25-49).

Example 3 Characteristics of typical CD3/CD20 TDB (CD20 TDB).

Additionally, two exemplary CD3/CD20 TDBs (CD20 TDBs) described above were characterized and demonstrated high performance in an in vitro B cell killing and T cell activation assay. The CD20 arm of each TDB antibody was the anti-CD20 clone 2H7.v16 (see FIG. 50), while the CD3 arm was the UCHT1v9 clone (see, e.g., Zhu et al., Int. J. Cancer. , 62:319-324, 1995) or the cynomolgus monkey cross-reacting clone 40G5c (see, for example, FIG. 51), which has comparable activity.

Materials and methods.

A. Obtaining antibodies.

T cell-dependent bispecific (TDB) antibodies were generated as full-length antibodies in the ridge-to-cavity format as human IgG1 as previously described (Atwell et al., J. Mol. Biol., 270:26-35, 1997 ). Antibody halves were expressed in E. coli and therefore were aglycosylated, purified by protein A affinity chromatography and the corresponding halves of antibody pairs were annealed in vitro as previously described (Spiess et al., Nat. Biotechnol., 2013). After annealing, the antibodies were purified by hydrophobic interaction chromatography (HIC) and analyzed by analytical size exclusion filtration, mass spectrometry and polyacrylamide gel electrophoresis. Purified antibodies produced a single peak (>99% signal) on gel filtration with no detectable aggregates (FIG. 52A) and no homodimers detectable by mass spectrometry (FIG. 52B).

B. In vitro B cell killing and T cell activation assay.

Tumor cell lines were obtained from ATCC, and PBMCs were isolated from whole blood of healthy donors by Ficoll separation. Separation of CD4+ and CD8+ T cells was performed using Miltenyi kits according to the manufacturer's instructions. Cells were cultured in RPMI1640 supplemented with 10% PBS (Sigma-Aldrich). In the case of the B cell kill assay, live B cells were isolated as PI-CD19+ B cells by FACS, and absolute cell counts were obtained using FITC beads added to the reaction mixture as an internal counting control. Activated T cells were detected by surface expression of CD69 and CD25. Intracellular induction of granzyme B was detected by FACS. Perforin concentration in the medium was determined by ELISA (eBioscience). All antibodies were purchased from BD Bioscience.

C. In vivo efficacy studies in mouse models

Humanized NSG and SCID mice were purchased from Jackson Labs. Human CD20 transgenic mice and human CD3 transgenic mice were prepared as previously described (Gong et al., J. Immunol., 174:817-826, 2005; and de la Here et al., J. Exp. Med., 173:7-17, 1991), and doubly transgenic for human CD20/CD3 mice were obtained by crossing two mice carrying one transgene. Mouse models of human lymphoma were generated by injecting 5x106 Bjab-luciferase cells, alone or mixed with 10x106 human donor PBMCs in HBSS, subcutaneously into the right flank of 40 female mice. Mice were intravenously treated with stock solution or 0.5 mg/kg CD20 TDB 1 hour after inoculation and one week after initial treatment. Tumors were measured 1-2 times a week, and body weight was measured twice a week up to 7 days after the last treatment. If no weight loss was observed, the animal was no longer weighed. If the weight loss was more than 15% of the total body weight, the affected mouse was weighed daily, and sacrificed (or placed under the supervision of a veterinarian) if the weight loss exceeded 20%. Clinical examination was performed twice a week throughout the study to monitor the health status of the animals; any animal with a tumor size or condition that adversely affected the health or activity of the animal was euthanized. Otherwise, animals were sacrificed 6 months after initial treatment, or if the tumor became ulcerated, or if its volume exceeded 2500 mm ³ .

Mouse models of chronic lymphocytic leukemia (CLL) from patients were obtained as previously described (Bagnara et al., Blood., 117:5463-5472, 2011). Briefly, 5x105 activated T cells were purified from CLL PBMC and retroorbitally injected into NSG mice. After inoculation of T-cells retro

- 266 040364 orbitally injected 2x10 ⁷ CLL PBMC. After 14 days, the circulation of transplanted B and T cells was confirmed by FACS analysis. Animals with successful engraftment at 3.5 weeks were treated with TDB antibodies administered intravenously by tail vein injection. Animals were sacrificed 6 or 14 days after treatment. Whole blood was taken by retroorbital sinus puncture using heparinized pipettes and transferred immediately to heparinized tubes while the animals were under anesthesia, or by terminal cardiac puncture with heparinized syringes after CO ₂ sacrifice. Spleens were obtained after CO2 sacrifice. In each study, a clinical examination was performed twice a week to monitor the health status of the animals. The body weight of the animals was measured at least once a week. PBMCs were isolated after lysis of red blood cells and analyzed by FACS for B cells (muCD45+CD19+) and T cells (muCD90.2+CD4+ or muCD90.2+CD8+). All antibodies used were purchased from BD Biosciences or eBiosciences.

D. FKFD study of cynomolgus macaques.

All studies with cynomolgus monkeys were conducted using specially bred, naïve cynomolgus monkeys of Chinese origin. In the case of a single-dose FCFD study, 3 male cynomolgus monkeys were administered a single slow bolus BB dose of 1 mg/kg CD20 TDB; in a repeat dose study, 4 cynomolgus monkeys were given a slow bolus BB dose of 1 mg/kg CD20 TDB once a week for a total of 4 doses. Whole blood or tissue was obtained at selected time points for B-cell and T-cell counting by FACS. Serum was obtained and stored at -70°C until analysis by ELISA to determine the amount of the test component in each serum sample. Serum concentration-time profiles for each animal were used to evaluate pharmacokinetic (PK) parameters using WinNonlin software (Pharsight; Mountain View, CA).

High quality CD20 TDB produced as a full-length humanized IgG with the PK properties of a conventional antibody.

To investigate targeting properties that may influence the effectiveness of TDB targeting B cells, including antigen identity, extracellular domain size, and epitope-to-membrane spacing, we generated over 40 different TDBs targeting epitopes on CD3ε, CD19, CD20, CD22, CD79a and CD79b. Typical results are shown in Fig. 56I. We found that the most effective TDBs were those that targeted cancer target antigens with small extracellular domains (ECDs) and epitopes close to the target cell membrane. Among the best targets were CD20, CD79a and CD79b with an efficiency of about 10 ng/ml or 67 pM to kill normal donor B cells with autologous T cells.

Ahtu-CD20/CD3 TDB (CD20-TDB) is described herein as a proof-of-concept molecule demonstrating the pharmacological activity of these B cell-targeted TDBs. CD20 TDB was obtained as a full-length fully humanized IgG with natural architecture antibodies from bacteria, free of homodimers and aggregates (Fig. 52). The pharmacokinetic (PK) properties of CD20 TDB in the non-binding rat species resemble those of other human IgG antibodies with a half-life of about 7 days (FIG. 53).

Destruction of CD20 TDB B cells is T-cell dependent via the granzyme-perforin pathway.

To evaluate CD20 TDB as a potential therapy for cell proliferative disorders such as CD20+ B cell malignancies, we first investigated the mechanism of action of a T cell recruiting bispecific antibody. Unlike ADCC activity, which is the main mechanism of action of classical monoclonal antibody therapy, CD20 TDB activity does not require an Fc region. The F(ab') ₂ portion of CD20 TDB retains the same potency as full length IgG CD20 TDB in killing B cells (FIG. 54A). CD20 TDB is a conditional agonist that requires expression of targets, T cells, and antibody for activity. The B cell killing activity of CD20 TDB is T cell dependent, as no B cell killing was detected in PBMCs lacking CD3+ T cells (FIG. 54B). Target expression is essential for T cell activation, as the lack of CD20 expression results in the absence of activated T cells (FIG. 54C). CD20 TDB is able to activate both CD4+ and CD8+ T cells according to CD69 and CD25 induction on T cells (FIG. 54D). Comparable killing of B cells can be achieved with any T cells as effectors, while CD8+ T cells are more efficient in killing BJAB cells, as CD8+ T cells lead to a higher rate of cell killing than an equivalent number of CD4+ T cells. (Fig. 54C). However, granzyme upregulation predominates in the case of CD8+ T cells (Fig. 54E), and higher levels of release of perforin and granzymes A and B (not shown) associated with CD8+T T cells (Fig. 54E) were detected in the medium by ELISA. .54F). Activated T cells are able to proliferate (FIG. 55). However, the total number of T cells did not increase significantly after 24 h in the presence of CD20 TDB and B cells without the addition of cytokines in vitro, probably due to culture conditions. Robust T cell expansion has indeed been observed in vivo in efficacy studies with mouse models

- 267 040364 and for cynomolgus monkeys (FIGS. 58A and 67C).

CD20 TDB effectively kills leukemia/lymphoma B cells and autologous B cells in vitro.

The killing efficiency of CD20 TDB B cells was also investigated with more than a dozen leukemia/lymphoma B cell lines in vitro. To evaluate the effectiveness of CD20-TDB, 8 lines were selected, which represented cells with a wide range of CD20 expression levels (FIG. 56B). Dose-response curves for killing B cells are shown for 8 cell lines with PBMC isolated from a healthy donor as effector cells (FIG. 56A). Notably, CD20-TDB did not show activity against SU-DHL1 cells that lack CD20 expression. The effectiveness of CD20-TDB correlated somewhat with different levels of surface CD20 detected by flow cytometry (56A). However, CD20 TDB effectively eliminated all 8 lines in a dose dependent manner with EC50 ranging from 0.38 to 11 ng/kg in a 24 hour assay. The degree of cell killing varies somewhat from 60 to 90% with concentrations up to 1000 ng/kg TDB in a 24 hour assay (FIG. 56C). In general, complete killing of B cells can be achieved with a higher antibody concentration or an extended assay time. SU-DHL-1 cells are included in the kill assay as a negative CD20 control, in which no kill is observed, demonstrating the need for expression of targets for CD20 TDB activity. CD20 TDB activity requires very low levels of target expression, as the Nalm-6 and SC-1 cells shown here have very low CD20 surface expression (FIG. 56B). The monovalent binding affinity of CD20 TDB for CD20 is weaker than the bivalent binding affinity of parental anti-CD20, with a Kd of 54 nM as determined by Scatchard. Together, the Kd value and the B-cell killing efficiency of CD20 TDB, the receptor occupancy required for CD20TDB activity is less than 0.1%. TDBs designed to target different B cell antigens are also effective in mediating B cell killing, as shown in FIG. 56D, where TDBs targeting 5 different B cell antigens, including CD20 TDB (TDB A: 2H7v16/UCHT1v9), kill 75 to 90% of B cells. CD20 TDB may further mediate the elimination of additional B-cell lymphoma lines with differential expression of the CD20 surface antigen (FIG. 56E).

CD20 TDB is also highly effective in killing autologous B cells, tested with human PBMC isolated from the peripheral blood of healthy donors (FIG. 56F). In FIG. 56F shows dose-response curves for killing for 8 random donors, as well as a summary plot for EC50 and B-cell killing (FIG. 56G) with 1000 ng/kg antibody in a 24-hour assay for 30 donors. Of the 30 samples tested, 57 to 96% of B cells were killed by antibody at concentrations up to 1000 ng/kg over 24 hours with an EC50 ranging from 0.43 to 135 ng/kg with an average value of less than 3 ng/kg. The rate of destruction of B cells within 24 hours of CD20 TDB is very close to or exceeds the destruction of B cells of anti-CD3/anti-CD19 scFv (Fig. 56H).

CD20 TDB effectively reduces B cells in vivo in mouse models.

Because test CD20 TDB does not recognize mouse CD20 and CD3 antigens, we used human CD20 and human CD3 transgenic mice (described above) to generate doubly human CD3/CD20 transgenic mice for subsequent in vivo efficacy studies. As shown in FIG. 57A, doubly human CD3/CD20 transgenic mice express huCD3ε on the surface of CD4+ and CD8+ T cells in addition to huCD20 on the surface of CD19+ B cells at detectable levels compared to human-derived T and B cells. In the case of human CD20 transgenic mice, only rituximab can reduce B cells, since CD20 TDB cannot activate mouse T cells without human CD3 expression (FIG. 57B). At the same time, in doubly transgenic human CD3/CD20 mice, CD20 TDB is able to activate mouse huCD3-expressing T cells and effectively reduces the number of mouse huCD20-expressing B cells (FIG. 57C). CD20 TDB reduces B cells more effectively in vivo, as fewer B cells were detected in mouse spleens 7 days after a single BB dose of CD20 TDB at a concentration of 0.5 mg/kg than after a single dose of rituximab at a concentration of 10 mg/kg. HER2 TDB, which contains the same CD3 arm while the other arm binds to HER2, was used herein as an isotype control and showed no cell reduction activity.

To determine the minimum effective dose of CD20 TDB to kill B cells in doubly transgenic human CD3/CD20 mice, mice were treated with a single dose of CD20 TDB ranging from 0.5 to 0.00005 mg/kg. Blood B cells were then counted at D1 (24 hours after dosing), D8 and D15. A decrease in the number of B cells was observed at D1, and the decrease in the number of B cells was maintained until D15 after treatment with CD20 TDB (FIG. 58A). Consistent with these observations of blood B cell count, a near complete reduction in B cell numbers in mouse spleens was achieved at D7 after a single dose of 0.5 mg/kg, while a lower dose of 0.05 mg/kg resulted in partial reduction in the number of B cells and approximately corresponded to the dose level of ED50 (Fig. 58B). A follow-up study with doubly transgenic mice showed that the reduction in the number of B cells in the spleens was almost complete as early as 3 days after treatment with a single dose of 0.5 mg/kg, with no significant signs of recovery of B cells to D14 (Fig. .58A). As shown in FIG. 58C, CD20 TDB mediates a reduction in B cells in the peripheral organs of huCD20/huCD3 doubly transgenic mice that is detectable in the blood as early as 2 hours post-treatment and persists up to 7 days post-treatment. In addition, activated CD8+ and CD4+ T cells are detected in the blood within 2 hours after CD20 TDB administration and then gradually disappear over 2 days after treatment (FIG. 58D).

In addition, CD20 TDB reduced the number of marginal zone B cells (MZB) (FIGS. 59A and 59B) as efficiently as follicular B cells (FOB) (FIGS. 59A and 59C) in mouse spleens after a single BB dose of 0 .5 mg/kg. We observed that splenic B cell counts decreased by ~50% from baseline on day 1 (24 hours post dosing) and continued to decline rapidly until reaching the lowest level on day 3 that persisted throughout the study. This is in stark contrast to the previous study with rituximab, in which the microenvironment was thought to play a role in the efficacy of rituximab, suggesting a different mechanism of action for CD20 TDB in vivo compared to rituximab. Mouse T cell activation is typically observed in the blood as early as 30 minutes after CD20 TDB treatment and mainly within the first 24 hours in the spleen (FIGS. 59D and 59E). After activation of T cells, an increase in the number of T cells by approximately D2-D3 was observed (FIGS. 59D and 59E) as a result of cell proliferation. By day 2, most T cells were no longer CD69 positive, although CD69+CD8+ cell levels continued to be in the 10-30% range for the remainder of the two-week study. At the same time, possibly due to the activation of induced cell death, pure T cells gradually decreased after the expansion phase. Ultimately, the number of T cells recovered after TDB treatment, suggesting that there was no inhibitory effect of CD20 TDB treatment in case of mouse T cell regeneration.

Humanized NSG mice were also used to further confirm the effectiveness of CD20 TDB in reducing the number of B cells in mouse models and in a repeated dosing regimen. Mice participating in the study illustrated in FIG. 60A-60D contained 35-80% of human CD45+ cells in peripheral blood, and the range of CD4+, CD8+, and CD20+ cells was 12-25, 2.1-8.7, and 32-60%, respectively (percentages are presented according to gate data). viable leukocytes). Typical examples of this basic characteristic are shown in FIG. 60E. Levels of target antigens CD3 and CD20 in these mice were compared to levels in normal human donors and found not to be significantly different (FIG. 60F). As shown in FIG. 59, humanized NSG mice were treated with three weekly doses of CD20 TDB at a concentration of 0.5 mg/kg. The number of B-cells in the blood was reduced at D7, and at D21 B-cells were practically not detected (Fig. 60A). A robust reduction in B cells was also observed in the spleens of TDB-treated mice at D21 (FIG. 60B). In addition, treatment of humanized NSG mice with CD20 TDB stimulated T cell proliferation and resulted in a reduction in the number of B cells, as shown in FIG. 60C. The number of CD8+ T cells in the blood increased 10-fold at D7 and returned to baseline or lower at D14 and D21 (FIG. 60D). A similar trend was also observed for CD4+ T cells.

CD20 TDB effectively destroys CLL B cells in vitro and in vivo.

We also investigated the efficacy of CD20 TDB in killing leukemia B cells via autologous T cells from CLL patients, in which B cell tumor burden is usually high while T cell numbers are low and T cell function can be potentially impaired (Riches et al., Semin. Cancer Biol., 20(6):431-438, 2010). PBMC isolated from the peripheral blood of nine CLL patients were incubated with a single high dose of 1000 ng/kg CD20 TDB for 48 hours. As shown in FIG. 61A, CD20 TDB effectively kills CLL B cells via autologous T cells. For the 2 samples shown, the B-cell leukemic tumor burden is 70% with 8.4% CD8+ T cells in PBMC for patient sample #1 and 80% with 4.4% CD8+ T cells for patient sample #2. with CD20 TDB, efficient B cell killing can be achieved at very low effector to target ratios (1:8 and 1:18 for the 2 samples shown). Destruction of CLL B cells by autologous T cells by CD20 TDB correlates well with the number of CD8+ T cells (FIG. 61B). We found that T cell content varied significantly (between 0.4 and 8% mononuclear cells) and, surprisingly, we found that the degree of B cell cytolysis compared to pre-treatment values correlated well with T cell content. By enrichment with purified T cells in CD8+ PBMC CLL, in which very few autologous T cells are present, there was an efficient killing of CD20 TDB leukemia B cells in a T-cell dependent manner (FIG. 61C).

CD20 TDB also effectively reduced the number of CLL-leukemia cells inoculated into mice (FIG. 62A). Briefly, NSG mice were grafted with patient leukemia cells after grafting patient-derived autologous activated T cells, and treatment was initiated after confirmation of sustained leukemia engraftment. IHC staining of representative examples of mouse spleens showed successful engraftment of leukemia B cells and autologous T cells from CLL patients in NSG mice. After treatment with a single dose of CD20-TDB at 0.1 or 0.5 mg/kg, very few B cells could be detected.

A reduction in the number of B cells was also observed with rituximab treatment, while for

HER2-TDB used as an isotype control, no reduction in the number of B cells was observed (FIG. 62B).

In the context of tumor progression, CD20 TDB treatment effectively prevents the growth of B-cell lymphoma tumors in the presence of human donor PBMCs. SCID (severe combined immunodeficiency) mice transplanted with human Bjab cells developed detectable tumors when treated with stock solution or CD20 TDB alone on day 12 post-inoculation. In addition, PBMC transplantation retarded tumor growth, but these mice developed detectable tumors at day 25 post-inoculation. Thus, CD20 TDB also effectively prevents tumor growth in vivo in the presence of PBMC effector cells (Fig. 63).

CD20 TDB requires very low levels of CD20 expression to be effective.

In addition to different antibody Fc region requirements for CD20 TDB activity compared to traditional anti-CD20, and possibly different dependence on the tumor microenvironment, CD20 TDB also requires a lower level of antigen expression to effectively kill B cells. For Bjab cells, which are characterized by high levels of CD20 expression (FIG. 64A), comparable cell killing was observed with rituximab and CD20 TDB (FIG. 64B). However, killing of Nalm-6, SC-1 and OCI-Ly19 cells with much lower levels of CD20 expression (FIG. 64A) was only achieved with CD20 TDB, while no cell killing was seen with rituximab (FIG. 64C). The estimated CD20 copy number for these low CD20 cell lines is less than 500 based on Scatchard and FACS binding data compared to BJAB cells (data not shown). In addition, the monovalent binding affinity of CD20-TDB to CD20 is ~50-100 nM, which is significantly less than the affinity of 1-5 nM rituximab (both determined by Scatchard). Overall, the efficacy of CD20-TDB is consistent with the observation that TCR initiation only requires low receptor occupancy corresponding to 10-100 molecules (Purbhoo, M.A. et al., Nat Immunol., 5:524-530, 2004; Irvine, D.J. et al. , Nature, 419:845-849, 2002; Sykulev, Y. et al., Immunity, 4:565-571, 1996).

CD20 TDB is active in the presence of rituximab and steroids.

Since rituximab and its combination with chemotherapy is widely used in the treatment of B-cell malignancies in the clinical setting, it is important to investigate how CD20 TDB can be used in this context, since CD20 TDB and rituximab target the same antigen. We used rituximab-DANA, a non-effector variant of rituximab (rituximab containing substitutions of residues 265 and 297 with alanine (DANA mutations are described in US Pat. -cells, according to studies on doubly transgenic against human CD20/CD3 mice (Fig. 64D). Pretreatment of normal donor B-target cells with such an inert rituximab molecule, which competes with CD20-TDB for binding, had minimal effect on reducing CD20-TDB activity. At rituximab-DANA concentrations up to 250 µg/mL (5000-fold EC50 dose level of 42 ng/kg), we observed only modest shifts in in vitro dose-response curves (less than 7-fold change in EC50, 42 vs 320 ng /kg). It is noteworthy that in this mode, CD20 TDB remains active. Although the EC50 for CD20-TDB increased up to ∼7-fold with increasing concentration of rituximab-DANA, the extent of B cell killing did not change significantly (FIG. 65A). This is consistent with our previous findings that CD20 TDB requires very low levels of antigen expression or very low receptor occupancy to be effective. The in vitro observations were repeated in vivo with CD3/CD20 doubly transgenic mice pretreated with 2 or 10 mg/kg rituximab-DANA protein and then stimulated with CD20-TDB. In this case, we show in vivo that CD20 TDB remains active in reducing the number of B cells in mice pretreated with rituximab-DANA (Fig. 66). These results indicate a wide range of future applications in the combination therapy of B-cell malignant tumors.

CD20 TDB is a T cell recruiting antibody and its efficacy depends on T cell activation. A study was also conducted to see if pretreatment with steroids, which could potentially interfere with the T-cell immune response, would affect CD20 TDB activity. In vitro, CD20 TDB retained B cell killing activity in the presence of high concentration of dexamethasone (FIG. 65B).

Preclinical validation of CD20 TDB as a potential therapy for CD20+B cell malignancies in cynomolgus monkeys.

A primary study of CD20 TDB FKFD was also performed in cynomolgus monkeys. In a single dose study in which 3 animals were treated once intravenously with 1 mg/kg CD20 TDB, complete depletion of B cells was observed in the blood (Fig. 67A) and in the spleens and lymph nodes (Figs. 67B and 67C) 7 days after antibody treatment. Primary control data is shown in

- 270 040364 mean and standard deviation for 4 animals treated with stock solution (FIG. 67D).

No apparent loss of T cells was observed as CD8+ T cells and CD4+ T cells were present at a comparable or higher level compared to control when calculated as % lymphocytes. T cell activation was detected in the blood 4 hours after dosing. No loss of T cells was observed, and at 7 days post-treatment a markedly higher number of CD8+ T cells were detected in the blood (FIG. 67A).

The long-term effect of CD20 TDB treatment on immune cells was also investigated in a 4-week repeat dose study followed by an 8-week recovery period. The number of B and T cells in the blood of 4 treated with a weekly dose of 1 mg/kg of animals, as well as the serum concentration of CD20 TDB, was determined and plotted for each individual animal over a period of 77 days (Fig. 68A). In all 4 animals, B cells ceased to be detected in the blood shortly after treatment and did not reappear as long as the serum CD20 TDB concentration remained above 100 ng/kg (animal 4502 compared with animals 4001, 4002 and 4503). The number of CD8+ T cells, and to a lesser extent CD4+ T cells, increased significantly after the first dose and gradually decreased in the range of 25-150% of the initial value. In general, CD20 TDB has a high activity in reducing the number of B cells, while not compromising T cells.

The PK properties of CD20 TDB are summarized in FIG. 68B with data on serum CD20 TDB measured in both studies. As shown in the repeat dose study, CD20 TDB maintained good exposure with about 17 ml/day/kg at the time of the first dosing (D0-D7). Target-mediated clearance was higher during the first dosing (D0-D7) as the CL value decreased to about 6 ml/day/kg during the fourth dosing (D21-28).

Combining CD20 TDB with a PD-L1 antagonist in a syngeneic tumor model.

The in vivo efficacy of CD20 TDB in combination with a PD-L1 antagonist (mouse anti-PD-L1 antibody of the isotype IgG2a, 25A1 with DANA mutations) was also investigated in a syngeneic tumor model. In this study, A20-huCD20 mouse lymphoma B cells, which express human CD20 and mouse PD-L1 on the cell surface, were used to create a syngeneic tumor model (see, eg, FIG. 69A). The CD20 TDB used was murine 2H7v16/2C11 TDB of the IgG2a isotype, produced in a ridge-to-hollow (K&H) format (see, e.g., Atwell et al., J. Mol Biol., 270:26-35, 1997), where the protrusion arm is anti-CD20 2H7v16, the trough arm is anti-CD3 2C11 (Leo et al., Proc. Natl. Acad. Sci., USA, 84:1374-8, 1987). The PD-L1 antagonist used was a mouse anti-PD-L1 antibody of the IgG2a isotype with DANA mutations in the Fc region (replacement of residues 265 and 297 with alanine; see, for example, US Pat. Nos. 7,332,581 and 8,219,149).

On day -7, 65 Balb/C mice were subcutaneously inoculated into the right chest region with 2.5 million A20pRK-CD20-GFP cells in HBSS in a volume of 100 μl (not to exceed 200 μl). Mice were left to grow tumors. The mice were then weighed and measured 1-2 times a week until the tumor volume reached an average value of approximately 100-200 mm ³ (approximately 7 days after inoculation). The animals were then divided into the following four treatment groups:

group 1: 2.5 ppm A20/CD20, stock solution, qwx3, BB, n=9;

group 2: 2.5 ppm A20/CD20, anti-CD20xCD3 K&H TDB (mouse 2H7v16-2C11 IgG2), 0.5 mg/kg, qwx3, BB, n=9;

group 3: 2.5 million A20/CD20, aPDL1 (25A1, mIgG2a DANA), 10 mg/kg, tiwx3, WB, n=9; and group 4: 2.5 million A20/CD20, aPDL1 (25A1, mIgG2a DANA), 10 mg/kg, tiwx3, WB+anti-CD20xCD3 K&H TDB (mouse 2H7-2C11 IgG2), 0.5 mg/kg, qwx3 , BB, n=9.

Mice not included in one of the above treatment groups due to differing tumor volumes were sacrificed. Treatment was started on day 0 and all antibody dosing was given intravenously in a volume of 100 ml as described above.

Tumors were measured 1-2 times a week. Body weight was measured twice a week up to 7 days after the last treatment. If no weight loss was observed, the weight was not measured again. If the observed weight loss was >15%, affected mice were weighed daily and sacrificed if the weight loss was greater than or equal to 20%. Clinical examination was performed twice a week throughout the study to monitor the health status of the animals; any animal with a tumor size or condition that adversely affected the health or activity of the animal was euthanized.

As shown in FIG. 69B, combined treatment of CD20 TDB with anti-PD-L1 antibody (group 4) showed an unexpected syngeneic tumor growth inhibitory effect compared to treatment with CD20 TDB, anti-PD-L1 antibody, or stock solution alone.

Combining CD20 TDB with a PD-1 antagonist in a syngeneic tumor model.

In addition, the in vivo efficacy of CD20 TDB in combination with a PD-1 antagonist (mouse anti-PD1 antibody of the IgG2 isotype, 8F11 with DANA mutations) in a syngeneic mouse model of A20/huCD20 B-cell lymphoma was also investigated. In this study, the CD20 TDB used was mouse 2H7v16/2C11 TDB of the IgG2a isotype and the PD-1 antagonist used was a mouse anti-PD-1 antibody of the IgG2 isotype with DANA mutations in the Fc region.

Mouse B-cell lymphoma A20 cells were transfected to express human

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CD20 and GFP, followed by sorting of individual cells for clonal selection and propagation for implantation. Female Balb/c mice (Charles River; Hollister, CA) 8-10 weeks old C were inoculated subcutaneously into the right chest region with 2.5 million A20.hCD20-GFP cells. When tumor volume reached an average value of 100-200 mm ³ , mice were randomly assigned to four treatment groups (n=9 mice/group) and antibody treatment was started on the following day 1:

group 1 (2.5 ppm A20/CD20, stock solution, qwx3, BB);

group 2 (2.5 million A20/CD20, anti-CD20xCD3 K&H TDB (mouse 2H7v16-2C11 IgG2), 0.5 mg/kg, qwx3, BB);

group 3 (2.5 million A20/CD20, anti-PD1 (8F11, mIgG2a DANA), 10 mg/kg, tiwx3, WB); and group 4 (2.5 million A20/CD20, anti-PD1 (8F11, mIgG2a DANA), 10 mg/kg, tiwx3, WB+anti-CD20xCD3 K&H TDB (mouse 2H7v16-2C11 IgG2), 0.5 mg/kg , qwx3, BB).

Mice were treated weekly with BB stock solution or CD20 TDB at 0.5 mg/kg for 3 weeks and/or anti-PD-1 antibody at 10 mg/kg BB at the time of the first dosing, followed by 3x/weekly IP dosing at for 3 weeks (N=9 mice/group).

As shown in FIG. 108A and 108B, combined treatment of CD20 TDB with anti-PD-1 antibody (group 4) demonstrated an unexpected syngeneic tumor growth inhibitory effect compared to treatment with CD20 TDB, anti-PD-1 antibody, or stock solution alone.

Example 4 Generic CD3/FcRH5 TDB (FcRH5 TDB) Preparation and Characterization.

We also investigated the ability of TDB antibodies to recruit the cytotoxic activity of T cells in relation to the destruction of tumor cells by recognizing another cell surface antigen, FcRH5. In this case, we generated and characterized anti-CD3 antibodies containing an anti-CD3 arm and an anti-FcRH5 arm (FcRH5 TDB). As described above, FcRH5 TDB was generated as full-length antibodies in a ridge-to-cavity format as human IgG1 as previously described (Atwell et al., J. Mol. Biol., 270:26-35, 1997). Antibody halves were expressed in E. coli, purified by protein A affinity chromatography, and the corresponding antibody pair halves were annealed in vitro as previously described (Spiess et al., Nat. Biotechnol., 2013). After annealing, FcRH5 TDB was purified by hydrophobic interaction chromatography (HIC) and analyzed by analytical gel filtration, mass spectrometry and polyacrylamide gel electrophoresis as described above. The Ahtu-FcRH5 arm used in the production of FcRH5 TDB was the anti-FcRH5 arm of the 1G7 antibody containing (a) a VH domain containing the amino acid sequence of SEQ ID NO: 268 and (b) a VL domain containing the amino acid sequence of SEQ ID NO: 269.

Ahtu-CD3 arms tested in the production of FcRH5 TDB included UCHT1v9, 40G5c and 38E4v1.

The FcRH5 TDB data were examined for binding to CD8+ T cells (CD3 binding) as well as activity as measured by in vitro cytotoxicity assays and T cell activation assays.

A. Binding affinity.

Binding affinity for each of the FcRH5 TDBs was examined by FACS analysis as described above for CD20 TDB. Briefly, for the FACS binding assay, CD8+ T cells were incubated with different concentrations of FcRH5 TDB antibodies at 4°C for 30 min, then the cells were washed and incubated with 2nd antibody (anti-huIgG-PE; BD Bioscience) for an additional 15 min , after which the cells were washed again and they were ready for FACS analysis. Fig. 70 illustrates the results of an in vitro FACS binding assay for FcRH5 TDB. The results demonstrate that the specific combination of the 38E4v1 anti-CD3 arm paired with the 1G7 anti-FcRH5 arm results in an FcRH5 antibody with higher binding affinity for effector cells.

B. In vitro assay for MOLP-2 target cell killing and T cell activation.

The generated FcRH5 TDBs were also investigated for their ability to promote the killing of FcRH5-expressing MOLP-2 target cells and the activation of the cytotoxic effect of T cells. In vitro cytotoxicity was studied by flow cytometry. Target cells were labeled with CFSE according to the manufacturer's protocol (Invitrogen, no. C34554). Carboxyfluorescein succinimidyl ether (CFSE) labeled target cells and purified CD8+ T cells from human PBMCs were mixed 3:1 with or without TDB for 48 hours. Cells were resuspended in an equivalent volume of PBS+2% FBS+1 mM EDTA+ propidium iodide (PI). Flow cytometry analysis was performed on a FACSCalibur in automatic mode. The number of live target cells was counted by ranking on CFSE+/PI negative cells. The percentage of cytotoxicity was calculated as follows:

% cytotoxicity (number of live target cells m/v TDB-number of live target cells m/TDB)/(number of live target cells m/v TDB)x100

As shown in FIG. 71A and 71B, FcRH5 TDBs with UCHT1v9 or 38E4v1 as anti-CD3 arms demonstrated robust in vitro killing of MOLP-2 target cells compared to FcRH5 TDBs containing 40G5c as anti-CD3 arms.

In the case of the T cell activation assay of FIG. 72A-72D demonstrate that FcRH5 TDB with UCHT1v9 or 38E4v1 as anti-CD3 arms were able to robustly induce T-cell

- 272 040364 in vitro activity compared to FcRH5 TDB containing 40G5c as aHTu-CD3 arms. In this assay, target cells and purified CD8+ T cells were mixed in the presence or absence of TDB, and T cell activation was analyzed by flow cytometry. At the end of the incubation, cells were stained with CD8-FITC (BD Bioscience, 555634), CD69-PE (BD Bioscience, 555531) and CD107a-Alexa-Fluor647 (eBioscience, 51-1079). Alternatively, after surface staining with CD8-FITC and CD69-PE, cells were fixed and permeabilized with Cytofix/CytoPerm solution (BD Bioscience, 554722) and stained intracellularly with anti-granzyme B-Alexa-Fluor647 (BD Bioscience, 560212). T cell activation was assessed by the percentage of CD8+CD69+, CD8+CD107a+ and CD8+CD69+granzyme B+ cells.

Example 5 Generation and characterization of generic CD3/HER2 TDBs (HER2 TDBs).

We also investigated the ability of TDB antibodies to recruit the cytotoxic activity of T cells in relation to the destruction of tumor cells by recognizing another cell surface antigen, HER2. In this case, we generated and characterized anti-CD3 antibodies containing an anti-CD3 arm and an anti-HER2 arm (HER2 TDB). As described above, HER2 TDB was generated as full-length antibodies in the ridge-to-cavity format as human IgG1 as previously described (Atwell et al., J. Mol. Biol., 270:26-35, 1997). Antibody halves were expressed in E. coli or Chinese hamster ovary (CHO) cells, purified by protein A affinity chromatography, and the corresponding halves of antibody pairs were annealed in vitro as previously described (Spiess et al., Nat. Biotechnol., 2013). If TDB antibody production was performed in CHO cells, the antibody contained an aglycosylation mutation, e.g., at residue N297 (e.g., N297G), so that the TDB antibody was a variant with no effector function and was unable to initiate antibody-dependent cell-mediated cytotoxicity (ADCC). ). After HER2 annealing, TDB was purified by hydrophobic interaction chromatography (HIC) and analyzed by analytical gel filtration, mass spectrometry and polyacrylamide gel electrophoresis as described above. One anti-HER2 arm used in the preparation of HER2 TDB was the anti-HER2 arm of the hu4D5 antibody containing (a) a VH domain containing the amino acid sequence of SEQ ID NO: 270 and (b) a VL domain containing the amino acid sequence of SEQ ID NO: : 271.

Additional HER2 TDBs have been generated to target different regions of the extracellular domain (ECD) of HER2. Ahtu-HER2 antibody 2C4 was used as an anti-HER2 arm containing (a) a VH domain containing the amino acid sequence of SEQ ID NO: 593 and (b) a VL domain containing the amino acid sequence of SEQ ID NO: 594.

Another anti-HER2 antibody used as the anti-HER2 arm was the anti-HER2 antibody 7C2 containing (a) a VH domain containing the amino acid sequence of SEQ ID NO: 595 and (b) a VL domain containing the amino acid sequence of SEQ ID NO: :596.

Other anti-HER2 arms used to generate HER2 TDB included the hu4D5 affinity variants hu4D5.91A and hu4D5.Y100A (described in US Pat. No. 7,435,797).

HER2 TDB data were examined for binding to CD8+ T cells (CD3 binding) and SKBR3 cells (HER2 binding), as well as activity as measured by in vitro cytotoxicity assays and T cell activation assays.

A. Binding affinity.

Binding affinity for each of the HER2 TDBs was examined by FACS analysis as described above for CD20 TDBs. Briefly, for the FACS binding assay, Jurkat cells (for CD3 antigen), human CD8+ cells (for CD3 antigen), or SKBR3 cells (for HER2 antigen) were incubated with various concentrations of HER2 TDB antibodies at 4°C for 30 min, then the cells were washed and incubated with 2nd antibody (anti-huIgG-PE, BD Bioscience; or anti-huIgG-AlexaFluor647, Southern Biotech) for an additional 15 min, after which the cells were washed again and were ready for FACS analysis. The geometric mean value of fluorescence was obtained by flow cytometry. Fig. 73, 76A, 78A-78C, 79A and 80A-80B illustrate the results of an in vitro FACS binding assay for HER2 TDB. Several HER2 arms that bind to different regions of HER2 were tested in combination with several CD3 arms that bind to different regions of CD3ε to characterize the binding properties for each combination. In FIG. 76A shows the crystal structure of HER2 and CD3ε EVA and highlights the regions to which different arms of HER2 and CD3 bind. The hu4D5 HER2 antibody is known as trastuzumab and binds to an epitope in domain IV of HER2, which is the region of the protein closest to the membrane. Recombinant humanized murine antibody 2C4 (rhuMAb 2C4), also known as pertuzumab, binds to an epitope in HER2 domain II that is 50 angstroms from the hu4D5 binding site. Pertuzumab (PERJETA®, Genentech, Inc, South San Francisco) is the first in a new class of agents known as HER dimerization inhibitors (HDIs), and its function is to inhibit the ability of HER2 to form active heterodimers or homodimers with other HER receptors (such as EGFR). /HER1, HER2, HER3 and HER4) (Harari,

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Yarden, Oncogene, 19:6102-6114, 2000; Yarden, Sliwkowski., Nat. Rev. Mol. Cell Biol., 2:127-137, 2001; Sliwkowski, Nat. Struct. Biol., 10:158-159, 2003; Cho et al., Nature, 421:756-60, 2003; and Malik et al., Pro. Am.

soc. Cancer Res., 44:176-177, 2003). Ahtu-HER2 mouse antibody 7C2 binds to an epitope in domain I

HER2 (PCT Publication No. WO 98/17797), which is 100 angstroms from the region

HER2 bound by hu4D5 (FIG. 76A).

In addition, the binding affinity of HER2 TDB to several anti-CD3 arms was examined. One of these anti-HER2 arms was combined with high affinity human CD3 targeting arms such as SP34 and 38E4v1. Other HER2 TDB combinations included the low affinity, human CD3-targeted 40G5c arm or the mouse CD3-targeted 2C11 arm. UCHT1v9 with its anti-CD3 arm and hu4D5 with its anti-HER2 arm, herein referred to as HER2 TDB (UCHT1v9/hu4D5) or HER2 TDB, were compared with the anti-HER2 antibody trastuzumab and trastuzumab-Fab fragments in a Scatchard competitive assay (Ramirez - Carrozzi et al., Nature Immunology., 12:1159-1166, 2011). In this assay, binding to SKBR-3 was determined by competitive binding of Fab ¹²⁵ I-trastuzumab to trastuzumab, trastuzumab-Fab or bispecific HER2 TDB. Fig. 74A illustrates the results of the Scatchard in vitro competitive assay for HER2 TDB.

B. In vitro assay for SKBR3 and MCF7 target cell killing and T cell activation.

Combinations of HER2 TDB of one of the three anti-HER2 arms (hu4D5, 2C4 and 7C2) with either high affinity 38E4v1 or low affinity 40G5c anti-CD3 arm were examined in vitro for their ability to mediate targeted killing of HER2 expressing SKBR3 or MCF7 cells (FIG. 77). In vitro activity of hu4D5 TDB with either anti-CD3 arm was more effective than 2C4 and 7C2 TDB in mediating maximum cell killing of SKBR3 and MCF7 as measured by EC50 values (FIG. 78). This killing activity also depended on the CD3 arm used. The combination of anti-CD3 arm 38E4v1 with any of the anti-HER2 arms hu4D5, 2C4 or 7C2 was more effective than combinations of 40G5c HER2 TDB (Fig. 79). Additionally, the study of combinations of 6 HER2 TDB revealed that their activity in relation to the targeted killing of cells does not depend on the level of expression of HER2 in target cells. Fig. 80 illustrates that HER2 TDBs were not selective for high HER2 expressing SKBR3 target cells compared to low HER2 expressing MCF7 target cells. However, HER2 TDB activity was dependent on the affinity of the anti-HER2 arm for HER2 (FIG. 81). Low affinity HER2 TDBs remained active in low HER2 expressing MCF7 cells and were unable to selectively kill HER2 amplified SKBR3 cells (FIG. 82).

Also HER2 TDB was investigated in relation to the specificity of anti-HER2 in relation to the corresponding epitopes of HER2. The killing activity of hu4D5-40G5c HER2-TDB was limited when combined with increasing concentrations of trastuzumab (hu4D5). However, the efficacy of trastuzumab was not affected by the combination of hu4D5 TDB with the hu4D5 antibody (Fig. 83). In contrast, targeted cell killing mediated by 2C4-40G5c or 7C2 38E4v1 was blocked by co-administration of the bivalent monospecific antibodies pertuzumab (2C4) or 7C2, respectively (FIG. 83). When additional anti-HER2 arms were tested in multiple affinity assays, all clones showing high or moderate HER2 TDB activity competed with either trastuzumab or pertuzumab (FIG. 84). To identify candidate TDBs for in vivo analysis, high affinity (38E4v1, 38E4 and SP34) and low affinity (40G5c and 2C11) CD3 arms were examined in vitro with mouse humanized CD3+ T cells in combination with anti-HER2 arms hu4D5, 2C4 and 7C2 ( Fig. 85, 86). Following this analysis, based on killing activity, three candidate TDBs were selected for further in vivo characterization studies: hu4D5-SP34, hu4D5-2C11 and 2C4-38E4. Treatment of HER2-expressing tumor-bearing animals with hu4D5-2C11 HER2 TDB resulted in an increase in CD45+ and CD8+ tumor cells as early as 4 hours post-treatment. Further analysis in HER2-TDB treated tumors revealed an increase in the number of IFNy+ and PD1+ CD8+ T cells, as well as an increase in the presence of regulatory T cells (Treg) (FIG. 87B). The observed increase in immune infiltrates in tumors also correlated with a decrease in tumor volume in HER2-TDB treated animals compared to stock solution control (FIG. 87A). In FIG. The 88A anti-HER2 arm hu4D5 in combination with the low affinity anti-CD3 arm 2C11 or the high affinity CD3 arm SP34 resulted in tumor regression in HER2 transgenic mice. However, this effect was not observed with the lower affinity antu-HER2 arm 2C4 in combination with the high affinity CD3 arm 38E4 (FIGS. 88A, 88B).

HER2 TDB was also compared with bivalent trastuzumab and trastuzumab-Fab fragments for its ability to directly inhibit SKBR3 proliferation. HER2-expressing SKBR3 target cells were seeded in 96-well plates at a density of 5x103 cells/well and incubated overnight for cell attachment prior to treatment with the indicated antibody or antibody fragment. Cell proliferation/viability was analyzed 6 days after treatment by the CELLTITERGLO® Fluorescent Cell Viability Assay (Promega, Madison, WI). The results of this analysis are shown in FIG. 74b. In addition, an additional in vitro

- 274 040364 cytotoxicity assay with trastuzumab, trastuzumab produced in E. coli, and HER2 TDB to determine their ability to induce NK cell-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) (Jefferis, Trends in Pharmacological sciences, 30:356-362 , 2009; Simmons et al., Journal of Immunological Methods, 263:133-147, 2002). Antibodies produced in E. coli are not glycosylated, resulting in impaired FcyR binding required to mediate ADCC. Cytotoxicity assays were performed as in Junttila et al. (Cancer Research., 70:44814489, 2010) using a cytotoxicity kit; LDH (Roche, Mannheim, Germany). Briefly lysed cells were detected by the release of lactate dehydrogenase (LDH) 4 hours after treatment with the defined antibody. The results are shown in FIG. 74C.

The generated HER2 TDBs were also investigated for their ability to promote the killing of HER2-expressing SKBR3 target cells and the activation of the cytotoxic effect of T cells. In vitro cytotoxicity was studied by flow cytometry. Target cells were labeled with carboxyfluorescein succinimidyl ether (CFSE) according to the manufacturer's protocol (Invitrogen, no. C34554). CFSE-labeled target cells and purified CD8+ T cells from human PBMCs were mixed at the specified E:T ratio (as indicated in figure legends) with or without TDB for 24 h. At the end of the incubation, cells were trypsinized and harvested from the plate. Cells were resuspended in an equivalent volume of PBS+2% FBS+1 mM EDTA+propidium iodide (PI). Flow cytometry analysis was performed on a FACSCalibur in automatic mode. The number of live target cells was counted by ranking on CFSE+/PI negative cells. The percentage of cytotoxicity was calculated as follows:

% cytotoxicity (number of live target cells m/v TDB-number of live target cells m/TDB)/(number of live target cells m/v TDB)x100

As shown in FIG. 75, HER2 TDB demonstrated robust in vitro killing of SKBR3 target cells compared to HER2 TDB containing either hu4D5 91A or Y100A affinity variant as anti-HER2 arm (EC50 for hu4D5/UCHT1v9 TDB=0.1 ng/kg; hu4D5.91 A /UCHT1v9 TDB=25.5 ng/kg; hu4D5.Y100A/UCHT1v9 TDB=not determined).

In addition, the binding affinity of the variant anti-HER2 hu4D5 (.4 nM) to the extracellular domain (ECD) of HER2 is higher than to the HER2 arms 2C4 (2.0 nM) and 7C2 (1.7 nM), as shown in FIG. 76b. In addition, FIG. 76C shows that hu4D5 HER2-TDB is a more effective mediator of targeted killing of MCF7 cells than 2C4 HER2-TDB and 7C2 HER2-TDB. Additionally, the kinetics of killing induced by HER2 TDB was analyzed. As seen in FIG. 94A, after 4-12 hours, no significant killing activity was detected. Robust destruction was detected after 24 h, and the destruction activity increased with time. As shown in FIG. 90A-90C and 92C, additional comparison of anti-CD3 arms hu4D5 HER2-TDB demonstrated the effectiveness of different clones in mediating the killing of HER2-expressing SKBR3 cells. In particular, two HER2 TDBs, hu4D5/38E4c and hu4D5/40G5c, were surprisingly as effective in mediating cell killing or even better than hu4D5/SP34 HER2 TDBs (FIGS. 90B and 90C).

In the case of the T cell activation assay, FIG. 89 illustrates that HER2 TDB was able to robustly induce T cell activation in vitro compared to HER2 TDB containing either hu4D5 91A or Y100A affinity variant as an anti-HER2 arm. The three anti-CD3 arms (SP34, 38E4c and 40G5c) of hu4D5 HER2-TDB analyzed showed different binding affinities for the CD3 antigen on human CD8+ T cells, as shown in FIG. 91A. All three HER2-TDBs were able to mediate the activation of CD8+ T cells (FIG. 91B). Additional analysis of the ability of anti-CD3 arms 38E4 and 38E4c hu4D5 HER2-TDB to mediate activation of CD8+ T cells is shown in FIG. 92D. Additionally, the kinetics of T cell activation induced by HER2 TDB was studied. Early signs of T cell activation (CD69) appeared 4 hours after the start of HER2 TDB treatment. At the same time, late markers of activation (extracellular CD107a) were detected later - after 24 hours (Fig. 94A). In addition, T cell activation was not detected after 48 hours if CD8+ cells were incubated with HER2 TDB or target cells that do not express human HER2 (BJAB cells). Robust T cell activation was observed when HER2+ SKBR3 cells were used as targets accompanied by the release of cytotoxic granules (FIG. 93A).

We also examined the ability of HER2 TDB to induce killing of BT474 target cells and activate T cells for the following five ratios of CD8+ effector T cells to target cells: 1:5, 1:2, 1:1, 3:1, and 5:1 . This experiment revealed that cytotoxicity, as measured by LDH release, was significantly reduced by titration of effector cells; however, even at a ratio of E:T<1:1, a weak LDH signal and robust activation of T cells were detected (Fig. 94B).

In this assay, target cells and purified CD8+ T cells were mixed in the presence or absence of TDB, and T cell activation was analyzed by flow cytometry. At the end of the incubation, cells were stained with CD8-FITC (BD Bioscience, 555634), CD69-PE (BD Bioscience, 555531) and CD107aAlexa-Fluor647 (eBioscience, 51-1079). Optionally, cells were stained with CD8-FITC and CD69-PE, and T cell activation was assessed by the percentage of CD8+CD69+ cells in CD8+ cells. Alternatively, after surface staining with CD8-FITC and CD69-PE, cells were fixed and permeabilized with Cytofix/CytoPerm solution (BD Bioscience, 554722) and stained intracellularly with anti-granzyme B-Alexa-Fluor647 (BD Bioscience, 560212). T cell activation was assessed by the percentage of CD8+CD107a+ cells.

Another way to determine T-cell dependent cytotoxicity for HER2 TDB (UCHT1v9/hu4D5) is by analyzing granule exocytosis. Fig. 93B illustrates results for soluble perforin (Cell Sciences), granzyme A, and granzyme B (eBioscience) detected in growth medium by ELISA according to manufacturer's protocols. In this assay, a control TDB (10 ng/kg), which contains the same CD3 arm as HER2 TDB but has an irrelevant target arm, or HER2 TDB (10 ng/kg) was used. Antibodies were separately incubated for 18 hours with SKBR3 target cells and effector peripheral blood mononuclear cells (PBMCs) isolated from the blood of healthy volunteers using lymphocyte separation medium (MP Biomedicals, Solon, OH). In vitro cytotoxicity was determined by LDH release as described above. A series of apoptosis experiments were performed with HER2 TDB (1 ng/kg), effector PBMCs and SKBR3 target cells. At 24 h after treatment, bead exocytosis was consistent with a significant HER2 TDB-induced increase in caspase 3/7 activity (CASPASE-GLO® 3/7 assay, Promega), apoptosis (ELISA ^plus cell death detection assay, Roche), and cytotoxicity as measured by lactate dehydrogenase release ( LDH) as described above (Fig. 93C).

The ability of HER2 TDB to induce killing of transfected HER2 or vector 3T3 cells was determined using the above LDH cytotoxicity assay, and after 19 hours no killing of 3T3 cells was detected; in contrast, HER2-transfected 3T3 cells were destroyed very efficiently (FIG. 93D). The kill assay was modified to block the HER2 binding arm with trastuzumab Fab (1 μg/mL) or HER2 soluble extracellular domain (HER2 EAC) (1 μg/mL), resulting in effective inhibition of the killing activity after 24 h (Fig. 93E). ). To confirm the T-cell killing dependency, CD3+ cells were purified from PBMCs using CD3+ microbeads from Miltenyi (No. 130-050-101). Fig. 93F illustrates that the purification resulted in a loss of targeted cell killing activity after 19 hours in the presence of HER2 TDB according to FACS analysis.

HER2 TDB induces T cell proliferation.

To investigate whether HER2 TDB induces T cell proliferation, CD8+ T cells, target cells (SKBR3) and 0.1 μg/ml HER2 TDB were co-cultured, followed by T cell culture in the absence of target cells and HER2 TDB. Proliferation of T cells was determined on day 3 by flow cytometry as a dilution of CFSE in CD8+/PI- cells with cell division. After 3 days, 75% of the T cells treated with HER2 TDB and target cells underwent cell division as shown in FIG. 95A. The number of HER2 TDB-induced T cells was assessed by labeling purified CD8+ T cells with CFSE according to the manufacturer's protocol (Invitrogen, no. C34554). CFSE-labeled CD8+ T cells were incubated with target cells in the presence or absence of TDB for 19 hours. T cells were harvested, washed and cultured for 2-7 days (RPMI+10% FBS). The number of live CD8+ cells (CD8+/PI-) and the percentage of cells with low brightness CFSE were determined by FACS. According to FIG. 95B the number of cells did not increase. Additional enrichment of growth medium with IL-2 (20 ng/kg) resulted in a signal consistent with CD8+ cell survival, and robust T cell proliferation was only detected when exposed to HER2 TDB and target cells (Fig. 95C) . Importantly, no utility effect was found for non-target-expressing cells under conditions where most of the HER2+ cells in culture were killed. HER2 TDB induced T-cell proliferation and polyclonal expansion, which may be critical for the amplification of tumor-infiltrating lymphocytes.

HER2 TDB activity correlates with the level of HER2 expression in target cells.

To investigate the relationship between target copy number and TDB activity, a panel of cancer cell lines with a predetermined number of HER2 receptors on the cell membrane was selected (Aguilar et al., Oncogene., 18:6050-62, 1999). HER2 protein expression levels in a HER2 negative cell line (BJAB LUC), 3 low HER2 cell lines (MDA435, MDA231, MCF7), and 3 HER2 amplification/overexpression cell lines (MD453, SKBR3, BT474) were determined by Western -blotting (FIG. 96A). HER2-negative, HER2-low and HER2-overexpressing cell lines were incubated with HER2 TDB and with effector PBMCs at an E:T ratio of 25:1 for 26 hours. For this time point, cytotoxicity was determined by LDH release assay. Fig. 96B illustrates that HER2 amplifying/overexpressing cells were significantly more susceptible to TDB-mediated killing (p=0.015, t-test) and efficiently lysed at femtomolar to low picomolar concentrations (EC50=0.8-3 pM). Cell lines expressing low levels of HER2 were significantly less sensitive to the HER2 TDB antibody (EC50=33-51 pM). Even <1000 copies of the target antigen was sufficient to sustain T-cell killing.

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For the studies illustrated in FIG. 96C, 96D, the MCF7 cell line or the BJAB cell line together with SKBR3 cells were targeted in the presence of HER2 TDB in one kill assay. In this assay, MCF7 or BJAB cells were labeled with CFSE and mixed with SKBR3 and PBMC (E:T 20:1) followed by 19 hours of HER2 TDB treatment. Cells were stained with anti-HER2 APC and PL. Fig. 96C illustrates the percentage of live SKBR3 (high HER2, PI-) and MCF7 (CFSE+, PI-) cells detected by FACS and normalized to fluorescent beads. For MCF7 cells, no killing was detected at an EC50 corresponding to killing SKBR3. The percentage of live SKBR3 (high HER2, PI-) and BJAB (CFSE+ PI-) cells detected by FACS and normalized to fluorescent beads is shown. There was no significant killing of BJAB cells at any concentration of HER2 TDB (FIG. 96D).

Very low target occupancy is sufficient for TDB activity.

Next, HER2 occupancy at EC50 for HER2 TDB was calculated using the formula [D]/[D]+Kd (where D=drug and Kd for HER2 TDB was 5.4 nM). The number of copies of HER2 has been determined previously (Aguilar et al., Oncogene., 18:6050-6062, 1999). EC50 values were calculated from the dose response data in FIG. 97b. Fig. 96E illustrates that in all cell lines tested, less than 1% target occupancy was sufficient for effective killing. In the case of cell lines with high expression of HER2, the required occupancy was even lower (0.01-0.05%). The calculated absolute amount of HER2 TDB associated with HER2 at EC50 was only 10-150 for low expression cell lines. These results demonstrate the high efficiency of HER2 TDB and are consistent with studies on TCR stimulation suggesting that only 1-25 RTKs are required to trigger T cell responses (Irvine et al., Nature., 419:845-849, 2002; Purbhoo et al., Nature Immunology. 5:524-530, 2004; Sykulev et al., Immunity. 4:565-571, 1996). The potency of HER2 TDB was stable over a low picomolar to femtomolar range. In addition, as few as 10-500 TDBs associated with HER2 were sufficient to induce significant in vitro cytotoxicity. Just ~1000 copies of HER2 on the plasma membrane were enough to induce killing. These studies also demonstrated a correlation between target expression levels and in vitro sensitivity to HER2 TDB.

HER2 TDB effectively destroys HER2+ cancer cells that are resistant to anti-HER2 therapy.

Next, we examined cell lines that have previously been shown to express high levels of HER2 but are not susceptible to the direct cellular effects of trastuzumab and lapatinib in vitro (Junttila et al., Cancer Cell, 15:429-40, 2009; Junttila et al. , Breast Cancer Res. Treat., 2010). For some cell lines, activation of the PI3K pathway due to acquired activation mutations in the PI3K catalytic subunit (KPL4, HCC202) or due to loss of PTEN (HCC1596) can lead to resistance. A panel of six cell lines (5 breast cancers, 1 lung cancer) was examined for LDH release as an indicator of cytotoxicity in the presence of effector PBMCs at a ratio of 10:1 and HER2 TDB for 19 hours. The EC50 for HER2 mediated TDB killing was femtomolar or low picomolar range (FIG. 97A). Parental and T-DM1 resistant clones of BT474-M1 were treated with T-DM1 for 3 days. For this time point, cell viability was determined using CELLTITERGLO® (FIG. 97B). Data on the sensitivity of cell lines to T-DM1 have been published previously (Junttila et al., Breast Cancer Res. Treat., 2010; Lewis Phillips et al., Cancer Research., 68:9280-9290, 2008). For comparison, parental and T-DM1 resistant BT474-M1 clones were treated with HER2 TDB in the presence of CD8+ effector T cells at a ratio of 3:1 for 24 hours. Cytotoxicity was determined by FACS analysis (Fig. 97C). In addition, HER2 TDB effectively killed HER2+ lung cancer cells. When using two independent models of cell lines KPL4 and BT474 (Fig. 97B, 97C) acquired resistance to T-DM1 did not affect the sensitivity to HER2 TDB.

HER2 TDB activation of T-cell killing activity is dependent on HER2 expression but independent of HER2 signaling, suggesting that HER2 TDB may be effective in treating tumors that are not amenable to current anti-HER2 therapies. Accordingly, the data showed similar potency when treated with trastuzumab/lapatinib multi-resistant cell lines and susceptible cells. Resistance in these cells is achieved by various mechanisms of action on the HER2 pathway. The data presented here suggest that switching to an alternative mode of action by using HER2 TDB broadly may overcome resistance to antibody-drug conjugates (e.g., T-DM1), targeted small molecule inhibitors (e.g., lapatinib), and therapeutic monoclonal drugs. antibodies that block the signaling pathway (eg, trastuzumab).

Pharmacokinetics of HER2 TDB in rats.

Sprague-Dawley rats were used to evaluate the pharmacokinetic (PK) profile of HER2 TDB. Animals were divided into the following two groups:

group 1: HER2 TDB (10 mg/kg, one BB, n=4);

group 2: trastuzumab (10 mg/kg, one BB, n=4).

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Samples were taken from 4 rats per group at specific time points during the 35 days following dosing. From the jugular vein collected approximately 0.2 ml of whole blood (under anesthesia CO ₂ /O ₂ ). The samples were allowed to clot and centrifuged under cold (5°C for 10 min at 2000xg) to obtain serum. Serum samples were analyzed for human IgG by ELISA, which used a microtiter plate coated with donkey anti-huFc to capture humanized anti-HER2 antibodies in circulation and goat anti-huFc-HRP (adsorbed by mice) for detection. PK parameters were determined by the 2-compartment method (model 7) using WINNONLIN® version 5.2.1 (Pharsight Corp., Mountain View, CA). HER2 TDB does not cross-react with rat CD3 or rat HER2 and exhibits a biphasic distribution typical of IgG1 with a short distribution phase and a slow elimination phase (FIG. 98). Both the clearance and half-life of HER2 TDB were similar to those of trastuzumab and were within the expected range of typical rat IgG1.

HER2 TDB inhibits tumor growth in vivo in immunodeficient mice.

In vivo efficacy of HER2 TDB was studied in NOD-SCID mice that lacked endogenous functional T and B cells and had reduced levels of NK cells, DCs, and macrophages. In this experiment, NOD/SCID mice (NOD.CB17-Prkdcscid/J, Jackson Labs West) were subcutaneously implanted with 0.36 mg estrogen granules with a 60-day release period (Innovative Research of America) 1-3 days prior to cell inoculation in the opposite tumor inoculation side. On day 0, 5x106 MCF7-neo/HER2 cells, alone or together with 10x106 unstimulated human PBMCs from one or two healthy donors (PBMCs 1, 2), were injected in HBSS matrigel into the right 2/3 of breast adipose tissue. Inoculated mice were divided into the following five groups:

group 1: stock solution (control TDB, 0.5 mg/kg, qwkx3, BB from day 0, n=5-10);

group 2: PBMC(1) (PBMC(1)+control TDB, 0.5 mg/kg, qwkx3, BB from day 0, n=5-10);

group 3: PBMC(1)+HER2 TDB (PBMC(1)+HER2 TDB, 0.5mg/kg, qwkx3, BB from day 0, n=5-10); group 4: PBMC(2) (PBMC(2)+control TDB, 0.5 mg/kg, qwkx3, BB from day 0, n=5-10); and group 5: PBMC(2)+HER2 TDB (PBMC(2)+HER2 TDB, 0.5 mg/kg, qwkx3, BB from day 0, n=5-10).

The first treatment was carried out 2 hours after inoculation. Tumor volumes of individual mice and approximate tumor volumes by treatment group are shown in FIG. 99A showing that HER2 TDB prevented the growth of HER2 expressing tumors.

Additionally, the dependence of HER2 TDB on human PBMCs was investigated in a similar immunodeficient mouse model. Again, 5x106 MCF7-neo/HER2 cells, alone or together with 10x106 unstimulated human PBMC from a healthy donor (PBMC 3), in HBSS matrigel were injected again into the right 2/3 of breast adipose tissue, and the first treatment was carried out 2 hours after inoculation. As shown in FIG. 100A, inoculated mice were divided into the following two groups:

group 1: no treatment (n=7);

group 2: HER2 TDB (HER2 TDB, 0.5 mg/kg, qwkx3, BB from day 0, n=7).

As shown in FIG. 100B, inoculated mice were divided into the following three groups: group 1: no treatment (n=7);

group 2: PBMC(3) (PBMC(3)+stock solution, 0.5 mg/kg, qwkx3, BB from day 0, n=7);

group 3: PBMC(3)+control TDB (PBMC(3)+control TDB-2C11, 0.5 mg/kg, qwkx3, BB, starting on day 0, n=7).

The resulting tumor volume measurements showed no effect on tumor growth in control TDB treated animals.

HER2 TDB induces regression of large mammary tumors in huHER2 transgenic mice.

To model HER2 TDB activity in immunocompetent mice, human MMTV-huHER2 transgenic mice were used (Finkle et al., Clinical Cancer Research., 10:2499-2511, 2004) IgG2A reactive antibody (Leo et al., Proc. Natl. Acad. Sci., USA, 84:1374-1378, 1987) was generated to avoid an immune response against TDB. For expression as muIgG2a, the same lip-to-bottom mutations were introduced into the Fc region (Atwell et al., J. Mol. Biol., 270:26-35, 1997), as well as D265A and N297G (EU numbering) to block effector function. In muIgG2a HER2 TDB, the shoulder of the ridge was the mouse anti-HER2 hu4D5 and the trough was any chimeric 2C11 directed against mouse CD3 (Leo et al., Proc. Natl. Acad. Sci., USA, 84:1374-1378, 1987) ( TDB 2C11/hu4D5), or SP34 directed against mouse CD3 (Pessano et al., The EMBO Journal, 4:337-344, 1985) (TDB SP34/hu4D5). Bispecific muIgG2a antibodies were expressed in CHO cells and collected by in vitro assembly. Bispecific antibodies were purified from contaminants by hydrophobic interaction chromatography (HIC) as described elsewhere (Speiss et al., Nat Biotechnology., 31:753-758, 2013). The resulting material was analyzed for endotoxin levels using the portable ENDOSAFE® test system (Charles River, USA) and, if necessary, endotoxin content was reduced by washing the protein with 0.1% TRITON™ X-114. In vitro activity of hu4D5/2C11-TDB

- 278 040364 was similar to human CD3 HER2 TDB reactive (FIG. 101).

As shown in FIG. 99B-99D, MMTV-huHER2 transgenic animals with established mammary tumors were divided into the following two groups:

group 1: stock solution (0.5 mg/kg, qwkx5, BB from day 0, n=7); and group 2: HER2 TDB (HER2 TDB (2C11/hu4D5), 0.5 mg/kg, qwkx5, BB from day 0, n=7).

Fig. 99B illustrates that regression was detected in 57% of mice and 43% of mice had no detectable tumors after treatment. Fig. 99C illustrates that HER2 TDB (2C11/hu4D5) resulted in over 50% tumor regression with the exception of one tumor. As seen in FIG. 99D, at the start of treatment, the responders had tumors that were >1000 mm ³ . In a similar experiment, two control TDBs were used, of which one was a CD3 arm control TDB in which the mouse CD3 specific arm was replaced by a mouse CD3 specific arm (HER2 TDB (SP34/hu4D5)), and the second was a control TDB containing the same CD3 arm as HER2 TDB (2C11/hu4D5) but with an irrelevant target arm (CTRL TDB-2C11). As shown in FIG. 99E, MMTV-huHER2 transgenic animals with established mammary tumors were divided into the following two groups:

group 1: CD3 arm TDB control (HER2 TDB (SP34/hu4D5), 0.5 mg/kg, qwkx5, BB from day 0, n=5); and group 2: control TDB (control TDB-2C11, 0.5 mg/kg, qwkx5, BB from day 0, n=5).

Control TDBs had no effect on the growth of transgenic MMTV-huHER2 tumors.

Additionally, HER2 TDB was studied for in vivo efficacy in huCD3 transgenic mice. Human CD3ε transgenic mice have been described previously ((huCD3 transgenic), de la Hera et al., J. Exp. Med., 173:7-17, 1991). In this study, 0.1 million CT26-HER2 cells were injected subcutaneously into huCD3 transgenic mice. After engraftment of CT26-HER2 tumors, animals were divided into the following two groups:

group 1: stock solution (0.5 mg/kg, qwkx3, BB, from day 0, n=7);

group 2: HER2 TDB (HER2 TDB (SP34/hu4D5), 0.5 mg/kg, qwkx3, BB from day 0, n=7).

HER2 TDB inhibited the growth of established tumors, but the effect was temporary and no full response was observed (FIG. 99F). The study demonstrated effective in vivo HER2 TDB activity, including striking responses in MMTV-huHER2 transgenic mice.

In a similar experiment, the in vivo efficacy of mouse reactive HER2 TDB (2C11/hu4D5) was studied in Balb/c mice. Again, Balb/c mice were engrafted with syngeneic tumors by subcutaneous injection of 1x105 CT26-HER2 cells. Tumor-bearing animals were divided into the following four groups:

group 1: stock solution (0.5 mg/kg, qwkx3, BB, from day 0, n=10);

group 2: HER2 TDB (HER2 TDB (2C11/hu4D5), 0.5 mg/kg, qwkx3, BB from day 0, n=10);

group 3: control TDB (CTRL TDB (2C11/hu4D5), 0.5 mg/kg, qwkx3, BB from day 0, n=10); and group 4: TDM-1 (TDM-1, 15 mg/kg, qwkx3, BB from day 0, n=10).

Fig. 99G illustrates that despite incomplete HER2 responses, TDB significantly prolonged the time to tumor progression (log-rank p-value <0.0001). In contrast, control TDB with an irrelevant tumor shoulder had no effect on tumor growth. In addition, the tumors were insensitive to TDM-1.

HER2 TDB inhibits the growth of established tumors in immunocompetent mice.

Human CD3ε transgenic mice (de la Hera et al., J. Exp. Med., 173:7-17, 1991) were used to model HER2 TDB activity in immunocompetent mice. In this experiment, huCD3 transgenic T cells were isolated from the spleens of huCD3 transgenic and BALB/c mice or from the peripheral blood of healthy human donors. Cells were stained with mouse or human CD8 and human CD3 (clone UCHT1) from FIG. 101A or mouse CD3 (clone 2C11) from FIG. 101b. CD8+ cells were detected by flow cytometry. Fig. 101A illustrates that huCD3 transgenic T cells express human CD3 at approximately 50% of human T cells, and FIG. 101B illustrates that huCD3 transgenic T cells express mouse CD3 at approximately 50% of BALB/c mice.

The huCD3 transgenic T cells were further evaluated for their ability to kill human HER2 expressing target CT26 cells in vitro. In this experiment, T cells were isolated from the spleens of huCD3 transgenic mice, BALB/c mice, or from the peripheral blood of healthy human donors. In vitro killing activity of CT26-HER2 cells was examined using the human CD3-specific HER2 TDB (UCHT1v9/hu4D5) of FIG. 102A or mouse CD3-specific HER2 TDB (2C11/hu4D5) of FIG. 102b. Effector T cells were added at a ratio of 20:1 to target cells in the presence of the indicated HER2 TDB for 40 hours. In vitro cytotoxicity was monitored by flow cytometry. Although the killing activity of mouse spleen T cells (EC50=2.4 ng/kg) was consistently lower than that of human peripheral T cells (EC50=0.4 ng/kg), huCD3 transgenic T cells killed expressing human 279 040364 target cell HER2 in vitro as seen in FIG. 102A. Mouse specific HER2 TDB (2C11/hu4D5) induced targeted cell killing by T cells from both huCD3 transgenic mice (eC50=11 ng/kg) and BALB/c mice (EC50=10 ng/kg) as seen in FIG. 102b.

The T-cell dependence of the antitumor activity of HER2 TDB was further evaluated in a syngeneic tumor model. As described above, 1x105 CT26-HER2 cells were injected subcutaneously into BALB/c mice. Mice with established tumors were assigned to one of the following two groups:

group 1: stock solution (n=10);

group 2: HER2 TDB (SP34/hu4D5) (HER2 TDB (SP34/hu4D5), 0.5 mg/kg, qwx3, BB, n=10).

Fig. 103 illustrates that HER2 TDB activity was T-cell dependent, as HER2 TDB had no effect in non-transgenic huCD3 mice. This study demonstrates that huCD3 transgenic mice can be used as a new efficient model for studying huCD3 targeting molecules.

Example 6 Preparation and characterization of generic CD3/LYPD1 TDBs (LYPD1 TDBs).

We also investigated the ability of TDB antibodies to recruit the cytotoxic activity of T cells in relation to the destruction of tumor cells by recognizing another cell surface antigen, LYPD1. In this case, we generated and characterized bispecific anti-CD3 antibodies containing an anti-CD3 arm and an anti-LYPD1 arm (LYPD1 TDB). As described above, LYPD1 TDB was generated as full-length antibodies in the ridge-to-cavity format as human IgG1 as previously described (Atwell et al., J. Mol. Biol., 270:26-35, 1997). Antibody halves were expressed in E. coli or Chinese hamster ovary (CHO) cells, purified by protein A affinity chromatography, and the corresponding halves of antibody pairs were annealed in vitro as previously described (Spiess et al., Nat. Biotechnol., 2013). If TDB antibody production was performed in CHO cells, the antibody contained an aglycosylation mutation, e.g., at the N297 residue (e.g., N297G), so that the TDB antibody was a variant with no effector function and was unable to initiate antibody-dependent cell-mediated cytotoxicity (AZKTS). After annealing LYPD1, TDB was purified by hydrophobic interaction chromatography (HIC) and analyzed by analytical gel filtration, mass spectrometry and polyacrylamide gel electrophoresis as described above. The anti-LYPDI arm used in the production of LYPD1 TDB was the arm of the anti-LYPD1 antibody YWO.49.H6 containing (a) a VH domain containing the amino acid sequence of SEQ ID NO: 272 and (b) a VL domain containing the amino acid sequence SEQ ID NO: 273.

Ahtu-CD3 arms investigated in the preparation of LYPD1 TDB included UCHT1v9, 40G5, SP34 and 38E4v1.

HER2 TDB data was examined for binding to CD8+ T cells (CD3 binding) as well as activity as measured by in vitro cytotoxicity assays and T cell activation assays.

A. Binding affinity.

Binding affinity for each of the LYPD1 TDBs was examined by FACS analysis as described above for CD20 TDBs. Briefly, for the FACS binding assay, CD8+ T cells were incubated with various concentrations of LYPD1 TDB antibodies at 4°C for 30 min, then cells were washed and incubated with 2nd antibody (anti-huIgG-PE; BD Bioscience) for an additional 15 min , after which the cells were washed again and they were ready for FACS analysis. Fig. 104 illustrates the results of an in vitro FACS binding assay for LYPD1 TDB. Binding studies show that LYPD1 TDBs containing UCHT1v9 or 38E4v1 as the anti-CD3 arm showed higher binding affinity for the resulting effector cells.

B. In vitro assay for OVCARS.Luc target cell killing and T cell activation.

The generated LYPD1 TDBs were also investigated for their ability to promote killing of LYPD1-expressing OVCAR3.Luc target cells and activating the cytotoxic effect of T cells. In vitro cytotoxicity was studied by flow cytometry. Target cells were labeled with CFSE according to the manufacturer's protocol (Invitrogen, no. C34554). Carboxyfluorescein succinimidyl ether (CFSE) labeled target cells and purified CD8+ T cells from human PBMCs were mixed 3:1 with or without TDB for 48 hours. Cells were resuspended in an equivalent volume of PBS+2% FBS+1 mM EDTA+ propidium iodide (PI). Flow cytometry analysis was performed on a FACSCalibur in automatic mode. The number of live target cells was counted by gating on CFSE+/PI negative cells. The percentage of cytotoxicity was calculated as follows:

% cytotoxicity (number of live target cells m/v TDB-number of live target cells m/TDB)/(number of live target cells m/v TDB)x100

As shown in FIG. 105, LYPD1 TDB with UCHT1v9, 38E4v1, or SP34 as anti-CD3 arms demonstrated robust in vitro killing of OVCAR3.Luc target cells compared to LYPD1 TDB containing 40G5c as anti-CD3 arm.

In the case of the T cell activation assay, FIG. 106 demonstrates that LYPD1 TDB with 38E4v1 and to a lesser extent UCHT1v9 and SP34 as aHTu-CD3 arms were able to robustly induce T cell activity in vitro compared to LYPD1 TDB containing 40G5c as antiCD3 arm. In this assay, target cells and purified CD8+ T cells were mixed in the presence or absence of TDB, and T cell activation was analyzed by flow cytometry. At the end of the incubation, cells were stained with CD8-FITC (BD Bioscience, 555634), CD69-PE (BD Bioscience, 555531) and CD107a-Alexa-Fluor647 (eBioscience, 51-1079). Alternatively, after surface staining with CD8-FITC and CD69-PE, cells were fixed and permeabilized with Cytofix/CytoPerm solution (BD Bioscience, 554722) and stained intracellularly with anti-granzyme B-Alexa-Fluor647 (BD Bioscience, 560212). T cell activation was assessed by the percentage of CD8+CD69+ and CD8+CD25+ cells.

Other embodiments of the invention

Although the foregoing invention has been described in some detail by way of illustration and examples for purposes of unambiguous understanding, the description and examples should not be taken as limiting the scope of the invention. The contents of all patents and scientific literature referenced in this document are expressly and in their entirety incorporated by reference.

Claims (50)

CLAIM 1. A bispecific antibody that binds to HER2 and CD3, wherein the bispecific antibody contains an anti-CD3 arm containing a first binding domain containing the following six hypervariable regions (HVRs): (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 2; (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 3; (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 4; (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 5; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 6; and an anti-HER2 arm containing a second binding domain containing the following six (HVRs): (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 169; (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 170; (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 171; (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 172; (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 173; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 174. 2. Bispecific antibody according to claim 1, characterized in that the first binding domain contains (a) a heavy chain variable domain (VH) containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 184; (b) a light chain variable domain (VL) containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 185; or (c) a VH domain according to (a) and a VL domain according to (b). 3. A bispecific antibody according to claim 2, characterized in that the VH domain contains the amino acid sequence of SEQ ID NO: 184 and/or the VL domain contains the amino acid sequence of SEQ ID NO: 185. 4. Bispecific antibody according to any one of claims 1 to 3, characterized in that the second binding domain contains (a) a VH domain containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 270; (b) a VL domain containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 271; or (c) a VH domain according to (a) and a VL domain according to (b). 5. Bispecific antibody according to claim 4, characterized in that the second binding domain contains (a) a VH domain containing the amino acid sequence of SEQ ID NO: 270; and/or (b) a VL domain containing the amino acid sequence of SEQ ID NO: 271. 6. A bispecific antibody according to any one of claims 1 to 5, characterized in that it contains an anti-CD3 arm containing a first binding domain containing (a) a VH domain containing the amino acid sequence of SEQ ID NO: 184; and (b) a VL domain containing the amino acid sequence of SEQ ID NO: 185, and an anti-HER2 arm containing a second binding domain containing (a) a VH domain containing the amino acid sequence of SEQ ID NO: 270; And - 281 040364 (b) VL domain containing the amino acid sequence of SEQ ID NO: 271. 7. A bispecific antibody according to any one of claims 1 to 6, characterized in that the first binding domain binds to a human CD3 polypeptide or a cynomolgus CD3 polypeptide. 8. The bispecific antibody of claim 7, wherein (a) the human CD3 polypeptide is a human CD3ε polypeptide or a human CD3y polypeptide; or (b) the cynomolgus CD3 polypeptide is a cynomolgus CD3ε polypeptide or a cynomolgus CD3y polypeptide. 9. A bispecific antibody according to any one of claims 1 to 8, characterized in that the bispecific antibody contains a substitution mutation in the Fc region that reduces effector function. 10. A bispecific antibody according to claim 9, characterized in that the substitution mutation occurs at the amino acid residue N297, L234, L235 and/or D265 (EU numbering). 11. The bispecific antibody of claim 10, wherein the substitution mutation is selected from the group consisting of N297G, N297A, L234A, L235A, and D265A. 12. Bispecific antibody according to any one of claims 1 to 11, characterized in that the bispecific antibody is one or more of (i) a humanized antibody or a chimeric antibody; and (ii) IgG antibodies. 13. A bispecific antibody according to any one of claims 1 to 12, wherein the bispecific antibody comprises one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from the first CH1 domain (CH11), the first CH2 domain ( CH21), first CH3 domain (CH31), second CH1 domain (CH12), second CH2 domain (CH22), and second CH3 domain (CH32). 14. The bispecific antibody of claim 13, wherein at least one of one or more heavy chain constant domains is conjugated to another heavy chain constant domain, wherein (i) each of the CH31 and CH32 domains contains a ridge or a trough, with that the ridge or trough in the CH31 domain is compatible with the trough or ridge in the CH32 domain, respectively; or (ii) each of the CH21 and CH22 domains contains a ridge or pit, with the ridge or pit in the CH21 domain being compatible with the pit or ridge in the CH22 domain, respectively. 15. A bispecific antibody according to claim 14, characterized in that the anti-CD3 arm contains a trough and the anti-HER2 arm contains a ridge. 16. A set of nucleic acids encoding a bispecific antibody according to any one of claims 1-15. 17. A set of expression vectors containing a set of isolated nucleic acids according to claim 16. 18. A set of host cells for expressing a set of nucleic acids, where the set of host cells contains a set of expression vectors according to claim 17. 19. An isolated nucleic acid encoding a bispecific antibody according to any one of claims 1-15. 20. An expression vector containing the isolated nucleic acid according to claim 19. 21. A host cell for expressing a nucleic acid, comprising an expression vector according to claim 20. 22. A method for producing a bispecific antibody according to any one of claims 1 to 15, comprising culturing the host cell according to claim 21 in a culture medium and isolating the bispecific antibody from the host cell or culture medium. 23. An immunoconjugate that binds HER2 and CD3, containing a bispecific antibody according to any one of claims 1-15 and a cytotoxic agent. 24. A composition for treating or slowing the progression of a cell proliferative disorder, wherein the composition comprises a bispecific antibody according to any one of claims 1 to 15 and a pharmaceutically acceptable carrier, excipient or diluent. 25. The composition according to claim 24, characterized in that the composition further comprises an antagonist that binds to a component of the PD-1 signaling pathway or an additional therapeutic agent. 26. The use of a bispecific antibody according to any one of claims 1 to 15 in the manufacture of a medicament for treating or slowing the progression of a cell proliferative disorder. 27. The use of a bispecific antibody according to any one of claims 1 to 15 in the manufacture of a medicament for enhancing immune function. 28. Use according to claim 26 or 27, wherein the cell proliferative disorder is a HER2 positive cancer. 29. Use according to claim 28, wherein the HER2 positive cancer is HER2 positive breast cancer or HER2 positive gastric cancer. 30. A method of treating or slowing the progression of a cell proliferative disorder in a subject in need thereof, comprising administering to the subject an effective amount of a bispecific antibody according to any one of claims 1-15. 31. A method for enhancing immune function in a subject having a cell proliferative disorder - 282 040364 disruption, comprising administering to the subject a bispecific antibody according to any one of claims 1-15. 32. The method of claim 30 or 31, wherein the cell proliferative disorder is a HER2 positive cancer. 33. The method of claim 32, wherein the HER2 positive cancer is HER2 positive breast cancer or HER2 positive stomach cancer. 34. The method of any one of claims 30-33, wherein the bispecific antibody is administered to the subject at a dose of from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg or about 1 mg/kg. 35. The method of any one of claims 30-34, further comprising administering to the subject an antagonist that binds to a component of the PD-1 signaling pathway and/or an additional therapeutic agent. 36. The method of claim 35, wherein the antagonist that binds to a component of the PD-1 signaling pathway is a PD-L1 binding antagonist. 37. The method of claim 36 wherein the PD-L1 binding antagonist is selected from the group consisting of MPDL3280A, MDX-1105 and MEDI4736. 38. The method of claim 35, wherein the antagonist that binds to a component of the PD-1 signaling pathway is a PD-1 binding antagonist. 39. The method of claim 38 wherein the PD-1 binding antagonist is selected from the group consisting of MDX-1106 (nivolumab), MK-3475 (lambrolizumab) and AMP-224. 40. The method of claim 35, wherein the antagonist that binds to a component of the PD-1 signaling pathway is a PD-L2 binding antagonist. 41. The method of claim 40 wherein the PD-L2 binding antagonist is an antibody or an immunoadhesin. 42. The method of any one of claims 30-41, further comprising administering a glucocorticoid or an antibody drug conjugate (ADC) to the subject. 43. The method of any one of claims 30-42, further comprising administering to the subject one or more therapeutic agents that target the HER pathway. 44. The method of claim 43 wherein the one or more additional therapeutic agents that target the HER pathway are selected from trastuzumab, T-DM1 and pertuzumab. 45. The method of claim 44 wherein the additional therapeutic agent is trastuzumab. 46. The method according to any one of claims 30-45, characterized in that the bispecific antibody is administered subcutaneously, intravenously, intramuscularly, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly or intranasally. 47. The method according to any one of claims 30-46, characterized in that the subject is a human. 48. A kit for treating or slowing the progression of a cell proliferative disorder in a subject, comprising the composition of claim 24 or 25 and an insert containing instructions for administering the composition to a subject to treat or slow the progression of a cell proliferative disorder. 49. The kit of claim 48, wherein the cell proliferative disorder is a HER2 positive cancer. 50. The kit according to claim 49, wherein the HER2 positive cancer is HER2 positive breast cancer or HER2 positive gastric cancer. QDGNEEMGGlTQTPYKVSISGTTVILTCPQYPGSEiLWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRG SKPEDANFYLYLRARVDDGSADDAKKDAAKKDDAKKDDAKKDGSQSIKGNHLVKVYDYQEDGSVLLTCDAEAKNITWFKD GKMIGFLTEDKKKWNLGSNAKMYDPRGQ2CK2