WO2024050421A2 - Molécules de liaison à l'antigène ciblant la protéine 1 de mort cellulaire programmée (pd-1) - Google Patents

Molécules de liaison à l'antigène ciblant la protéine 1 de mort cellulaire programmée (pd-1) Download PDF

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WO2024050421A2
WO2024050421A2 PCT/US2023/073172 US2023073172W WO2024050421A2 WO 2024050421 A2 WO2024050421 A2 WO 2024050421A2 US 2023073172 W US2023073172 W US 2023073172W WO 2024050421 A2 WO2024050421 A2 WO 2024050421A2
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seq
amino acid
acid sequence
lcdr2
hcdr1
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PCT/US2023/073172
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WO2024050421A3 (fr
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Yue Liu
Gevorg GRIGORYAN
Alexis Hiram Ramos
Tate TABTIENG
Adam Reid Root
Cheuk Lun Leung
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Flagship Pioneering Innovations Vi, Llc
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Publication of WO2024050421A3 publication Critical patent/WO2024050421A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/75—Agonist effect on antigen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

  • PD-1 Programmed cell death protein 1
  • IBDs inflammatory bowel diseases
  • the disclosure provided herein is based, in part, on the discovery of polypeptides that specifically bind to PD-1. Accordingly, the disclosure generally relates to polypeptides (e.g., antibodies), compositions (e.g., pharmaceutical compositions) and methods that are useful for binding to PD-1 and, in some embodiments, modulating (e.g., increasing, enhancing) PD-1 signaling (e.g., in vivo).
  • polypeptides e.g., antibodies
  • compositions e.g., pharmaceutical compositions
  • modulating e.g., increasing, enhancing
  • PD-1 signaling e.g., in vivo
  • polypeptides e.g., antibodies and antigen binding fragments thereof
  • PD-1 e.g., full-length human PD-1 - 1 - 3820371.v1 5708.1067001 or a variant thereof.
  • polypeptides disclosed herein function as agonists of PD-1 signaling.
  • the disclosure provides, among other things, a polypeptide comprising a paratope that is substantially similar to a paratope of an antibody comprising a VH/VL pair selected from: SEQ ID NO:206 and SEQ ID NO:217 (AB-65); SEQ ID NO:215 and SEQ ID NO:104 (AB-75); SEQ ID NO:214 and SEQ ID NO:226 (AB-74); SEQ ID NO:3 and SEQ ID NO:60 (AB-1); SEQ ID NO:4 and SEQ ID NO:61 (AB-2); SEQ ID NO:5 and SEQ ID NO:62 (AB-3); SEQ ID NO:3 and SEQ ID NO:63 (AB-4); SEQ ID NO:6 and SEQ ID NO:64 (AB-5); SEQ ID NO:7 and SEQ ID NO:65 (AB-6); SEQ ID NO:8 and SEQ ID NO:66 (AB-7); SEQ ID NO:9 and SEQ ID NO:60 (AB-8); SEQ ID NO:10 and SEQ ID NO:
  • the disclosure also provides, among other things, a polypeptide comprising: an immunoglobulin heavy chain variable domain (VH) amino acid sequence comprising a heavy chain complementarity determining region 1 (HCDR1), a heavy chain complementarity determining region 2 (HCDR2) and a heavy chain complementarity determining region 3 (HCDR3) that are substantially similar to an HCDR1, an HCDR2 and an HCDR3, respectively, of a V H amino acid sequence set forth in any of SEQ ID NOs:3-17, SEQ ID NOs:19-58, and SEQ ID NOs:206-216; and an immunoglobulin light chain variable domain (VL) amino acid sequence comprising a light chain complementarity determining region 1 (LCDR1), a light chain complementarity determining region 2 (LCDR2) and a light chain complementarity determining region 3 (LCDR3) that are substantially similar to an LCDR1, an LCDR2 and an LCDR3, respectively, of a VL amino acid sequence set forth in any of SEQ ID NO
  • a polypeptide comprises the HCDR1, HCDR2 and HCDR3, and the LCDR1, LCDR2 and LCDR3, of an antibody comprising a VH/VL pair selected from: SEQ ID NO:206 and SEQ ID NO:217 (AB-65); - 4 - 3820371.v1 5708.1067001 SEQ ID NO:215 and SEQ ID NO:104 (AB-75); SEQ ID NO:214 and SEQ ID NO:226 (AB-74); SEQ ID NO:3 and SEQ ID NO:60 (AB-1); SEQ ID NO:4 and SEQ ID NO:61 (AB-2); SEQ ID NO:5 and SEQ ID NO:62 (AB-3); SEQ ID NO:3 and SEQ ID NO:63 (AB-4); SEQ ID NO:6 and SEQ ID NO:64 (AB-5); SEQ ID NO:7 and SEQ ID NO:65 (AB-6); SEQ ID NO:8 and SEQ ID NO:66 (AB-7); SEQ ID NO:
  • a polypeptide comprises a paratope that is identical to a paratope of an antibody comprising a VH/VL pair selected from: SEQ ID NO:206 and SEQ ID NO:217 (AB-65); SEQ ID NO:215 and SEQ ID NO:104 (AB-75); SEQ ID NO:214 and SEQ ID NO:226 (AB-74); SEQ ID NO:3 and SEQ ID NO:60 (AB-1); SEQ ID NO:4 and SEQ ID NO:61 (AB-2); SEQ ID NO:5 and SEQ ID NO:62 (AB-3); SEQ ID NO:3 and SEQ ID NO:63 (AB-4); SEQ ID NO:6 and SEQ ID NO:64 (AB-5); SEQ ID NO:7 and SEQ ID NO:65 (AB-6); SEQ ID NO:8 and SEQ ID NO:66 (AB-7); SEQ ID NO:9 and SEQ ID NO:60 (AB-8); SEQ ID NO:10 and SEQ ID NO:67 (AB-9);
  • the disclosure also provides, among other things, a polypeptide comprising: an HCDR1 comprising the amino acid sequence of SEQ ID NO:118, an HCDR2 comprising the amino acid sequence of SEQ ID NO:147, an HCDR3 comprising the amino acid sequence of SEQ ID NO:227, an LCDR 1 comprising the amino acid sequence of SEQ ID NO:229, an LCDR2 comprising the amino acid sequence of SEQ ID NO:183, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:200 (AB-65); an HCDR1 comprising the amino acid sequence of SEQ ID NO:118, an HCDR2 comprising the amino acid sequence of SEQ ID NO:148, an HCDR3 comprising the amino acid sequence of SEQ ID NO:228, an LCDR 1 comprising the amino acid sequence of SEQ ID NO:177, an LCDR2 comprising the amino acid sequence of SEQ ID NO:183, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:200 (AB-75);
  • the disclosure further provides, among other things, a polypeptide that comprises a VH comprising: a) the amino acid sequence of SEQ ID NO:2, wherein: X 1 is L or F; X 2 is G, A, S, T or P; X3 is V, F or absent; X 4 is S or absent; X 5 is S, G, N or absent; X6 is F, D, I, T, S or V; X 7 is A, S, R, N or K; X 8 is A, H or T; X9 is M or I; X10 is S or G; X 11 is S or G; X12 is S or G; X13 is G, D, A, R, E or T; X 14 is H, D, A, S or N; X 15 is A or I; X16 is H, A, I, Y or V; X 17 is S or D; X 18 is Y, T or H; or - 21 - 3820371.v1 5708.
  • a polypeptide comprises: a) a VL comprising the amino acid sequence of SEQ ID NO:59, wherein: X 20 is H, Q, A, S, Y, R or K; or X 21 is A, S, T or G, or any combination of the foregoing; or b) a V L comprising the amino acid sequence of SEQ ID NO:70, wherein: X 46 is V, I or F; X47 is V, K, T, M, R or L; X48 is P or T; X 49 is P or Q; X50 is P, F or S; X51 is P or S; X 52 is V or L; X 53 is H or Q; X54 is D, G or Y; X 55 is D, T or N; X 56 is C, Y or A; - 23 - 3820371.v1 5708.1067001 X57 is K or E; X58 is M, T, I or S; X 59
  • a polypeptide disclosed herein modulates (e.g., increases, enhances, promotes) binding between PD-1 and one or more of its ligands, such as PD-L1 and PD-L2. In some embodiments, a polypeptide disclosed herein modulates (e.g., increases, enhances, promotes) PD-1-mediated signaling in vitro, ex vivo, and/or in vivo.
  • a polypeptide is a fusion protein.
  • the disclosure provides a polynucleotide encoding a polypeptide disclosed herein, a vector comprising such polynucleotide, and/or a host cell comprising such polynucleotide and/or vector.
  • the disclosure provides methods of treating a patient and/or subject in need thereof (e.g., a subject having a disease or condition, such as an inflammatory disease or condition), comprising administering to the subject an effective amount (e.g., a therapeutically effective amount) of one or more of any of the polypeptides disclosed herein and/or a composition (e.g., pharmaceutical composition) comprising one or more of any of the polypeptides disclosed herein.
  • the disclosure provides a method of modulating (e.g., increasing, enhancing, promoting) PD-1-mediated signaling in a cell (e.g., a cell in a subject), comprising contacting the cell with a composition comprising a polypeptide disclosed herein or a composition (e.g., pharmaceutical composition) comprising a polypeptide disclosed herein.
  • FIG.1 depicts the amino acid sequence of human programmed cell death-1 (PD- 1) (SEQ ID NO:1). Epitope residues predicted to be bound by one or more antibodies disclosed herein are indicated by asterisks.
  • FIGs.2A and 2B depict an alignment of non-limiting examples of heavy chain variable domain (VH) amino acid sequences that are useful in polypeptides as disclosed herein.
  • VH heavy chain variable domain
  • HCDR heavy chain complementarity determining region amino acid sequences as determined by ImMunoGeneTics (IMGT) numbering (www.imgt.org/IMGTScientificChart/Nomenclature/IMGT-FRCDRdefinition.html, also accessible at www.imgt.org/) are indicated using bold letters within boxed portions of the sequences. Green highlighting indicates non-limiting examples of variable residues (designated throughout this disclosure by “Xn”) in the depicted sequences. Also see a first VH consensus sequence (SEQ ID NO:2) in Table 4. “*” indicates predicted paratope residues.
  • FIGs.3A-3D depict an alignment of non-limiting examples of VH amino acid sequences that are useful in polypeptides as disclosed herein.
  • the HCDR amino acid sequences as determined by IMGT numbering are indicated using bold letters within boxed portions of the sequences.
  • Green highlighting indicates non-limiting examples of variable residues (designated throughout this disclosure by “Xn”) in the depicted sequences.
  • Xn variable residues
  • FIGs.4A and 4B depict an alignment of non-limiting examples of light chain variable domain (VL) amino acid sequences that are useful in polypeptides as disclosed herein.
  • VL light chain variable domain
  • LCDR light chain complementarity determining region
  • Green highlighting indicates non-limiting examples of variable residues (designated throughout this disclosure by “Xn”) in the depicted sequences.
  • Xn variable residues
  • FIGs.5A-5D depict an alignment of non-limiting examples of V L amino acid sequences that are useful in polypeptides as disclosed herein.
  • the LCDR amino acid sequences as determined by IMGT numbering are indicated using bold letters within boxed portions of the sequences.
  • Green highlighting indicates non-limiting examples of variable residues (designated throughout this disclosure by “Xn”) in the depicted sequences.
  • Xn variable residues
  • FIGs.6A-6D depict structural validation of an example de-novo generated PD-1- agonizing antibody disclosed herein (AB-49).
  • FIG.6A shows the structure of PD-1 (light gray surface) with the desired epitope region shown in dark gray.
  • FIG.6B shows a computationally-generated model of AB-49 bound to the desired epitope on PD-1.
  • FIG.6C shows a crystal structure of the Fab fragment of AB-49 in FIG.6B alone, solved at 2.46 ⁇ resolution.
  • FIG.6D shows superpositions of the Fab-alone crystal structure and the corresponding computational model.
  • Polypeptides that Specifically Bind Programmed Cell Death-1 are provided herein, among other things, are polypeptides that specifically bind to PD-1 (e.g., full-length human PD-1, e.g., SEQ ID NO: 1).
  • a polypeptide modulates (e.g., increases, enhances, promotes) binding between PD-1 and one or more of its ligands, PD-L1 and PD-L2 and/or modulates (e.g., increases, enhances, promotes) PD-1-mediated signaling.
  • polypeptide “peptide” or “protein” denotes a polymer of at least two amino acids covalently linked by an amide bond, regardless of length or post-translational modification (e.g., glycosylation or phosphorylation).
  • a protein, peptide or polypeptide can comprise any suitable L-and/or D-amino acid, for example, common ⁇ -amino acids (e.g., alanine, glycine, valine), non- ⁇ -amino acids (e.g., ⁇ -alanine, 4-aminobutyric acid, 6- aminocaproic acid, sarcosine, statine), and unusual amino acids (e.g., citrulline, homocitruline, homoserine, norleucine, norvaline, ornithine).
  • the amino, carboxyl and/or other functional groups on a peptide can be free (e.g., unmodified) or protected with a suitable protecting group.
  • Suitable protecting groups for amino and carboxyl groups, and methods for adding or removing protecting groups are known in the art and are disclosed in, for example, Green and Wuts, “Protecting Groups in Organic Synthesis,” John Wiley and Sons, 1991.
  • the functional groups of a protein, peptide or polypeptide can also be derivatized (e.g., alkylated) or labeled (e.g., with a detectable label, such as a fluorogen or a hapten) using methods known in the art.
  • a protein, peptide or polypeptide can comprise one or more modifications (e.g., amino acid linkers, acylation, acetylation, amidation, methylation, terminal modifiers (e.g., cyclizing modifications), N-methyl- ⁇ -amino group substitution), if desired.
  • a protein, peptide or polypeptide can be an analog of a known and/or naturally-occurring peptide, for example, a peptide analog having conservative amino acid residue substitution(s).
  • PD-1 includes full-length PD-1 proteins (e.g., having the amino acid sequence of SEQ ID NO:1 (GenBank: AIC54874.1) or homologs thereof) and truncated forms thereof, mutant and engineered versions of full-length and truncated
  • a polypeptide disclosed herein binds to a PD-1 protein comprising the amino acid sequence of SEQ ID NO:1. In some embodiments, a polypeptide binds to a PD-1 protein comprising the amino acid sequence of SEQ ID NO:1 and a PD-1 protein comprising the amino acid sequence of SEQ ID NO:205. [0035] In some embodiments, a polypeptide disclosed herein binds to one or more epitope residues of a PD-1 protein (e.g., one or more epitope residues in SEQ ID NO:1).
  • a polypeptide is capable of binding to one or more epitope residues in the full-length human PD-1, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 residues of the full-length human PD-1.
  • a polypeptide is capable of binding to one or more epitope residues (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or all 16 residues) selected from D48, N49, T51, T53, P83, E84, R96, V97, T98, L100, P101, N102, D105, H107, S109 and V111 of SEQ ID NO:1.
  • a polypeptide binds to a mutant, engineered or modified form of PD-1.
  • the mutant, engineered or modified form of PD-1 comprises an amino acid sequence that has at least about 90% sequence identity to a wildtype full-length PD-1 sequence (e.g., SEQ ID NO:1), for example, having at least about: 91%, - 28 - 3820371.v1 5708.1067001 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% sequence identity to a wildtype full-length PD-1 sequence.
  • sequence identity is about: 90-99.9%, 90-99.8%, 92-99.8%, 92-99.6%, 94- 99.6%, 94-99.5%, 95-99.5%, 95-99.4%, 96-99.4%, 96-99.2%, 97-99.2% or 97-99%.
  • sequence identity refers to the extent to which two nucleotide sequences, or two amino acid sequences, have the same residues at the same positions when the sequences are aligned to achieve a maximal level of identity, expressed as a percentage. For sequence alignment and comparison, typically one sequence is designated as a reference sequence, to which a test sequence is compared.
  • sequence identity is expressed as the percentage of positions across the entire length of the reference sequence where the reference and test sequences share the same nucleotide or amino acid upon alignment of the reference and test sequences to achieve a maximal level of identity.
  • two sequences are considered to have 70% sequence identity when, upon alignment to achieve a maximal level of identity, the test sequence has the same nucleotide or amino acid residue at 70% of the same positions over the entire length of the reference sequence.
  • Alignment of sequences for comparison to achieve maximal levels of identity can be readily performed by a person of ordinary skill in the art using an appropriate alignment method or algorithm. In some instances, the alignment can include introduced gaps to provide for the maximal level of identity. Examples include the local homology algorithm of Smith & Waterman, Adv. Appl.
  • the sequence comparison algorithm then calculates the percent sequence identity for the test sequence(s) relative to the reference sequence, based on the designated program parameters.
  • a commonly used tool for determining percent sequence identity is Protein Basic Local Alignment Search Tool (BLASTP) available through National Center for Biotechnology Information, National - 29 - 3820371.v1 5708.1067001 Library of Medicine, of the United States National Institutes of Health. (Altschul et al., 1990).
  • BLASTP Protein Basic Local Alignment Search Tool
  • the disclosure provides a polypeptide that specifically binds PD-1.
  • a polypeptide comprises a paratope that is substantially similar to a paratope of an antibody comprising a VH/VL pair selected from: SEQ ID NO:206 and SEQ ID NO:217 (AB-65); SEQ ID NO:215 and SEQ ID NO:104 (AB-75); SEQ ID NO:214 and SEQ ID NO:226 (AB-74); SEQ ID NO:3 and SEQ ID NO:60 (AB-1); SEQ ID NO:4 and SEQ ID NO:61 (AB-2); SEQ ID NO:5 and SEQ ID NO:62 (AB-3); SEQ ID NO:3 and SEQ ID NO:63 (AB-4); SEQ ID NO:6 and SEQ ID NO:64 (AB-5); SEQ ID NO:7 and SEQ ID NO:65 (AB-6); SEQ ID NO:8 and SEQ ID NO:66 (AB-7); SEQ ID NO:9 and SEQ ID NO:60 (AB-8); SEQ ID NO:10 and SEQ ID NO:67 (AB-9); SEQ ID NO:10 and
  • a polypeptide comprises a paratope that is substantially similar to a paratope of an antibody comprising a VH/VL pair selected from: SEQ ID NO:206 and SEQ ID NO:217 (AB-65); SEQ ID NO:215 and SEQ ID NO:104 (AB-75); or SEQ ID NO:214 and SEQ ID NO:226 (AB-74), or any combination of the foregoing.
  • a polypeptide comprises a paratope that is substantially similar to a paratope of an antibody, wherein the antibody comprises a VH comprising the amino acid sequence of SEQ ID NO:206 and a VL comprising the amino acid sequence of SEQ ID NO:217 (AB-65).
  • a polypeptide comprises a paratope that is substantially similar to a paratope of an antibody, wherein the antibody comprises a VH comprising the amino acid sequence of SEQ ID NO:215, and a V L comprising the amino acid sequence of SEQ ID NO:104 (AB-75).
  • a polypeptide comprises a paratope that is substantially similar to a paratope of an antibody, wherein the antibody comprises a V H comprising the - 32 - 3820371.v1 5708.1067001 amino acid sequence of SEQ ID NO:214, and a VL comprising the amino acid sequence of SEQ ID NO:226 (AB-74).
  • the disclosure provides a polypeptide that specifically binds PD-1.
  • a polypeptide comprises a paratope that is identical to a paratope of an antibody comprising a VH/VL pair selected from: SEQ ID NO:206 and SEQ ID NO:217 (AB-65); SEQ ID NO:215 and SEQ ID NO:104 (AB-75); SEQ ID NO:214 and SEQ ID NO:226 (AB-74); SEQ ID NO:3 and SEQ ID NO:60 (AB-1); SEQ ID NO:4 and SEQ ID NO:61 (AB-2); SEQ ID NO:5 and SEQ ID NO:62 (AB-3); SEQ ID NO:3 and SEQ ID NO:63 (AB-4); SEQ ID NO:6 and SEQ ID NO:64 (AB-5); SEQ ID NO:7 and SEQ ID NO:65 (AB-6); SEQ ID NO:8 and SEQ ID NO:66 (AB-7); SEQ ID NO:9 and SEQ ID NO:60 (AB-8); SEQ ID NO:10 and SEQ ID NO:67 (AB-9); SEQ ID NO:
  • a polypeptide comprises a paratope that is identical to a paratope of an antibody comprising a VH/VL pair selected from: SEQ ID NO:206 and SEQ ID NO:217 (AB-65); SEQ ID NO:215 and SEQ ID NO:104 (AB-75); or SEQ ID NO:214 and SEQ ID NO:226 (AB-74), or any combination of the foregoing.
  • a polypeptide comprises a paratope that is identical to a paratope of an antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:206 and a VL comprising the amino acid sequence of SEQ ID NO:217 (AB-65).
  • a polypeptide comprises a paratope that is identical to a paratope of an antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:215, and a VL comprising the amino acid sequence of SEQ ID NO:104 (AB-75).
  • a polypeptide comprises a paratope that is identical to a paratope of an antibody comprising a V H comprising the amino acid sequence of SEQ ID NO:214, and a VL comprising the amino acid sequence of SEQ ID NO:226 (AB-74).
  • FIGs.3A-3D for paratope residues of antibodies comprising SEQ ID Nos:19-58
  • FIGs.4A-4B for paratope residues of antibodies comprising SEQ ID Nos:60-69
  • FIGs.5A-5D for paratope residues of antibodies comprising SEQ ID NOs:71-106.
  • Amino acid residues of a paratope contribute to an antibody’s interaction with an epitope of its target protein.
  • An interaction can be a hydrogen bond, a salt bridge, a van der Waals interaction, an electrostatic interaction, a hydrophobic interaction, pi-interaction effects, an ionic bond, and/or any combination thereof.
  • An interaction can be direct, or indirect, e.g., via a coordinated intermediate molecule, such as an ion or water.
  • the residues of a paratope in some embodiments, comprise only residues that are part of a defined CDR. In some embodiments, the residues of a paratope further comprise one or more residues that are not part of a defined CDR (e.g., residues within a defined framework region).
  • a paratope is oriented less than about 5.0 angstroms from an epitope on a target antigen when the polypeptide is bound to the target antigen, e.g., less than about: 4.5, 4.0, 3.5, 3.0, 2.5, 2.4, 2.3, 2.2, 2.1, 2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0 or 0.9 angstroms, or about: 0.9-5.0, 0.9-4.8.1.0-5, 1.0-4.5, 1.0-4.0, 1.0-3.5, 1.1-3.5, 1.1-3.0, 1.2-3.0, 1.2-2.5, 1.3-2.5, 1.3-2.4, 1.4-2.4, 1.4-2.3, 1.5-2.3, 1.5-2.2, 1.6-2.2, 1.6-2.1, 1.7-2.1, 1.7-2.0 or 1.8-2.0 angstroms, from the epitope.
  • all of the amino acid residues constituting the paratope are oriented less than about 5.0 angstroms from an epitope on a target antigen when the polypeptide is bound to the target antigen.
  • less than all of the amino acid residues constituting the paratope (e.g., about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% of the amino acid residues)) in the paratope are oriented less than about 5.0 angstroms from an epitope on a target antigen when the polypeptide is bound to the target antigen.
  • the term “substantially similar to” refers to a polypeptide disclosed herein that is substantially similar in amino acid sequence (e.g., has at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the amino acid residues amino acid sequence identity) and substantially preserves one or more functional properties of a specified polypeptide disclosed herein.
  • the one or more functional properties are selected from, without limitation, a substantially similar binding affinity, a substantially similar - 36 - 3820371.v1 5708.1067001 binding specificity, a substantially similar inhibitory activity, a substantially similar neutralization activity, and a substantially similar self-association property.
  • a polypeptide comprises a paratope that is substantially similar to a paratope of a polypeptide selected from any one of AB-1 to AB-76. In some embodiments, a polypeptide comprises a paratope comprising only conservative substitutions (e.g., only highly conservative substitutions) relative to a paratope of a polypeptide selected from any one of AB-1 to AB-76.
  • a polypeptide comprises a paratope comprising up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 conservative substitutions (e.g., up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 highly conservative substitutions) relative to a paratope of a polypeptide selected from any one of AB-1 to AB-76.
  • a polypeptide comprises a paratope having 100% sequence identity to a paratope of a polypeptide selected from any one of AB-1 to AB-76.
  • a polypeptide comprises a paratope that is substantially similar to the paratope of an antibody comprising a VH/VL pair selected from: SEQ ID NO:206 and SEQ ID NO:217 (AB-65); SEQ ID NO:215 and SEQ ID NO:104 (AB-75); SEQ ID NO:214 and SEQ ID NO:226 (AB-74); SEQ ID NO:3 and SEQ ID NO:60 (AB-1); SEQ ID NO:4 and SEQ ID NO:61 (AB-2); SEQ ID NO:5 and SEQ ID NO:62 (AB-3); SEQ ID NO:3 and SEQ ID NO:63 (AB-4); SEQ ID NO:6 and SEQ ID NO:64 (AB-5); SEQ ID NO:7 and SEQ ID NO:65 (AB-6); SEQ ID NO:8 and SEQ ID NO:66 (AB-7); SEQ ID NO:9 and SEQ ID NO:60 (AB-8); SEQ ID NO:10 and SEQ ID NO:67 (AB-9);
  • the paratope comprises amino acid residues corresponding to each of A50, X11 (position 54), X15 (position 59), and V106 of SEQ ID NO: 2 and D1, I2, Q27, Y32, Y49, Y50, F91, X20 (position 92), X21 (position 93), Y94 and P95 of SEQ ID NO: 59, or a subset thereof.
  • a polypeptide comprising a paratope disclosed herein comprises an immunoglobulin heavy chain variable domain (VH) and an immunoglobulin light chain variable domain (V L ).
  • the paratope residues are contained within the V H and V L of a polypeptide.
  • a polypeptide comprises an immunoglobulin light chain variable region, an immunoglobulin heavy chain variable region, or an immunoglobulin light chain variable region and an immunoglobulin heavy chain variable region.
  • a polypeptide comprises six CDRs of a polypeptide disclosed herein.
  • a polypeptide has fewer than six (e.g., 1, 2, 3, 4 or 5) of the CDRs of a polypeptide disclosed herein.
  • the disclosure provides a polypeptide that specifically binds PD-1, wherein the polypeptide comprises: a V H amino acid sequence comprising a heavy chain complementarity determining region 1 (HCDR1), a heavy chain complementarity determining region 2 (HCDR2) and a heavy chain complementarity determining region 3 (HCDR3) that are substantially similar in amino acid sequence to an HCDR1, an HCDR2 and an HCDR3, respectively, of a VH amino acid sequence set forth in any of SEQ ID NOs:3-17, SEQ ID NOs:19-58, and SEQ ID NOs:206-216; and a VL amino acid sequence comprising a light chain complementarity determining region 1 (LCDR1), a light chain complementarity determining region 2 (LCDR2) and a light chain complementarity determining region 3 (LCDR3) that are substantially similar in amino acid sequence to an LCDR1, an LCDR2 and an LCDR3, respectively, of a VL amino acid sequence set forth in any of S
  • a polypeptide comprises an HCDR1, an HCDR2, an HCDR3, an LCDR1, an LCDR2 and an LCDR3 that substantially preserve one or more functional properties (e.g., binding to PD-1, PD-1 agonist activity, increased PD-1 signaling) of an HCDR1, an HCDR2, an HCDR3, an LCDR1, an LCDR2 and an LCDR3 of a polypeptide selected from any one of AB-1 to AB-76.
  • one or more functional properties e.g., binding to PD-1, PD-1 agonist activity, increased PD-1 signaling
  • a polypeptide comprises an HCDR1, an HCDR2, an HCDR3, an LCDR1, an LCDR2 and an LCDR3 comprising only one or more conservative substitutions (e.g., only one or more highly conservative substitutions), relative an HCDR1, an HCDR2, an HCDR3, an LCDR1, an LCDR2 and an LCDR3 of a polypeptide selected from any one of AB-1 to AB-76.
  • a polypeptide comprises an HCDR1, an HCDR2, an HCDR3, an LCDR1, an LCDR2 and an LCDR3 comprising up to 1, 2, or 3 conservative substitutions (e.g., up to 1, 2, or 3 highly conservative substitutions), relative to an HCDR1, - 40 - 3820371.v1 5708.1067001 an HCDR2, an HCDR3, an LCDR1, an LCDR2 and an LCDR3 of a polypeptide selected from any one of AB-1 to AB-76.
  • a polypeptide disclosed herein comprises an HCDR1, an HCDR2, an HCDR3, an LCDR1, an LCDR2 and an LCDR3 having 100% sequence identity to an HCDR1, an HCDR2, an HCDR3, an LCDR1, an LCDR2 and an LCDR3 of a polypeptide selected from any one of AB-1 to AB-76.
  • a polypeptide comprises an HCDR1, an HCDR2 and an HCDR3, and an LCDR1, an LCDR2 and an LCDR3, of an antibody comprising a VH/VL pair selected from: SEQ ID NO:206 and SEQ ID NO:217 (AB-65); SEQ ID NO:215 and SEQ ID NO:104 (AB-75); SEQ ID NO:214 and SEQ ID NO:226 (AB-74); SEQ ID NO:3 and SEQ ID NO:60 (AB-1); SEQ ID NO:4 and SEQ ID NO:61 (AB-2); SEQ ID NO:5 and SEQ ID NO:62 (AB-3); SEQ ID NO:3 and SEQ ID NO:63 (AB-4); SEQ ID NO:6 and SEQ ID NO:64 (AB-5); SEQ ID NO:7 and SEQ ID NO:65 (AB-6); SEQ ID NO:8 and SEQ ID NO:66 (AB-7); SEQ ID NO:9 and SEQ ID NO:60 (AB-8); SEQ ID NO:6 and SEQ
  • a polypeptide comprises an HCDR1, an HCDR2 and an HCDR3, and an LCDR1, an LCDR2 and an LCDR3, of an antibody comprising a VH/VL pair selected from: SEQ ID NO:206 and SEQ ID NO:217 (AB-65); SEQ ID NO:215 and SEQ ID NO:104 (AB-75); or SEQ ID NO:214 and SEQ ID NO:226 (AB-74).
  • a polypeptide comprises an HCDR1, an HCDR2 and an HCDR3, and an LCDR1, an LCDR2 and an LCDR3, of an antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:206 and a VL comprising the amino acid sequence of SEQ ID NO:217 (AB-65).
  • a polypeptide comprises an HCDR1, an HCDR2 and an HCDR3, and an LCDR1, an LCDR2 and an LCDR3, of an antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:215, and a V L comprising the amino acid sequence of SEQ ID NO:104 (AB-75).
  • a polypeptide comprises an HCDR1, an HCDR2 and an HCDR3, and an LCDR1, an LCDR2 and an LCDR3, of an antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:214, and a V L comprising the amino acid sequence of SEQ ID NO:226 (AB-74).
  • a CDR (e.g., HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and/or LCDR3) can be a CDR defined by any art-recognized method for identifying CDR residues of an antibody, as described further herein (e.g., a CDR as defined by Kabat, a CDR as defined by Chothia, a CDR as defined by IMGT).
  • a polypeptide comprises a paratope that is substantially similar to the paratope of an antibody comprising a V H /V L pair selected from: SEQ ID NO:206 and SEQ ID NO:217 (AB-65); SEQ ID NO:215 and SEQ ID NO:104 (AB-75); SEQ ID NO:214 and SEQ ID NO:226 (AB-74); SEQ ID NO:3 and SEQ ID NO:60 (AB-1); SEQ ID NO:4 and SEQ ID NO:61 (AB-2); SEQ ID NO:5 and SEQ ID NO:62 (AB-3); SEQ ID NO:3 and SEQ ID NO:63 (AB-4); SEQ ID NO:6 and SEQ ID NO:64 (AB-5); SEQ ID NO:7 and SEQ ID NO:65 (AB-6); SEQ ID NO:8 and SEQ ID NO:66 (AB-7); SEQ ID NO:9 and SEQ ID NO:60 (AB-8); SEQ ID NO:10 and SEQ ID NO:67 (AB-9
  • a polypeptide comprises a paratope that is identical to the paratope of an antibody comprising a V H /V L pair selected from: SEQ ID NO:206 and SEQ ID NO:217 (AB-65); SEQ ID NO:215 and SEQ ID NO:104 (AB-75); SEQ ID NO:214 and SEQ ID NO:226 (AB-74); SEQ ID NO:3 and SEQ ID NO:60 (AB-1); SEQ ID NO:4 and SEQ ID NO:61 (AB-2); SEQ ID NO:5 and SEQ ID NO:62 (AB-3); SEQ ID NO:3 and SEQ ID NO:63 (AB-4); SEQ ID NO:6 and SEQ ID NO:64 (AB-5); SEQ ID NO:7 and SEQ ID NO:65 (AB-6); SEQ ID NO:8 and SEQ ID NO:66 (AB-7); SEQ ID NO:9 and SEQ ID NO:60 (AB-8); - 46 - 3820371.v1 5708.1067001
  • the disclosure also provides, among other things, a polypeptide comprising: - 48 - 3820371.v1 5708.1067001 an HCDR1 comprising the amino acid sequence of SEQ ID NO:118, an HCDR2 comprising the amino acid sequence of SEQ ID NO:147, an HCDR3 comprising the amino acid sequence of SEQ ID NO:227, an LCDR 1 comprising the amino acid sequence of SEQ ID NO:229, an LCDR2 comprising the amino acid sequence of SEQ ID NO:183, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:200 (AB-65); an HCDR1 comprising the amino acid sequence of SEQ ID NO:118, an HCDR2 comprising the amino acid sequence of SEQ ID NO:148, an HCDR3 comprising the amino acid sequence of SEQ ID NO:228, an LCDR 1 comprising the amino acid sequence of SEQ ID NO:177, an LCDR2 comprising the amino acid sequence of SEQ ID NO:183, and an LCDR3 comprising:
  • a polypeptide comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO:118, an HCDR2 comprising the amino acid sequence of SEQ ID NO:147, an HCDR3 comprising the amino acid sequence of SEQ ID NO:227, an LCDR 1 comprising the amino acid sequence of SEQ ID NO:229, an LCDR2 comprising the amino acid sequence of SEQ ID NO:183, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:200 (AB-65); an HCDR1 comprising the amino acid sequence of SEQ ID NO:118, an HCDR2 comprising the amino acid sequence of SEQ ID NO:148, an HCDR3 comprising the amino acid sequence of SEQ ID NO:228, an LCDR 1 comprising the amino acid sequence of SEQ ID NO:177, an LCDR2 comprising the amino acid sequence of SEQ ID NO:183, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:200 (AB-75); or - 60
  • a polypeptide comprises: a) an HCDR1 comprising the amino acid sequence of SEQ ID NO:118, an HCDR2 comprising the amino acid sequence of SEQ ID NO:147, and an HCDR3 comprising the amino acid sequence of SEQ ID NO:227; and b) an LCDR 1 comprising the amino acid sequence of SEQ ID NO:229, an LCDR2 comprising the amino acid sequence of SEQ ID NO:183, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:200 (AB-65).
  • a polypeptide comprises: a) an HCDR1 comprising the amino acid sequence of SEQ ID NO:118, an HCDR2 comprising the amino acid sequence of SEQ ID NO:148, and an HCDR3 comprising the amino acid sequence of SEQ ID NO:228; and b) an LCDR 1 comprising the amino acid sequence of SEQ ID NO:177, an LCDR2 comprising the amino acid sequence of SEQ ID NO:183, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:200 (AB-75).
  • a polypeptide comprises: a) an HCDR1 comprising the amino acid sequence of SEQ ID NO:118, an HCDR2 comprising the amino acid sequence of SEQ ID NO:139, and an HCDR3 comprising the amino acid sequence of SEQ ID NO:170, and b) an LCDR 1 comprising the amino acid sequence of SEQ ID NO:178, an LCDR2 comprising the amino acid sequence of SEQ ID NO:183, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:194 (AB-74).
  • the disclosure provides a polypeptide that specifically binds PD-1, comprising a VH comprising: a) the amino acid sequence of SEQ ID NO:2, wherein: X 1 is L or F; X2 is G, A, S, T or P; X 3 is V, F or absent; X 4 is S or absent; - 61 - 3820371.v1 5708.1067001 X5 is S, G, N or absent; X6 is F, D, I, T, S or V; X 7 is A, S, R, N or K; X8 is A, H or T; X9 is M or I; X 10 is S or G; X 11 is S or G; X12 is S or G; X 13 is G, D, A, R, E or T; X 14 is H, D, A, S or N; X15 is A or I; X16 is H, A, I, Y or V; X 17 is S or D;
  • polypeptides disclosed herein further comprise a VL.
  • the polypeptide comprises a VL comprising: a) the amino acid sequence of SEQ ID NO:59, wherein: X20 is H, Q, A, S, Y, R or K; or X21 is A, S, T or G, or any combination of the foregoing; or b) the amino acid sequence of SEQ ID NO:70, wherein: X46 is V, I or F; X 47 is V, K, T, M, R or L; X 48 is P or T; X49 is P or Q; X50 is P, F or S; X 51 is P or S; X52 is V or L; X53 is H or Q; X 54 is D, G or Y; X 55 is D, T or N; X56 is C, Y or A; X 57 is K or E; X 58 is M, T, I or S; X59 is Y or S; X 60 is R, G, S or D; X 61 is R or S;
  • SEQ ID NO:59 is a consensus VL sequence for SEQ ID Nos:60-69 herein
  • SEQ ID NO:70 is a consensus V L sequence for SEQ ID Nos:71-106 herein.
  • the disclosure provides a polypeptide that specifically binds PD-1, comprising a VH comprising the amino acid sequence of SEQ ID NO:2, wherein: X 1 is L or F; X 2 is G, A, S, T or P; X3 is V, F or absent; X4 is S or absent; X 5 is S, G, N or absent; X6 is F, D, I, T, S or V; X7 is A, S, R, N or K; X 8 is A, H or T; X 9 is M or I; X10 is S or G; X 11 is S or G; X 12 is S or G; X13 is G, D, A, R, E or T; X 14 is H, D, A, S or N; X 15 is A or I; X16 is H, A, I, Y or V; X17 is S or D; X 18 is Y, T or H; or X19 is A, Y or T
  • polypeptides disclosed herein further a V L comprising the amino acid sequence of SEQ ID NO:59, wherein: X20 is H, Q, A, S, Y, R or K; or X 21 is A, S, T or G, or any combination of the foregoing.
  • the disclosure provides a polypeptide that specifically binds PD-1, comprising a VH comprising the amino acid sequence of SEQ ID NO:18, wherein: X1 is V or E; X2 is L or I; X 3 is V or A; X 4 is G or S; X5 is H, Q or L; X 6 is P or L; X 7 is T or A; X8 is F, G or S; X9 is G, D or S; X 10 is Y, S or A; X11 is T, Y or A; X12 is L or I; X 13 is K, R or E; X 14 is V or M; X15 is V, T or I; X 16 is K, R, T or S; X 17 is C, G, Q or S; X18 is K, G or S; X 19 is G or S; X 20 is C or Y; X
  • polypeptides disclosed herein comprises a V L comprising the amino acid sequence of SEQ ID NO:70, wherein: X 46 is V, I or F; X 47 is V, K, T, M, R or L; X48 is P or T; X 49 is P or Q; X 50 is P, F or S; X51 is P or S; X52 is V or L; X 53 is H or Q; X54 is D, G or Y; X55 is D, T or N; X 56 is C, Y or A; X 57 is K or E; X58 is M, T, I or S; X 59 is Y or S; X 60 is R, G, S or D; - 67 - 3820371.v1 5708.1067001 X61 is R or S; X62 is Y, I or F; X 63 is Y or S; X64 is V, R or T; X65 is T or S;
  • a polypeptide disclosed herein comprises a VH that comprises an HCDR1, an HCDR2 and an HCDR3 that are substantially similar in amino acid sequence to an HCDR1, an HCDR2 and an HCDR3, respectively, of a V H amino acid sequence set forth in any of SEQ ID NOs:3-17, SEQ ID NOs:19-58, and SEQ ID NOs:206- 216 (see Table 4 for SEQ ID NOs:3-17, SEQ ID NOs:19-58, and SEQ ID NOs:206-216, and Table 6 for non-limiting examples of corresponding HCDR1, HCDR2 and HCDR3 sequences).
  • a polypeptide comprises a V H that comprises an HCDR1, an HCDR2 and an HCDR3 that are substantially similar in amino acid sequence to an HCDR1, an HCDR2 and an HCDR3, respectively, of a VH amino acid sequence set forth in any one of SEQ ID NO:206, SEQ ID NO:215 and SEQ ID NO:214.
  • a polypeptide comprises a V H that comprises an HCDR1, an HCDR2 and an HCDR3 that are substantially similar in amino acid sequence to an HCDR1, an HCDR2 and an HCDR3, respectively, of a VH amino acid sequence set forth in SEQ ID NO:206.
  • a polypeptide comprises a V H that comprises an HCDR1, an HCDR2 and an HCDR3 that are substantially similar in amino acid sequence to an HCDR1, an HCDR2 and an HCDR3, respectively, of a VH amino acid sequence set forth in SEQ ID NO:215.
  • a polypeptide comprises a V H that comprises an HCDR1, an HCDR2 and an - 68 - 3820371.v1 5708.1067001 HCDR3 that are substantially similar in amino acid sequence to an HCDR1, an HCDR2 and an HCDR3, respectively, of a VH amino acid sequence set forth in SEQ ID NO:214.
  • a polypeptide disclosed herein comprises a V L that comprises an LCDR1, an LCDR2 and an LCDR3 that are substantially similar in amino acid sequence to an LCDR1, an LCDR2 and an LCDR3, respectively, of a VL amino acid sequence set forth in any of SEQ ID NOs:60-69, SEQ ID NOs:71-106, and SEQ ID NOs:217-226 (see Table 5 for SEQ ID NOs:60-69, SEQ ID NOs:71-106, and SEQ ID NOs:217-226, and Table 6 for non-limiting examples of corresponding LCDR1, LCDR2 and LCDR3 sequences).
  • a polypeptide comprises a V L that comprises an LCDR1, an LCDR2 and an LCDR3 that are substantially similar in amino acid sequence to an LCDR1, an LCDR2 and an LCDR3, respectively, of a VL amino acid sequence set forth in any one of SEQ ID NO:217, SEQ ID NO:104 and SEQ ID NO:226.
  • a polypeptide comprises a VL that comprises an LCDR1, an LCDR2 and an LCDR3 that are substantially similar in amino acid sequence to an LCDR1, an LCDR2 and an LCDR3, respectively, of a V L amino acid sequence set forth in SEQ ID NO:217.
  • a polypeptide comprises a V L that comprises an LCDR1, an LCDR2 and an LCDR3 that are substantially similar in amino acid sequence to an LCDR1, an LCDR2 and an LCDR3, respectively, of a V L amino acid sequence set forth in SEQ ID NO:104.
  • a polypeptide comprises a V L that comprises an LCDR1, an LCDR2 and an LCDR3 that are substantially similar in amino acid sequence to an LCDR1, an LCDR2 and an LCDR3, respectively, of a V L amino acid sequence set forth in SEQ ID NO:226.
  • a polypeptide disclosed herein comprises a V H that comprises an HCDR1, an HCDR2 and an HCDR3 that are identical in amino acid sequence to an HCDR1, an HCDR2 and an HCDR3, respectively, of a VH amino acid sequence set forth in any of SEQ ID NOs:3-17, SEQ ID NOs:19-58, and SEQ ID NOs:206-216 (see Table 4 for SEQ ID NOs:3-17, SEQ ID NOs:19-58, and SEQ ID NOs:206-216, and Table 6 for non-limiting examples of corresponding HCDR1, HCDR2 and HCDR3 sequences).
  • a polypeptide comprises a V H that comprises an HCDR1, an HCDR2 and an HCDR3 that are identical in amino acid sequence to an HCDR1, an HCDR2 and an HCDR3, respectively, of a VH amino acid sequence set forth in any one of SEQ ID NO:206, SEQ ID NO:215 and SEQ ID NO:214.
  • a polypeptide comprises a V H that comprises an HCDR1, an HCDR2 and an HCDR3 that are - 69 - 3820371.v1 5708.1067001 identical in amino acid sequence to an HCDR1, an HCDR2 and an HCDR3, respectively, of a VH amino acid sequence set forth in SEQ ID NO:206.
  • a polypeptide comprises a V H that comprises an HCDR1, an HCDR2 and an HCDR3 that are identical in amino acid sequence to an HCDR1, an HCDR2 and an HCDR3, respectively, of a VH amino acid sequence set forth in SEQ ID NO:215.
  • a polypeptide comprises a V H that comprises an HCDR1, an HCDR2 and an HCDR3 that are identical in amino acid sequence to an HCDR1, an HCDR2 and an HCDR3, respectively, of a V H amino acid sequence set forth in SEQ ID NO:214.
  • a polypeptide disclosed herein comprises a V L that comprises an LCDR1, an LCDR2 and an LCDR3 that are identical in amino acid sequence to an LCDR1, an LCDR2 and an LCDR3, respectively, of a VL amino acid sequence set forth in any of SEQ ID NOs:60-69, SEQ ID NOs:71-106, and SEQ ID NOs:217-226 (see Table 5 for SEQ ID NOs:60-69, SEQ ID NOs:71-106, and SEQ ID NOs:217-226, and Table 6 for non- limiting examples of corresponding LCDR1, LCDR2 and LCDR3 sequences).
  • a polypeptide comprises a VL that comprises an LCDR1, an LCDR2 and an LCDR3 that are identical in amino acid sequence to an LCDR1, an LCDR2 and an LCDR3, respectively, of a V L amino acid sequence set forth in any one of SEQ ID NO:217, SEQ ID NO:104 and SEQ ID NO:226.
  • a polypeptide comprises a V L that comprises an LCDR1, an LCDR2 and an LCDR3 that are identical in amino acid sequence to an LCDR1, an LCDR2 and an LCDR3, respectively, of a VL amino acid sequence set forth in SEQ ID NO:217.
  • a polypeptide comprises a V L that comprises an LCDR1, an LCDR2 and an LCDR3 that are identical in amino acid sequence to an LCDR1, an LCDR2 and an LCDR3, respectively, of a V L amino acid sequence set forth in SEQ ID NO:104.
  • a polypeptide comprises a VL that comprises an LCDR1, an LCDR2 and an LCDR3 that are identical in amino acid sequence to an LCDR1, an LCDR2 and an LCDR3, respectively, of a V L amino acid sequence set forth in SEQ ID NO:226.
  • a polypeptide disclosed herein comprises a paratope that is substantially similar to a paratope of a V H/ V L combination selected from: a) SEQ ID NO:206/SEQ ID NO:217 (AB-65), SEQ ID NO:215/SEQ ID NO:104 (AB-75), SEQ ID NO:214/SEQ ID NO:226 (AB-74), SEQ ID NO:207/SEQ ID NO:218 (AB-66), SEQ ID NO:208/SEQ ID NO:219 (AB-67), SEQ ID NO:209/SEQ ID NO:220 (AB-68), SEQ ID NO:53/SEQ ID NO:221 (AB-69), - 70 - 3820371.v1 5708.1067001 SEQ ID NO:210/SEQ ID NO:222 (AB-70), SEQ ID NO:211/SEQ ID NO:223 (AB-71), SEQ ID NO:212/SEQ ID NO:224 (AB-72), SEQ ID NO:210/SEQ
  • a polypeptide disclosed herein comprises a paratope that is identical to a paratope of a V H/ V L combination selected from: a) SEQ ID NO:206/SEQ ID NO:217 (AB-65), SEQ ID NO:215/SEQ ID NO:104 (AB-75), SEQ ID NO:214/SEQ ID NO:226 (AB-74), SEQ ID NO:207/SEQ ID NO:218 (AB-66), SEQ ID NO:208/SEQ ID NO:219 (AB-67), SEQ ID NO:209/SEQ ID NO:220 (AB-68), SEQ ID NO:53/SEQ ID NO:221 (AB-69), SEQ ID NO:210/SEQ ID NO:222 (AB-70), SEQ ID NO:211/SEQ ID NO:223 (AB-71), SEQ ID NO:212/SEQ ID NO:224 (AB-72), SEQ ID NO:213/SEQ ID NO:225 (AB-73), or
  • a polypeptide disclosed herein comprises a paratope that differs from a paratope of a V H/ V L combination selected from: a) SEQ ID NO:206/SEQ ID NO:217 (AB-65), SEQ ID NO:215/SEQ ID NO:104 (AB-75), SEQ ID NO:214/SEQ ID NO:226 (AB-74), SEQ ID NO:207/SEQ ID NO:218 (AB-66), SEQ ID NO:208/SEQ ID NO:219 (AB-67), SEQ ID NO:209/SEQ ID NO:220 (AB-68), SEQ ID NO:53/SEQ ID NO:221 (AB-69), SEQ ID NO:210/SEQ ID NO:222 (AB-70), SEQ ID NO:211/SEQ ID NO:223 (AB-71), SEQ ID NO:212/SEQ ID NO:224 (AB-72), SEQ ID NO:213/SEQ ID NO:225 (AB-73), or
  • a polypeptide disclosed herein comprises a V H that has at least about 70% sequence identity to the amino acid sequence of a VH amino acid sequence set forth in any of SEQ ID NOs:3-17, SEQ ID NOs:19-58, and SEQ ID NOs:206-216.
  • the V H can have at least about: 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of a VH amino acid sequence set forth in any of SEQ ID NOs:3-17, SEQ ID NOs:19-58, and SEQ ID NOs:206- 216.
  • the V H has at least about 85% or at least about 90% sequence identity to the amino acid sequence of a VH amino acid sequence set forth in any of SEQ ID NOs:3-17, SEQ ID NOs:19-58, and SEQ ID NOs:206-216.
  • a polypeptide comprises a V H that has at least about 70% sequence identity to the amino acid sequence of a VH amino acid sequence set forth in any one of SEQ ID NO:206, SEQ ID NO:215, and SEQ ID NO:214.
  • the VH can have at least about: 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of a VH amino acid sequence set forth in any one of SEQ ID NO:206, SEQ ID NO:215, and SEQ ID NO:214.
  • the V H has at least about 85% or at least about 90% sequence identity to the amino acid sequence of a VH amino acid sequence set forth in any one of SEQ ID NO:206, SEQ ID NO:215, and SEQ ID NO:214.
  • a polypeptide disclosed herein comprises a V H that has at least about 70% sequence identity to the amino acid sequence of a VH amino acid sequence set forth in SEQ ID NO:206.
  • the VH can have at least about: 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of a VH amino acid sequence set forth in SEQ ID NO:206.
  • the V H has at least about 85% or at least about 90% sequence identity to the amino acid sequence of a V H amino acid sequence set forth in SEQ ID NO:206.
  • a polypeptide disclosed herein comprises a VH that has at least about 70% sequence identity to the amino acid sequence of a V H amino acid sequence set forth in SEQ ID NO:215.
  • the V H can have at least about: 71%, 72%, 73%, - 75 - 3820371.v1 5708.1067001 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of a V H amino acid sequence set forth in SEQ ID NO:215.
  • the VH has at least about 85% or at least about 90% sequence identity to the amino acid sequence of a VH amino acid sequence set forth in SEQ ID NO:215.
  • a polypeptide disclosed herein comprises a V H that has at least about 70% sequence identity to the amino acid sequence of a V H amino acid sequence set forth in SEQ ID NO:214.
  • the VH can have at least about: 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of a VH amino acid sequence set forth in SEQ ID NO:214.
  • the VH has at least about 85% or at least about 90% sequence identity to the amino acid sequence of a V H amino acid sequence set forth in SEQ ID NO:214.
  • a polypeptide disclosed herein comprises a VL that has at least about 70% sequence identity to the amino acid sequence of a VL amino acid sequence set forth in any of SEQ ID NOs:60-69, SEQ ID NOs:71-106, and SEQ ID NOs:217-226.
  • the V L can be at least about: 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of a V L amino acid sequence set forth in any of SEQ ID NOs:60-69, SEQ ID NOs:71-106, and SEQ ID NOs:217-226.
  • the VL has at least about 85% or at least about 90% sequence identity to the amino acid sequence of a V L amino acid sequence set forth in any of SEQ ID NOs:60-69, SEQ ID NOs:71-106, and SEQ ID NOs:217-226.
  • a polypeptide comprises a VL that has at least about 70% sequence identity to the amino acid sequence of a VL amino acid sequence set forth in any one of SEQ ID NO:217, SEQ ID NO:104, and SEQ ID NO:226.
  • the V L can be at least about: 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of a V L amino acid sequence set forth in any one of SEQ ID NO:217, SEQ ID NO:104, and SEQ ID NO:226.
  • the VL has at least about 85% or at least about 90% sequence identity to the amino acid sequence of a V L amino acid sequence set forth in any one of SEQ ID NO:217, SEQ ID NO:104, and SEQ ID NO:226. - 76 - 3820371.v1 5708.1067001 [00103]
  • a polypeptide comprises a VL that has at least about 70% sequence identity to the amino acid sequence of a VL amino acid sequence set forth in SEQ ID NO:217.
  • the V L can be at least about: 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of a V L amino acid sequence set forth in SEQ ID NO:217.
  • the V L has at least about 85% or at least about 90% sequence identity to the amino acid sequence of a V L amino acid sequence set forth in SEQ ID NO:217.
  • a polypeptide comprises a V L that has at least about 70% sequence identity to the amino acid sequence of a V L amino acid sequence set forth in SEQ ID NO:104.
  • the VL can be at least about: 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of a VL amino acid sequence set forth in SEQ ID NO:104.
  • the VL has at least about 85% or at least about 90% sequence identity to the amino acid sequence of a VL amino acid sequence set forth in SEQ ID NO:104.
  • a polypeptide comprises a V L that has at least about 70% sequence identity to the amino acid sequence of a VL amino acid sequence set forth in SEQ ID NO:226.
  • the V L can be at least about: 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of a V L amino acid sequence set forth in SEQ ID NO:226.
  • the V L has at least about 85% or at least about 90% sequence identity to the amino acid sequence of a V L amino acid sequence set forth in SEQ ID NO:226.
  • a polypeptide disclosed herein comprises a VH that comprises at least 1 amino acid substitution relative to the amino acid sequence of a V H amino acid sequence set forth in any of SEQ ID NOs:3-17, SEQ ID NOs:19-58, and SEQ ID NOs:206-216.
  • the number of amino acid substitutions can be at least about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, or about: 1-20, 1-19, 2-19, 2-18, 2-17, 3-17, 3-16, 4-16, 4-15, 5-15, 5-14, 6-14, 6-13, 7-13, 7-12, 8-12, 8-11 or 9-11.
  • the VH comprises about 1-10 amino acid substitutions, relative to the amino acid sequence of a V H amino acid sequence set forth in any of SEQ ID NOs:3-17, SEQ ID NOs:19-58, and SEQ ID NOs:206-216.
  • the at least 1 amino acid - 77 - 3820371.v1 5708.1067001 substitution replaces only an HCDR1, an HCDR2 and/or an HCDR3 residue, of a VH amino acid sequence set forth in any of SEQ ID NOs:3-17, SEQ ID NOs:19-58, and SEQ ID NOs:206-216.
  • the at least 1 amino acid substitution replaces only a non-CDR residue (e.g., within a framework region), of a VH amino acid sequence set forth in any of SEQ ID NOs:3-17, SEQ ID NOs:19-58, and SEQ ID NOs:206-216.
  • a polypeptide comprises a V H that comprises at least 1 amino acid substitution relative to the amino acid sequence of a V H amino acid sequence set forth in any one of SEQ ID NO:206, SEQ ID NO:215, and SEQ ID NO:214.
  • the number of amino acid substitutions can be at least about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, or about: 1-20, 1-19, 2-19, 2-18, 2-17, 3-17, 3-16, 4-16, 4-15, 5-15, 5-14, 6-14, 6-13, 7-13, 7-12, 8-12, 8-11 or 9-11.
  • the VH comprises about 1-10 amino acid substitutions, relative to the amino acid sequence of a VH amino acid sequence set forth in any one of SEQ ID NO:206, SEQ ID NO:215, and SEQ ID NO:214.
  • the at least 1 amino acid substitution replaces only an HCDR1, an HCDR2 and/or an HCDR3 residue, of a VH amino acid sequence set forth in any one of SEQ ID NO:206, SEQ ID NO:215, and SEQ ID NO:214. In some embodiments, the at least 1 amino acid substitution replaces only a non-CDR residue (e.g., within a framework region), of a VH amino acid sequence set forth in any one of SEQ ID NO:206, SEQ ID NO:215, and SEQ ID NO:214.
  • a polypeptide comprises a V H that comprises at least 1 amino acid substitution relative to the amino acid sequence of a VH amino acid sequence set forth in SEQ ID NO:206.
  • the number of amino acid substitutions can be at least about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, or about: 1-20, 1-19, 2- 19, 2-18, 2-17, 3-17, 3-16, 4-16, 4-15, 5-15, 5-14, 6-14, 6-13, 7-13, 7-12, 8-12, 8-11 or 9-11.
  • the VH comprises about 1-10 amino acid substitutions, relative to the amino acid sequence of a V H amino acid sequence set forth in SEQ ID NO:206.
  • the at least 1 amino acid substitution replaces only an HCDR1, an HCDR2 and/or an HCDR3 residue, of a VH amino acid sequence set forth in SEQ ID NO:206. In some embodiments, the at least 1 amino acid substitution replaces only a non-CDR residue (e.g., within a framework region), of a V H amino acid sequence set forth in SEQ ID NO:206.
  • a polypeptide comprises a VH that comprises at least 1 amino acid substitution relative to the amino acid sequence of a V H amino acid sequence set forth in SEQ ID NO:215.
  • the number of amino acid substitutions can be at least - 78 - 3820371.v1 5708.1067001 about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, or about: 1-20, 1-19, 2- 19, 2-18, 2-17, 3-17, 3-16, 4-16, 4-15, 5-15, 5-14, 6-14, 6-13, 7-13, 7-12, 8-12, 8-11 or 9-11.
  • the V H comprises about 1-10 amino acid substitutions, relative to the amino acid sequence of a VH amino acid sequence set forth in SEQ ID NO:215.
  • the at least 1 amino acid substitution replaces only an HCDR1, an HCDR2 and/or an HCDR3 residue, of a V H amino acid sequence set forth in SEQ ID NO:215. In some embodiments, the at least 1 amino acid substitution replaces only a non-CDR residue (e.g., within a framework region), of a VH amino acid sequence set forth in SEQ ID NO:215.
  • a polypeptide comprises a V H that comprises at least 1 amino acid substitution relative to the amino acid sequence of a V H amino acid sequence set forth in SEQ ID NO:214.
  • the number of amino acid substitutions can be at least about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, or about: 1-20, 1-19, 2- 19, 2-18, 2-17, 3-17, 3-16, 4-16, 4-15, 5-15, 5-14, 6-14, 6-13, 7-13, 7-12, 8-12, 8-11 or 9-11.
  • the VH comprises about 1-10 amino acid substitutions, relative to the amino acid sequence of a VH amino acid sequence set forth in SEQ ID NO:214.
  • the at least 1 amino acid substitution replaces only an HCDR1, an HCDR2 and/or an HCDR3 residue, of a V H amino acid sequence set forth in SEQ ID NO:214.
  • the at least 1 amino acid substitution replaces only a non-CDR residue (e.g., within a framework region), of a V H amino acid sequence set forth in SEQ ID NO:214.
  • the amino acid substitutions are conservative substitutions.
  • conservative amino acid substitution(s) or “conservative substitution(s)” refers to an amino acid substitution having a value of 0 or greater in BLOSUM62.
  • the amino acid substitutions are highly conservative substitutions.
  • the term “highly conservative amino acid substitution(s)” or “highly conservative substitution(s)” refers to an amino acid substitution having a value of at least 1 (e.g., at least 2) in BLOSUM62.
  • a polypeptide disclosed herein comprises a VL that comprises at least 1 amino acid substitution relative to the amino acid sequence of a VL amino acid sequence set forth in any of SEQ ID NOs:60-69, SEQ ID NOs:71-106, and SEQ ID NOs:217-226.
  • the number of amino acid substitutions can be at least about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, or about: 1-20, 1-19, 2-19, 2- 18, 2-17, 3-17, 3-16, 4-16, 4-15, 5-15, 5-14, 6-14, 6-13, 7-13, 7-12, 8-12, 8-11 or 9-11.
  • the V L comprises about 1-10 amino acid substitutions, relative to the - 79 - 3820371.v1 5708.1067001 amino acid sequence of a VL amino acid sequence set forth in any of SEQ ID NOs:60-69, SEQ ID NOs:71-106, and SEQ ID NOs:217-226.
  • the at least 1 amino acid substitution replaces only an LCDR1, an LCDR2 and/or an LCDR3 residue, of a V L amino acid sequence set forth in any of SEQ ID NOs:60-69, SEQ ID NOs:71-106, and SEQ ID NOs:217-226.
  • the at least 1 amino acid substitution replaces only a non-CDR residue (e.g., within a framework region), of a V L amino acid sequence set forth in any of SEQ ID NOs:60-69, SEQ ID NOs:71-106, and SEQ ID NOs:217-226.
  • a polypeptide comprises a VL that comprises at least 1 amino acid substitution relative to the amino acid sequence of a V L amino acid sequence set forth in any one of SEQ ID NO:217, SEQ ID NO:104, and SEQ ID NO:226.
  • the number of amino acid substitutions can be at least about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, or about: 1-20, 1-19, 2-19, 2-18, 2-17, 3-17, 3-16, 4-16, 4-15, 5-15, 5-14, 6-14, 6-13, 7-13, 7-12, 8-12, 8-11 or 9-11.
  • the V L comprises about 1-10 amino acid substitutions, relative to the amino acid sequence of a VL amino acid sequence set forth in any one of SEQ ID NO:217, SEQ ID NO:104, and SEQ ID NO:226.
  • the at least 1 amino acid substitution replaces only an LCDR1, an LCDR2 and/or an LCDR3 residue, of a V L amino acid sequence set forth in any one of SEQ ID NO:217, SEQ ID NO:104, and SEQ ID NO:226. In some embodiments, the at least 1 amino acid substitution replaces only a non-CDR residue (e.g., within a framework region), of a V L amino acid sequence set forth in any one of SEQ ID NO:217, SEQ ID NO:104, and SEQ ID NO:226.
  • a polypeptide comprises a V L that comprises at least 1 amino acid substitution relative to the amino acid sequence of a V L amino acid sequence set forth in SEQ ID NO:217.
  • the number of amino acid substitutions can be at least about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, or about: 1-20, 1-19, 2- 19, 2-18, 2-17, 3-17, 3-16, 4-16, 4-15, 5-15, 5-14, 6-14, 6-13, 7-13, 7-12, 8-12, 8-11 or 9-11.
  • the VL comprises about 1-10 amino acid substitutions, relative to the amino acid sequence of a VL amino acid sequence set forth in SEQ ID NO:217.
  • the at least 1 amino acid substitution replaces only an LCDR1, an LCDR2 and/or an LCDR3 residue, of a V L amino acid sequence set forth in SEQ ID NO:217. In some embodiments, the at least 1 amino acid substitution replaces only a non-CDR residue (e.g., within a framework region), of a V L amino acid sequence set forth in SEQ ID NO:217. - 80 - 3820371.v1 5708.1067001 [00116] In some embodiments, a polypeptide comprises a VL that comprises at least 1 amino acid substitution relative to the amino acid sequence of a VL amino acid sequence set forth in SEQ ID NO:104.
  • the number of amino acid substitutions can be at least about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, or about: 1-20, 1-19, 2- 19, 2-18, 2-17, 3-17, 3-16, 4-16, 4-15, 5-15, 5-14, 6-14, 6-13, 7-13, 7-12, 8-12, 8-11 or 9-11.
  • the V L comprises about 1-10 amino acid substitutions, relative to the amino acid sequence of a V L amino acid sequence set forth in SEQ ID NO:104.
  • the at least 1 amino acid substitution replaces only an LCDR1, an LCDR2 and/or an LCDR3 residue, of a V L amino acid sequence set forth in SEQ ID NO:104.
  • the at least 1 amino acid substitution replaces only a non-CDR residue (e.g., within a framework region), of a VL amino acid sequence set forth in SEQ ID NO:104.
  • a polypeptide comprises a VL that comprises at least 1 amino acid substitution relative to the amino acid sequence of a V L amino acid sequence set forth in SEQ ID NO:226.
  • the number of amino acid substitutions can be at least about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, or about: 1-20, 1-19, 2- 19, 2-18, 2-17, 3-17, 3-16, 4-16, 4-15, 5-15, 5-14, 6-14, 6-13, 7-13, 7-12, 8-12, 8-11 or 9-11.
  • the V L comprises about 1-10 amino acid substitutions, relative to the amino acid sequence of a VL amino acid sequence set forth in SEQ ID NO:226.
  • the at least 1 amino acid substitution replaces only an LCDR1, an LCDR2 and/or an LCDR3 residue, of a V L amino acid sequence set forth in SEQ ID NO:226.
  • a polypeptide comprises: a) an HCDR1 comprising at least 1 amino acid substitution relative to at least one amino acid sequence set forth in any one of SEQ ID NOs:107-126; b) an HCDR2 comprising at least 1 amino acid substitution relative to at least one amino acid sequence set forth in any one of SEQ ID NOs:127-150; c) an HCDR3 comprising at least 1 amino acid substitution relative to at least one amino acid sequence set forth in any one of SEQ ID NOs:151-171, SEQ ID NO:227, and SEQ ID NO:228; d) an LCDR1 comprising at least 1 amino acid substitution relative to at least one amino acid sequence set forth in any one of SEQ ID NOs:172-178 and SEQ ID NO:229; -
  • a polypeptide disclosed herein comprises a V H that comprises an amino acid sequence set forth in any of SEQ ID NOs:3-17, SEQ ID NOs:19-58, and SEQ ID NOs:206-216.
  • a polypeptide comprises a V H that comprises an amino acid sequence set forth in any one of SEQ ID NO:206, SEQ ID NO:215, and SEQ ID NO:214.
  • a polypeptide comprises a VH that comprises an amino acid sequence set forth in SEQ ID NO:206.
  • a polypeptide comprises a VH that comprises an amino acid sequence set forth in SEQ ID NO:215.
  • a polypeptide comprises a VH that comprises an amino acid sequence set forth in SEQ ID NO:214.
  • a polypeptide disclosed herein comprises a V L that comprises an amino acid sequence set forth in any of SEQ ID NOs:59-69, SEQ ID NOs:71- 106, and SEQ ID NOs:217-226.
  • a polypeptide comprises a V L that comprises an amino acid sequence set forth in any one of SEQ ID NO:217, SEQ ID NO:104, and SEQ ID NO:226.
  • a polypeptide comprises a VL that comprises an amino acid sequence set forth in SEQ ID NO:217.
  • a polypeptide comprises a V L that comprises an amino acid sequence set forth in SEQ ID NO:104. In some embodiments, a polypeptide comprises a VL that comprises an amino acid sequence set forth in SEQ ID NO:226. [00123] In some embodiments, a polypeptide disclosed herein comprises: a V H comprising an amino acid sequence set forth in any of SEQ ID NOs:3-17, SEQ ID NOs:19-58, and SEQ ID NOs:206-216; and a VL comprising an amino acid sequence set forth in any of SEQ ID NOs:60-69, SEQ ID NOs:71-106, and SEQ ID NOs:217-226.
  • a polypeptide comprises: a VH comprising an amino acid sequence set forth in any one of SEQ ID NO:53 and SEQ ID NOs:206-216; and - 82 - 3820371.v1 5708.1067001 a VL comprising an amino acid sequence set forth in any one of SEQ ID NO:104, SEQ ID NO:106, and SEQ ID NOs:217-226.
  • a polypeptide comprises: a VH comprising an amino acid sequence set forth in any one of SEQ ID NO:206, SEQ ID NO:215, and SEQ ID NO:214; and a V L comprising an amino acid sequence set forth in any one of SEQ ID NO:217, SEQ ID NO:104, and SEQ ID NO:226.
  • a polypeptide comprises: a V H comprising an amino acid sequence set forth in SEQ ID NO:206; and a V L comprising an amino acid sequence set forth in SEQ ID NO:217.
  • a polypeptide comprises: a VH comprising an amino acid sequence set forth in SEQ ID NO:215; and a V L comprising an amino acid sequence set forth in SEQ ID NO:104.
  • a polypeptide comprises: a VH comprising an amino acid sequence set forth in SEQ ID NO:214; and a V L comprising an amino acid sequence set forth in SEQ ID NO:226.
  • a polypeptide disclosed herein comprises: a VH comprising an amino acid sequence set forth in any of SEQ ID NOs:3-17; and a V L comprising an amino acid sequence set forth in any of SEQ ID NOs:59-69.
  • a polypeptide disclosed herein comprises: a VH comprising an amino acid sequence set forth in any of SEQ ID NOs:19-58; and a V L comprising an amino acid sequence set forth in any of SEQ ID NOs:71-106.
  • a polypeptide disclosed herein comprises a V H and V L that are human.
  • a polypeptide disclosed herein comprises a VH and VL that are humanized, contain human framework regions, or a combination thereof.
  • a polypeptide disclosed herein is an immunoglobulin molecule, such as an antibody (e.g., a whole antibody, an intact antibody) or an antigen- binding fragment of an antibody.
  • a polypeptide disclosed herein is an antibody.
  • the term “antibody” refers to an immunoglobulin molecule capable of specific binding to a target, such as a carbohydrate, polynucleotide, lipid, polypeptide, etc., through at least one antigen recognition site, located in the variable domain of the immunoglobulin molecule.
  • the term “antibody” refers to a full-length antibody. - 83 - 3820371.v1 5708.1067001
  • a polypeptide disclosed herein is a single-domain antibody or an antigen-binding fragment thereof.
  • single-domain antibody refers to an immunoglobulin molecule consisting of a single monomeric variable antibody domain and capable of specific binding to a target.
  • the single- domain antibody can be of any species, such as a murine antibody, a human antibody or a humanized single-domain antibody.
  • a polypeptide disclosed herein is a heavy-chain antibody comprising two or more heavy chains, but lacking light chains, or an antigen-binding fragment thereof.
  • heavy chain antibodies include camelid Vhh (also referred to as VHH or V H H) antibodies.
  • Camelid antibodies are antibodies from the Camelidae family of mammals that include llamas, camels, and alpacas.
  • a polypeptide disclosed herein is an antibody comprising two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds or multimers thereof (for example, IgM).
  • Each heavy chain comprises a heavy chain variable domain (VH) and a heavy chain constant domain (comprising domains CH1, hinge CH2 and CH3).
  • Each light chain comprises a light chain variable domain (V L ) and a light chain constant domain (CL).
  • V H and the V L regions may be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed within framework regions (FR).
  • CDR complementarity determining regions
  • FR framework regions
  • V H and V L each comprises three CDRs and four FR segments, arranged from the amino-terminus to the carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the antibody can be of any species, such as a murine antibody, a human antibody or a humanized antibody.
  • the extent of the framework region and the CDRs of an antibody can be identified using one of several suitable methodologies that are well known in the art, for example, by the Kabat definition, the Chothia definition, the AbM definition, and/or the contact definition.
  • a “CDR” encompasses any CDR defined by an art-recognized method for identifying the CDR residues on an antibody. See, e.g., Kabat, E.A., et al., (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No.91-3242, Chothia et al., (1989) Nature 342:877; Chothia, C. et al., (1987) J. Mol. Biol.196:901-917; Al-lazikani et al., (1997) J. Molec. Biol. 273:927-948; and Almagro, J. Mol.
  • a polypeptide disclosed herein is an antigen-binding fragment of an antibody.
  • the term “antigen-binding fragment” refers to a portion of an immunoglobulin molecule (e.g., antibody) that retains the antigen binding properties of the full-length antibody.
  • Non-limiting examples of antigen-binding fragments include a VH region, a V L region, an Fab fragment, an F(ab’) 2 fragment, an Fd fragment, an Fv fragment, and a domain antibody (dAb) consisting of one V H domain or one V L domain, etc.
  • V H and V L domains may be linked together via a synthetic linker to form various types of single-chain antibody designs in which the V H /V L domains pair intramolecularly, or intermolecularly in those cases when the V H and V L domains are expressed by separate chains, to form a monovalent antigen binding site, such as single chain Fv (scFv) or diabody.
  • a polypeptide disclosed herein is an antigen binding fragment selected from Fab, F(ab’) 2 , Fab’, scFv, or Fv. In some embodiments, a polypeptide is a scFv. [00140] In some embodiments, a polypeptide disclosed herein is a modified or engineered antibody. Examples of modified or engineered antibodies include chimeric antibodies, multiparatopic antibodies (e.g., biparatopic antibodies), and multispecific antibodies (e.g., bispecific antibodies).
  • multispecific antibodies e.g., bispecific antibodies
  • targets or, where relevant, their receptors IL-1beta, IL-1RA, IL-2, IL4, IL-5, IL-13, IL-18, IL-23, IL-36, CLTA-4, OX40, GITR, BTLA, VISTA, TNF-alpha and other TNF family or TNF receptor family members, interferon-beta or interferon-gamma.
  • multiparatopic antibody means an antibody that comprises at least two single domain antibodies, in which at least one single domain antibody is directed against a first antigenic determinant on an antigen and at least one other single domain antibody is directed against a second antigenic determinant on the same antigen.
  • a “biparatopic” antibody comprises at least one single domain antibody directed against a first antigenic determinant on an antigen and at least one further single domain antibody directed against a second antigenic determinant on the same antigen.
  • multispecific antibody means an antibody that comprises at least two single domain antibodies, in which at least one single domain antibody is directed against a first antigen and at least one other single domain antibody is directed against a second antigen (different from the first antigen).
  • a “bispecific” antibody is one that comprises at least one single domain antibody directed against a first antigen and at least one further single domain antibody directed against a second antigen, e.g., different from the first antigen.
  • a polypeptide is an antibody mimetic.
  • antibody mimetic refers to polypeptides capable of mimicking an antibody’s ability to bind an antigen, but structurally differ from native antibody structures.
  • Non-limiting examples of antibody mimetics include Adnectins, Affibodies, Affilins, Affimers, Affitins, Alphabodies, Anticalins, Avimers, DARPins, Fynomers, Kunitz domain peptides, monobodies, nanobodies, nanoCLAMPs, and Versabodies.
  • a polypeptide disclosed herein competes with a reference antibody for binding to a full-length PD-1 (e.g., SEQ ID NO:1).
  • a polypeptide disclosed herein comprises: a) an antibody heavy chain constant domain sequence; b) an antibody light chain constant domain sequence; or c) both an antibody heavy chain constant domain sequence and an antibody light chain constant domain sequence.
  • a polypeptide disclosed herein comprises an antibody heavy chain constant domain sequence.
  • the antibody heavy chain constant domain is selected from the group consisting of an IgA constant domain, an IgD - 86 - 3820371.v1 5708.1067001 constant domain, an IgE constant domain, an IgG constant domain and an IgM constant domain.
  • the IgG constant domain is an IgG1 constant domain, an IgG2 constant domain, an IgG3 constant domain or an IgG4 constant domain.
  • the IgG2 constant domain is an IgG2a, an IgG2b constant domain or an IgG2c constant domain.
  • the IgA constant domain is an IgA1 constant domain or an IgA2 constant domain.
  • the antibody heavy chain constant domain is an IgG2 constant domain.
  • a polypeptide disclosed herein comprises an immunoglobulin light chain variable domain (V L ).
  • V L immunoglobulin light chain variable domain
  • the V H and V L domains may be linked together via a linker (e.g., a synthetic linker) to form various types of single-chain antibody designs in which the VH/VL domains pair intramolecularly, or intermolecularly in those cases when the VH and VL domains are expressed by separate chains, to form a monovalent antigen binding site.
  • a polypeptide disclosed herein comprises an antibody light chain constant domain sequence.
  • the antibody light chain constant domain is selected from the group consisting of a ⁇ constant domain and a ⁇ constant domain.
  • the antibody heavy chain constant domain is an IgG2 constant domain, and the antibody light chain constant domain is a ⁇ constant domain.
  • the antibody heavy chain constant domain sequence has at least about 60% sequence identity to the amino acid sequence of SEQ ID NO:202.
  • the antibody heavy chain constant domain sequence can have at least about: 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO:202.
  • the antibody heavy chain constant domain sequence has at least about 70% or at least about 80% sequence identity to the amino acid sequence of SEQ ID NO:202.
  • SEQ ID NO:202 The sequence identified as SEQ ID NO:202 is shown below: [00150] ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVH TFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPP CPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHN AKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTFPPMLDS - 87 - 3820371.v1 5708.1067001 DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSPGK (SEQ ID NO:202).
  • the antibody light chain constant domain sequence has at least about 60% sequence identity to the amino acid sequence of SEQ ID NO:203 or SEQ ID NO:204.
  • the antibody light chain constant domain sequence can have at least about: 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO:203 or SEQ ID NO:204.
  • the antibody light chain constant domain sequence has at least about 70% or at least about 80% sequence identity to SEQ ID NO:203 or SEQ ID NO:204.
  • the sequences identified as SEQ ID NO:203 or SEQ ID NO:204 are shown below: [00152] RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:203).
  • an antibody heavy chain constant domain sequence comprises at least 1 amino acid substitution relative to the amino acid sequence of SEQ ID NO:202.
  • an antibody heavy chain constant domain sequence comprises about 1-10 amino acid substitutions, relative to the amino acid sequence of SEQ ID NO:202.
  • an antibody light chain constant domain sequence comprises at least 1 amino acid substitution relative to the amino acid sequence of SEQ ID NO:203 or SEQ ID NO:204.
  • an antibody light chain constant domain sequence comprises about 1-10 amino acid substitutions, relative to the amino acid sequence of SEQ ID NO:203 or SEQ ID NO:204. - 88 - 3820371.v1 5708.1067001 [00156] In some embodiments, an antibody light chain constant domain sequence comprises at least 1 amino acid substitution relative to the amino acid sequence of SEQ ID NO:203.
  • the number of amino acid substitutions can be at least about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, or about: 1-20, 1-19, 2-19, 2-18, 2-17, 3-17, 3-16, 4-16, 4-15, 5-15, 5-14, 6-14, 6-13, 7-13, 7-12, 8-12, 8-11 or 9-11.
  • the antibody light chain constant domain sequence comprises about 1-10 amino acid substitutions, relative to the amino acid sequence of SEQ ID NO:203.
  • one or more amino acid substitutions are conservative substitutions.
  • one or more amino acid substitutions are highly conservative substitutions.
  • a polypeptide disclosed herein is an isolated polypeptide.
  • the isolated polypeptide is recombinantly produced. In some embodiments, the isolated polypeptide is synthetically produced.
  • a polypeptide disclosed herein is linked to a second polypeptide.
  • the term “linked” means attached, via a covalent or noncovalent interaction. Conjugation can employ a suitable linking agent. Non-limiting examples include peptide linkers, compound linkers, and chemical cross-linking agents. In some embodiments, the linker is a disulfide bond.
  • a polypeptide disclosed herein is conjugated to a heterologous moiety. The term “conjugated” refers to attached, via a covalent or noncovalent interaction.
  • the heterologous moiety is a therapeutic agent, a diagnostic agent or a combination thereof.
  • the heterologous moiety is polyethylene glycol (PEG), hexadecanoic acid, hydrogels, nanoparticles, multimerization domains and carrier peptides.
  • PEG polyethylene glycol
  • the nanoparticle is a lipid nanoparticle.
  • the nanoparticle is a polymer nanoparticle.
  • the polymer is an amphiphilic polymer.
  • the polymer is a hydrophobic or hydrophilic polymer.
  • Non-limiting examples of polymers include poly(lactic acid)- poly(ethylene glycol), poly(lactic-co-glycolic acid)-poly(ethylene glycol), poly(lactic-co- glycolic) acid (PLGA), poly(lactic-co-glycolic acid)-d- ⁇ -tocopheryl polyethylene glycol succinate, poly(lactic-co-glycolic acid)-ethylene oxide fumarate, poly(glycolic acid)- - 89 - 3820371.v1 5708.1067001 poly(ethylene glycol), polycaprolactone-poly(ethylene glycol), or any salts thereof.
  • the polymer nanoparticle comprises poly(lactic-co-glycolic) acid (PLGA).
  • the carrier polypeptide is albumin or an Fc polypeptide.
  • a polypeptide described herein comprises an Fc polypeptide, or Fc domain (e.g., an IgG1 domain, an IgG2 domain or an IgG4 domain).
  • the Fc domain comprises a mutation that for example, decreases (e.g., inhibits, ablates) an effector function of the Fc domain, increases half-life of an antibody or antibody fragment that comprises the Fc domain, or a combination thereof.
  • an Fc domain comprises an LS modification (M428L/N434S substitutions with numbering determined by Kabat) or a YTE modification (i.e., M252Y/S254T/T256E substitutions as determined by Kabat numbering). In some embodiments, an Fc domain comprises a YTE modification.
  • a polypeptide binds PD-1 with a binding constant (K D ) of about 100 pM or less.
  • K D binding constant
  • affinity constant is a measure of the extent of a reversible association between two molecular species (e.g., antibody and target protein) and includes both the actual binding affinity as well as the apparent binding affinity.
  • Binding affinity can be determined using methods known in the art including, for example, by measurement of surface plasmon resonance, e.g., using a Biolayer interferometry (Octet, ForteBio) or a surface plasmon resonance (Biacore) system and assay.
  • a Biolayer interferometry Octet, ForteBio
  • a surface plasmon resonance Biacore
  • a reference that compares various surface technologies for measuring binding affinity and kinetics is Yang, D., Singh, A., Wu, H., & Kroe-Barrett, R., Comparison of biosensor platforms in the evaluation of high affinity antibody-antigen binding kinetics, Analytical Biochemistry 508: 78-96 (2016), the contents of which are incorporated by reference herein in their entirety.
  • a polypeptide disclosed herein competes with one or more other antibodies disclosed herein for binding to a PD-1 protein (e.g., SEQ ID NO:1). Techniques and assays for assessing competition between antibodies are known in the art. - 90 - 3820371.v1 5708.1067001 Fusion Proteins [00166] In some embodiments, the disclosure provides a fusion protein comprising one or more of polypeptides described herein. [00167] The term “fusion protein” refers to a synthetic, semi-synthetic or recombinant single protein molecule.
  • a fusion protein can comprise all or a portion of two or more different proteins and/or polypeptides that are attached by covalent bonds (e.g., peptide bonds).
  • a fusion protein can comprise a full-length polypeptide disclosed herein (e.g., a whole antibody), or a fragment thereof (e.g., an antigen-binding fragment of an antibody).
  • the heterologous partner can be a full-length protein or a fragment thereof (e.g., a truncated protein).
  • Fusion proteins can be produced recombinantly or synthetically, using routine methods and reagents that are well known in the art.
  • a fusion protein can be produced recombinantly in a suitable host cell (e.g., bacteria) according to methods known in the art. See, e.g., Current Protocols in Molecular Biology, Second Edition, Ausubel et al. eds., John Wiley & Sons, 1992; and Molecular Cloning: a Laboratory Manual, 2nd edition, Sambrook et al., 1989, Cold Spring Harbor Laboratory Press.
  • a nucleic acid molecule comprising a nucleotide sequence encoding a fusion protein described herein can be introduced and expressed in suitable host cell (e.g., E.
  • the expressed fusion protein can be isolated/purified from the host cell (e.g., in inclusion bodies) using routine methods and readily available reagents.
  • DNA fragments coding for different protein sequences e.g., a light-responsive domain, a heterologous peptide component
  • the fusion gene can be synthesized by conventional techniques including automated DNA synthesizers.
  • PCR amplification of nucleic acid fragments can be carried out using anchor primers that give rise to complementary overhangs between two consecutive nucleic acid fragments that can subsequently be annealed and re-amplified to generate a chimeric nucleic acid sequence (see Ausubel et al., Current Protocols in Molecular Biology, 1992).
  • the disclosure provides one or more polynucleotides (e.g., DNA, RNA, or analogs of either, e.g., optionally including one or more modified nucleotides; the polynucleotide may be linear or circular, e.g., linear or circular RNA) encoding any one - 91 - 3820371.v1 5708.1067001 of the polypeptides or fusion proteins described herein.
  • polypeptides or fusion proteins disclosed herein is encoded by a single polynucleotide.
  • polypeptides or fusion proteins disclosed herein is encoded by multiple polynucleotides.
  • the polynucleotide comprises a nucleotide sequence that is codon-optimized for a chosen host cell.
  • the disclosure provides a vector (e.g., an expression vector, including a viral-delivery vector) comprising any one or more of the polynucleotides described herein.
  • expression vector refers to a replicable nucleic acid from which one or more proteins can be expressed when the expression vector is transformed into a suitable expression host cell.
  • the vector (e.g., expression vector) comprises an expression control polynucleotide sequence operably linked to the polynucleotide, a polynucleotide sequence encoding a selectable marker, or both.
  • the expression control polynucleotide sequence comprises a promoter sequence, an enhancer sequence, or both.
  • the expression control polynucleotide sequence comprises an inducible promoter sequence.
  • promoter refers to a region of DNA to which RNA polymerase binds and initiates the transcription of a gene.
  • operably linked means that the nucleic acid is positioned in the recombinant polynucleotide, e.g., vector, in such a way that enables expression of the nucleic acid under control of the element (e.g., promoter) to which it is linked.
  • element e.g., promoter
  • selectable marker element is an element that confers a trait suitable for artificial selection. Selectable marker elements can be negative or positive selection markers.
  • the disclosure provides an expression host cell comprising any one or more of the polynucleotides or expression vectors described herein.
  • expression host cell refers to a cell useful for receiving, maintaining, reproducing and/or amplifying a vector.
  • Non-limiting examples of expression host cells include mammalian cells such as hybridoma cells, Chinese hamster ovary (CHO) cells, COS cells, human embryonic kidney (HEK), yeast cells such as Pichia pastoris cells, or bacterial cells such as E. coli, including DH5 ⁇ , etc. - 92 - 3820371.v1 5708.1067001 Compositions [00177] In some embodiments, the disclosure provides a composition comprising any one of the polypeptides or fusion proteins described herein. In some embodiments, the composition is a pharmaceutical composition.
  • the composition (e.g., pharmaceutical composition) comprises pharmaceutically acceptable carriers, excipients, stabilizers, diluents or tonifiers (Remington's Pharmaceutical Sciences 16 th edition, Osol, A. Ed. (1980)). Suitable pharmaceutically acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed.
  • Non-limiting examples of pharmaceutically acceptable carriers, excipients, stabilizers, diluents or tonifiers include buffers (e.g., phosphate, citrate, histidine), antioxidants (e.g., ascorbic acid or methionine), preservatives, proteins (e.g., serum albumin, gelatin or immunoglobulins); hydrophilic polymers, amino acids, carbohydrates (e.g., monosaccharides, disaccharides, glucose, mannose or dextrins); chelating agents (e.g., EDTA), sugars (e.g., sucrose, mannitol, trehalose or sorbitol), salt- forming counter-ions (e.g., sodium), metal complexes (e.g., Zn-protein complexes); non-ionic surfactants (e.g., Tween), PLURONICSTM and polyethylene glycol (PEG).
  • buffers e.g., phosphate, citrate,
  • the composition (e.g., pharmaceutical composition) disclosed herein is formulated for a suitable administration schedule and route.
  • administration routes include oral, rectal, mucosal, intravenous, intramuscular, subcutaneous and topical, etc.
  • the composition (e.g., pharmaceutical composition) disclosed herein is stored in the form of an aqueous solution or a dried formulation (e.g., lyophilized).
  • the composition is formulated to be administered by infusion (e.g., intravenous infusion).
  • the composition is formulated to be administered with a second therapeutic agent as a combination therapy.
  • the second therapeutic agent reduces (e.g., decreases, inhibits) an immune response, such as an inflammatory response. In some embodiments, the second therapeutic agent promotes immune tolerance.
  • a polypeptide or composition disclosed herein is used in conjunction with other immune modulators, such as immune modulators that target aberrant T- or B-cell responses with complementary or orthogonal mechanisms, in a multispecific (e.g., bispecific) molecule (e.g., antibody) or co-administered format.
  • Such agents include, for example, molecules modulating the following targets or, where relevant, their receptors: - 93 - 3820371.v1 5708.1067001 IL-1beta, IL-1RA, IL-2, IL4, IL-5, IL-13, IL-18, IL-23, IL-36, CLTA-4, OX40, GITR, BTLA, VISTA, TNF-alpha and other TNF family or TNF receptor family members, interferon-beta or interferon-gamma.
  • Non-limiting examples of second therapeutic agents that are useful in combination with polypeptides and compositions described herein include disease-modifying anti- rheumatic drugs (DMARs), anti-TNF agents, TNF-Fcs, non-steroidal anti-inflammatory drugs (NSAIDs), Immune Selective Anti-Inflammatory Derivatives (ImSAIDs), corticosteroids (e.g., glucocorticoids), therapeutic Treg cells, autophagy-related (ATG) proteins, ⁇ -l-guluronic acid (ALG), interferons, anti-inflammatory interleukins (e.g., IL-2, IL- 10), macrolides and biologics (e.g., dupilumab).
  • DMARs disease-modifying anti- rheumatic drugs
  • anti-TNF agents e.g., TNF-Fcs
  • NSAIDs non-steroidal anti-inflammatory drugs
  • ImSAIDs Immune Selective Anti-Inflammatory Derivatives
  • second therapeutic agents that are useful in combination with polypeptides and compositions described herein include an insulin preparation (e.g., human insulin, insulin glargine, insulin lispro, insulin detemir, or insulin aspart), a sulfonylurea agent (e.g., glibenclamide, gliclazide, or glimepiride), a quick-acting insulin secretion promoter (e.g., nateglinide), a biguanide preparation (e.g., metformin), an insulin sensitizer (e.g., pioglitazone), an alpha-glucosidase inhibitor (e.g., acarbose or voglibose), a diabetic neuropathy therapeutic agent (e.g., epalrestat, mexiletine, or imidapril), a GLP-1 analog preparation (e.g., liraglutide, exenatide, or lixisenatide),
  • the disclosure provides a method of modulating (e.g., inhibiting) PD-1 signaling in a subject, comprising administering to the subject an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier - 94 - 3820371.v1 5708.1067001 and, wherein as an active ingredient, any one of the polypeptides or fusion proteins described herein.
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier - 94 - 3820371.v1 5708.1067001 and, wherein as an active ingredient, any one of the polypeptides or fusion proteins described herein.
  • subject and “patient” are used herein interchangeably to refer to an animal (e.g., a mammal, such as a human) who is to be treated according to a method disclosed herein.
  • a subject to be treated according to methods described herein may be one who has been diagnosed with inflammation, such as inflammation associated with an inflammatory bowel disease (IBD) and/or autoimmune disease. Diagnosis may be performed by any method or technique known in the art. One skilled in the art will understand that a subject to be treated according to the present disclosure may have been subjected to standard tests or may have been identified, without examination, as one at risk due to the presence of one or more risk factors associated with the disease or condition. [00185] In some embodiments, the subject is a mammal.
  • the subject is a mammal selected from the group consisting of a dog, a cat, a mouse, a rat, a hamster, a guinea pig, a horse, a pig, a sheep, a cow, a chimpanzee, a macaque, a cynomolgus, and a human.
  • the subject is a primate.
  • the subject is a human.
  • the subject is 18 years of age or older, for example, about: 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75 or 80 years of age or older. In some embodiments, the subject is 65 years of age or older.
  • the subject is about: 18-80, 20-80, 20-75, 25-75, 25-70, 30-70, 30-65, 35-65, 35-60, 40-60, 40-55, 45-55 years of age. In some embodiments, the subject is about 18-65 years of age. [00187] In some embodiments, the subject is about 18 years of age or younger. In some embodiments, the subject is about: 16, 14, 12, 10, 8, 6, 4 or 2 years of age or older. In some embodiments, the subject is two years of age or older, for example, about: 2-18, 3-18, 3-16, 4-16, 4-14, 5-14, 5-12, 6-12, 6-10 or 8-10 years of age. [00188] In some embodiments, methods disclosed herein are useful for treating inflammation.
  • methods disclosed herein are useful for treating an inflammatory disease, condition, or disorder.
  • inflammatory diseases, conditions, or disorders include inflammatory bowel diseases (IBD) (e.g., Crohn’s disease, ulcerative colitis, and other forms of colitis or inflammation along the digestive tract thought to be caused by aberrant T-or B-cell biology), asthma and airway inflammation, autoimmune diseases (e.g., idiopathic autoimmune conditions), graft-versus-host disease - 95 - 3820371.v1 5708.1067001 (GvHD), and other conditions with aberrant T- or B-cell biology manifest as anti-self clinical syndromes.
  • IBD inflammatory bowel diseases
  • autoimmune diseases e.g., idiopathic autoimmune conditions
  • graft-versus-host disease - 95 - 3820371.v1 5708.1067001 (GvHD) graft-versus-host disease - 95 - 3820371.v1 5708.1067001
  • GvHD graft-versus-
  • Non-limiting examples of autoimmune diseases that can be treated using the compositions and methods described herein include achalasia, Addison’s disease, adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti- GBM/anti-TBM nephritis, antiphospholipid syndrome, atopic dermatitis and other autoimmune dermatologic or mixed dermatologic-rheumatologic syndromes, autoimmune angioedema, autoimmune dermatitis, autoimmune dysautonomia, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal and neuronal neuropathy (AMAN), Baló disease, Behcet’s disease, benign mucosal pemphigoid
  • treating refers to the medical management of a subject with the intent to improve, ameliorate, stabilize (i.e., not worsen), prevent or cure a disease, pathological condition, or disorder—such as the particular indications exemplified herein.
  • This term includes active treatment (treatment directed to improve the disease, pathological condition, or disorder), causal treatment (treatment directed to the cause of the associated disease, pathological condition, or disorder), palliative treatment (treatment designed for the relief of symptoms), preventative treatment (treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder); and supportive treatment (treatment employed to supplement another therapy).
  • Treatment also includes diminishment of the extent of the disease or condition; preventing spread of the disease or condition; delay or slowing the progress of the disease or condition; amelioration or palliation of the disease or condition; and remission (whether partial or total), whether detectable or undetectable.
  • “Ameliorating” or “palliating” a disease or condition - 97 - 3820371.v1 5708.1067001 means that the extent and/or undesirable clinical manifestations of the disease, disorder, or condition are lessened and/or time course of the progression is slowed or lengthened, as compared to the extent or time course in the absence of treatment.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • a therapeutically effective amount is an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result (e.g., treatment, healing, inhibition or amelioration of physiological response or condition, etc.).
  • the therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations.
  • a therapeutically effective amount may vary according to factors such as disease state, age, sex, and weight of a mammal, mode of administration and the ability of a therapeutic, or combination of therapeutics, to elicit a desired response in an individual.
  • Desired response or desired results include effects at the cellular level, tissue level, or clinical results.
  • “a therapeutically effective amount” or synonym thereto depends upon the context in which it is being applied. For example, in some embodiments it is an amount of the composition sufficient to achieve a treatment response as compared to the response obtained without administration of the composition. In some embodiments, it is an amount that results in a beneficial or desired result in a subject as compared to a control.
  • a therapeutically effective amount of a composition disclosed herein may be readily determined by one of ordinary skill by routine methods known in the art. Dosage regimen and route of administration may be adjusted to provide the optimum therapeutic response.
  • a therapeutic agent described herein can be administered via a variety of routes of administration, including, for example, topical, transdermal, parenteral (e.g., intra-arterial, intravenous, intramuscular, subcutaneous injection, intradermal injection), intravenous infusion and inhalation (e.g., intrabronchial, intranasal or oral inhalation, intranasal drops) routes of administration, depending on the compound and the particular disease to be treated.
  • parenteral e.g., intra-arterial, intravenous, intramuscular, subcutaneous injection, intradermal injection
  • intravenous infusion and inhalation e.g., intrabronchial, intranasal or oral inhalation, intranasal drops
  • a polypeptide, composition, or pharmaceutical composition disclosed herein is administered to a subject as a monotherapy. - 98 - 3820371.v1 5708.1067001 [00195] In some embodiments, a polypeptide, composition, or pharmaceutical composition disclosed herein is administered to a subject in combination with one or more additional therapeutic agents (e.g., concurrently or sequentially with one or more additional therapeutic agents). In some embodiments, a subject has been previously treated with one or more therapeutic agents prior to being administered a polypeptide, composition, or pharmaceutical composition disclosed herein.
  • the method comprises administering a therapeutically effective amount of one or more additional therapeutic agents to the subject at the same time as, or following administration of a polypeptide, composition, or pharmaceutical composition disclosed herein.
  • the subject previously received a therapeutic agent.
  • Administration of the two or more therapeutic agents encompasses co- administration of the therapeutic agents in a substantially simultaneous manner, such as in a pharmaceutical combination.
  • such administration encompasses co- administration in multiple containers, or separate containers (e.g., capsules, powders, and liquids) for each therapeutic agent.
  • Such administration also encompasses use of each type of therapeutic agent in a sequential manner, either at approximately the same time or at different times.
  • composition described herein and the second therapeutic agent can be administered via the same administration route or via different administration routes.
  • Administration can be local or systemic as indicated.
  • the preferred mode of administration can vary depending on the particular compound chosen.
  • the disclosure provides, among other things, a method of increasing (e.g., enhancing, promoting) binding of PD-L1 and/or PD-L2 to PD-1 in a cell, comprising contacting the cell an effective amount of any one of the polypeptides or fusion proteins described herein.
  • the disclosure provides, among other things, a method of inhibiting PD-1 signaling in a cell (e.g., a T cell), comprising contacting the cell an effective amount of any one of the polypeptides or fusion proteins described herein.
  • a cell e.g., a T cell
  • all terms of art, notations and other scientific terms or terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this disclosure pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and/or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art.
  • the conjunctive term “and/or” between multiple recited elements is understood as encompassing both individual and combined options. For instance, where two elements are conjoined by “and/or,” a first option refers to the applicability of the first element without the second. A second option refers to the applicability of the second element without the first. A third option refers to the applicability of the first and second elements together.
  • the description “at least 1, 2, 3, 4, or 5” also describes, inter alia, the ranges 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, 3-5, and 4-5, et cetera.
  • Headings used in this application are for convenience only and do not affect the interpretation of this application.
  • Preferred features of each of the aspects or embodiments provided by the invention are applicable to all of the other aspects or embodiments of the invention mutatis mutandis and, without limitation, are exemplified by the dependent claims and also encompass combinations and permutations of individual features (e.g., elements, including numerical ranges and exemplary embodiments) of some embodiments and aspects of the invention, including the working examples.
  • each of the combinations A-E, A-F, B- D, B-E, B-F, C-D, C-E, and C-F are specifically contemplated and should be considered disclosed from disclosure of A, B, and C; D, E, and F; and the example combination A-D.
  • any subset or combination of these is also specifically contemplated and disclosed.
  • the sub-groups of A-E, B-F, and C-E are specifically contemplated and should be considered disclosed from disclosure of A, B, and C; D, E, and F; and the example combination A-D.
  • PD-1 plays a role in mediating immune homeostasis and T cell tolerance by inhibiting T cell receptor (TCR) signaling [1-3]. While antagonizing PD-1 has been a common approach in oncology, agonizing PD-1 is a relatively underexplored approach for ameliorating auto-immune disease. For example, mice deficient of PD-1 have been shown to spontaneously develop autoimmune disorders such as a lupus-like disease, suggesting an important role of PD-1 signaling in the regulation of autoimmunity [1, 4]. Activation of PD-1 leads to a downregulation of PD-1 expression, reduced cytokine release, and suppression of immune response, representing a promising treatment for autoimmune diseases.
  • TCR T cell receptor
  • Agonistic activity of an antibody is driven by targeting specific epitopes on the target, which Applicant identified.
  • PD-1 antagonist antibodies such as Pembrolizumab and Nivolumab disrupt PD-1 binding with its natural ligands PD-L1 and PD-L2
  • PD-1 agonist antibodies show no competition with PD-L1 or PD- L2, indicating that they bound a distinct epitope space on PD-1.
  • binding agonist epitopes leads to crosslinking of PD-1 on the surface of T cells and elicits an immune inhibitory signaling pathway.
  • MCS magnetic-activated cell sorting
  • FACS fluorescence-activated cell sorting
  • Antibodies were formatted into full-length human immunoglobulin 1 (IgG1) by subcloning the variable heavy (V H ) chain and variable light (V L ) chains into mammalian expression vectors containing corresponding constant regions (SEQ ID NO:202 and SEQ ID NO:203) using conventional methods. Each IgG protein was expressed in ExpiCHO cells following manufacturer’s methods (Thermo Fisher Scientific, Waltham, MA).
  • Binding kinetics and affinity to PD-1 were measured with Bio-layer interferometry (BLI) using a ForteBio (Fremont, CA) Octet Red96e instrument or surface plasmon resonance (SPR) using a CARTERRA ® (Andover, MA) LSATM instrument.
  • the SPR data are shown in Tables 1-3. Binding to PD-1 expressed on Raji cells was assessed by flow cytometry using an Intellicyt (Albuquerque, NM) iQue3 instrument (Table 1).
  • an engineered Jurkat cell line expressing both PD-1 and a luciferase reporter driven by an NFAT response element was used.
  • binding Kinetics & Functional Characterization of PD-1 Agonistic Antibodies [00214] a) Structural characterization of clone AB-49 [00215] The structure of AB-49 alone (without the antigen) was solved using X-ray crystallography, at 2.46 A resolution. The structure is shown in FIG.6B, with - 103 - 3820371.v1 5708.1067001 superimposition onto the corresponding computational model in FIG.6D. There is close agreement between the model and experimental structure (i.e., backbone RMSD over all CDR residues is 1.6 ⁇ , despite the fact that the comparison is between a Fab-only crystal structure and a computational model of the antibody in the bound state).
  • Binding to PD-1 expressed on Jurkat cell cells was assessed by flow cytometry using an Intellicyt iQue3 instrument.
  • PD-1 agonism was assessed in vitro using the same engineered Jurkat cell line expressing both PD-1 and a luciferase reporter driven by an NFAT response element (Promega, Madison, WI).
  • KD binding affinity
  • NFAT response element Promega, Madison, WI
  • AB-58 to AB-64 were further optimized computationally and expressed as full- length IgG and expressed in Expi293 cells.
  • the hits were functionally characterized for on- cell binding and TCR inhibition as described previously with one change: Jurkat cells expressing PD-1 were used to assess on-cell binding instead.
  • Overall, computationally optimized hits showed 2-fold improvement in TCR inhibition (Table 3).
  • - 105 - 3820371.v1 5708.1067001 Table 3.
  • Functional Characterization of PD-1 Agonistic Antibodies Example 3.
  • PBMC-Based Assay to Measure PD-1 Agonist Effects Peripheral blood mononuclear cells (PBMCs) are stimulated with anti-CD3 and anti-CD28 T cell activators prior to incubation with an anti-PD1 antibody disclosed herein.
  • PD-1 agonist activity is measured by detecting a decrease in PD-1 surface expression, inhibition of T cell proliferation in a CD4 + T cell population, and/or reduction of secreted cytokines (e.g., TNF ⁇ and IFN ⁇ ) in the cell supernatant as a result of antibody treatment.
  • cytokines e.g., TNF ⁇ and IFN ⁇

Abstract

L'invention concerne, dans divers modes de réalisation, des polypeptides (par exemple, des anticorps et des fragments de liaison à l'antigène de ceux-ci) qui se lient spécifiquement à la protéine de mort cellulaire programmée 1 (PD-1). L'invention concerne également, dans divers modes de réalisation, des protéines de fusion comprenant un polypeptide décrit ici, des polynucléotides codant pour un polypeptide décrit ici, des vecteurs et des cellules hôtes appropriés pour exprimer des polypeptides décrits ici, et des méthodes de traitement d'une maladie ou d'une affection (par exemple, un cancer) à l'aide de polypeptides décrits ici.
PCT/US2023/073172 2022-08-30 2023-08-30 Molécules de liaison à l'antigène ciblant la protéine 1 de mort cellulaire programmée (pd-1) WO2024050421A2 (fr)

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