US20230312757A1 - Bispecific antibodies against cd3 and cd20 for treating chronic lymphocytic leukemia - Google Patents

Bispecific antibodies against cd3 and cd20 for treating chronic lymphocytic leukemia Download PDF

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US20230312757A1
US20230312757A1 US18/025,202 US202118025202A US2023312757A1 US 20230312757 A1 US20230312757 A1 US 20230312757A1 US 202118025202 A US202118025202 A US 202118025202A US 2023312757 A1 US2023312757 A1 US 2023312757A1
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dose
administered
bispecific antibody
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Brian Elliott
Jenny J. CHEN
Tahamtan Ahmadi
Christopher W.L. CHIU
Esther C.W. BRElJ
Ida HIEMSTRA
Maria N. JURE-KUNKEL
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Genmab AS
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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
    • C07K16/2809—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 the T-cell receptor (TcR)-CD3 complex
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/46—Hybrid immunoglobulins
    • C07K16/468—Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • C07K16/2887—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • 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]

Definitions

  • the present invention relates to bispecific antibodies targeting both CD3 and CD20 and the use of such antibodies in the treatment of chronic lymphocytic leukemia (CLL).
  • CLL chronic lymphocytic leukemia
  • Chronic lymphocytic leukemia is a B-cell malignancy that originates from uncontrolled proliferation of immature lymphocytes in the bone marrow and involves circulating tumor cells in the blood.
  • CLL is characterized by accumulation of clonal CD5+CD19+CD20+CD23+ B cells in the bone marrow, blood, and lymphoid organs such as lymph nodes and spleen (Zenz et al., Nat Rev Cancer 2010; 10:37-50).
  • CLL is often a slow-growing cancer.
  • CLL is primarily a disease of older adults, with a median age of 70 years at the time of diagnosis.
  • CLL is the most common leukemia in adults in Western countries, accounting for approximately 25% to 30% of all leukemias in the US with estimated 20,720 new cases and 3,930 deaths (Siegel et al., CA Cancer J Clin 2019; 69:7-34). Worldwide, there are approximately 105,000 cases per year, of which 35,000 are deaths (Global Burden of Disease Cancer, Fitzmaurice et al., JAMA Oncol 2018; 4:1553-68).
  • lymphoma originates from uncontrolled proliferation of lymphocytes in organs outside of the bone marrow. Although in some lymphomas, bone marrow can also have tumor cell infiltrates. Lymphoma cells will usually not appear in the peripheral blood.
  • CD20 was observed to be lower on CLL than on normal peripheral B cells or on other malignant NHL (Almasri et al., Am J Hematol 1992:40:259-63; Pedersen et al., Blood 2002; 99:1314-9; Prevodnik et al., Diagn Pathol 2011; 6:33; Olejniczak et al., Immunol Invest 2006; 35:93-114; Ginaldi et al., J Clin Pathol 1998; 51:364-9; D'Arena et al., Am J Hematol 2000; 64:275-81).
  • CLL cancer-derived neurotrophic factor
  • standard of care includes cytotoxic chemotherapy (i.e. fludarabine, cyclophosphamide, bendamustine, or chlorambucil) in combination with an anti-CD20 monoclonal antibody (i.e., rituximab or obinutuzumab)
  • cytotoxic chemotherapy i.e. fludarabine, cyclophosphamide, bendamustine, or chlorambucil
  • an anti-CD20 monoclonal antibody i.e., rituximab or obinutuzumab
  • rituximab or obinutuzumab anti-CD20 monoclonal antibody
  • novel agents with a low toxicity profile are of particular importance as a replacement of these highly toxic and intensive regimens.
  • chemotherapy-free regimens such as ibrutinib plus rituximab (Burger et al., Ann Intern Med 2015; 163:461-4), venetoclax plus rituximab (Seymour et al., N Engl J Med 2018; 378:1107-20), venetoclax plus obinutuzumab (Fisher et al. N Engl J Med; 2019; 380(23):2225-36)), ibrutinib plus venetoclax (Niemann et al., Blood 2019; 134:4292; Tam et al., 2019 ASH Annual Meeting; Dec. 7 to 10, 2019; Orlando, FL. Abstract 35.
  • CLL remains an incurable disease outside of aggressive therapy with stem cell transplantation.
  • kits for treating human subjects who have CLL by administering a bispecific antibody which binds to CD3 and CD20 and, in particular, advantageous clinical treatment regimens.
  • a method of treating CLL for example, relapsed and/or refractory CLL, in a human subject, the method comprising administering (e.g., subcutaneously) to the subject an effective amount of a bispecific antibody (e.g., epcoritamab) comprising:
  • the bispecific antibody is administered once every week, e.g., for 2.5 28-day cycles (i.e., days 15 and 22 of cycle 1, and days 1, 8, 15, and 22 of cycles 2-3). In some embodiments, the bispecific antibody is administered once every two weeks after the weekly administration, e.g., for six 28-day cycles. In some embodiments, the bispecific antibody is administered once every four weeks after the biweekly administration.
  • a priming dose e.g., 0.05-0.35 mg, for example, 0.16 mg or about 0.16 mg
  • the priming dose is administered one week before the intermediate dose, and the intermediate dose is administered one week before the first weekly dose of 24 mg or 48 mg.
  • the bispecific antibody is administered in 28-day cycles, wherein:
  • the subject is intolerant to a BTK inhibitor.
  • the subject has received at least two prior lines of antineoplastic therapy, e.g., wherein at least one of the two prior lines of antineoplastic therapy comprises treatment with a BTK inhibitor, such as ibrutinib.
  • a BTK inhibitor such as ibrutinib.
  • the subject's CLL is refractory to a BTK inhibitor (e.g., ibrutinib or acalabrutinib).
  • the subject's CLL relapsed during treatment with a BTK inhibitor (ibrutinib).
  • the subject has refractory and/or relapsed CLL after receiving the two prior antineoplastic therapies.
  • the subject is treated with prophylaxis for cytokine release syndrome (CRS).
  • the prophylaxis comprises administering a corticosteroid (e.g., prednisolone at a dose of, e.g., 100 mg or equivalent thereof, including oral dose) on, for example, the same day as the bispecific antibody.
  • the corticosteroid is further administered on the second, third, and fourth days after administering the bispecific antibody.
  • the subject is administered premedication, such as antihistamine (e.g., diphenhydramine, intravenously or orally at a dose of, e.g., 50 mg or equivalent thereof) and/or antipyretic (e.g., acetaminophen at a dose of, e.g., 560-1000 mg), to reduce reactions to injections.
  • premedication such as antihistamine (e.g., diphenhydramine, intravenously or orally at a dose of, e.g., 50 mg or equivalent thereof) and/or antipyretic (e.g., acetaminophen at a dose of, e.g., 560-1000 mg), to reduce reactions to injections.
  • premedication such as antihistamine (e.g., diphenhydramine, intravenously or orally at a dose of, e.g., 50 mg or equivalent thereof) and/or antipyretic (e.g., acetaminophen at a dose of, e
  • the prophylaxis and premedication are administered during cycle 1.
  • the prophylaxis is administered during cycle 2 when the subject experiences CRS greater than grade 1 after the last administration of the bispecific antibody in cycle 1.
  • the prophylaxis is continued in a subsequent cycle, when in the last administration of the bispecific antibody of the previous cycle, the subject experiences CRS greater than grade 1.
  • the premedication is administered during cycle 2.
  • the premedication is administered during subsequent cycles.
  • the subject is treated with antipyretics and hydration if the subject develops Grade 1 CRS. In some embodiments, the subject is treated with tocilizumab and/or dexamethasone or its equivalent of methylprednisolone if the subject develops Grade 2 CRS. In some embodiments, the subject is treated with tocilizumab and dexamethasone (e.g., at a dose of 10-20 mg or its equivalent of methylprednisolone, e.g., administered once every 6 hours) if the subject develops Grade 3 CRS.
  • tocilizumab and dexamethasone e.g., at a dose of 10-20 mg or its equivalent of methylprednisolone, e.g., administered once every 6 hours
  • the subject is treated with tocilizumab and methylprednisolone (e.g., at a dose of 1000 mg/day) if the subject develops Grade 4 CRS.
  • tocilizumab is switched to siltuximab if the subject does not respond to tocilizumab.
  • the subject is administered prophylaxis for tumor lysis syndrome (TLS).
  • the prophylaxis for TLS comprises administering one or more uric acid reducing agents prior to administration of the bispecific antibody.
  • allopurinol and rasburicase are administered as the uric acid reducing agents.
  • allopurinol is administered at least 72 hours prior to administration of the bispecific antibody.
  • rasburicase is administered after administering allopurinol and prior to administering the bispecific antibody.
  • supportive therapy such as rasburicase and/or allopurinol, may be used.
  • the subject treated with the methods described herein achieves a complete response, a partial response, or stable disease, e.g., as defined by iwCLL response criteria.
  • the first antigen-binding region of the bispecific antibody comprises VHCDR1, VHCDR2, and VHCDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 1, 2, and 3, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising the amino acid sequences set forth in SEQ ID NO: 4, the sequence GTN, and SEQ ID NO: 5, respectively; and the second antigen-binding region comprises VHCDR1, VHCDR2, and VHCDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 8, 9, and 10, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising the amino acid sequences set forth in SEQ ID NO: 11, the sequence DAS, and SEQ ID NO: 12, respectively.
  • the first antigen-binding region of the bispecific antibody comprises a VH region comprising the amino acid sequence of SEQ ID NO: 6, and the VL region comprising the amino acid sequence of SEQ ID NO: 7; and the second antigen-binding region comprises a VH region comprising the amino acid sequence of SEQ ID NO: 13, and the VL region comprising the amino acid sequence of SEQ ID NO: 14.
  • the first binding arm of the bispecific antibody is derived from a humanized antibody, preferably from a full-length IgG1, ⁇ (lambda) antibody.
  • the second binding arm of the bispecific antibody is derived from a human antibody, preferably from a full-length IgG1, ⁇ (kappa) antibody.
  • the bispecific antibody is a full-length antibody with a human IgG1 constant region.
  • the bispecific antibody comprises an inert Fc region, for example, an Fc region in which the amino acids in the positions corresponding to positions L234, L235, and D265 in the human IgG1 heavy chain constant region of SEQ ID NO: 15 are F, E, and A, respectively.
  • the bispecific antibody comprises substitutions which promote bispecific antibody formation, for example, wherein in the first heavy chain, the amino acid in the position corresponding to F405 in the human IgG1 heavy chain constant region of SEQ ID NO: 15 is L, and wherein in the second heavy chain, the amino acid in the position corresponding to K409 in the human IgG1 heavy chain constant region of SEQ ID NO: 15 is R, or vice versa.
  • the bispecific antibody has both an inert Fc region (e.g., substitutions at L234, L235, and D265 (e.g., L234F, L235E, and D265A)) and substitutions which promote bispecific antibody formation (e.g., F405L and K409R).
  • the bispecific antibody comprises heavy chain constant regions comprising the amino acid sequences of SEQ ID NOs: 19 and 20.
  • the bispecific antibody comprises a first heavy chain and a first light chain comprising (or consisting of) the amino acid sequences set forth in SEQ ID NOs: 24 and 25, respectively, and a second heavy chain and a second light chain comprising (or consisting of) the amino acid sequences set forth in SEQ ID NOs: 26 and 27, respectively.
  • the bispecific antibody is epcoritamab, or a biosimilar thereof.
  • FIGS. 1 A- 1 C are a series of graphs showing the effects of epcoritamab on CD4+( FIG. 1 A ) and CD8+( FIG. 1 B ) T cell activation, as well as B cell viability ( FIG. 1 C ), in PBMCs obtained from a CLL patient (left panel) and a healthy donor (right panel). Data shown are percentages ⁇ SD of duplicate wells from one representative donor out of three donors tested. Panels on the left show results for PBMCs from the CLL patient (CFSE-negative), panels on the right for healthy donor PBMCs (CFSE-positive).
  • Filled circles represent epcoritamab
  • open squares represent a control bispecific antibody containing a CD3-specific arm and a control (non-binding) arm
  • open triangles represent a control bispecific antibody containing a CD20-specific arm and a control (non-binding) arm.
  • FIG. 2 is a schematic of the clinical trial design. *additional dose levels (higher or lower) may be explored. MTD: maximum tolerated dose, RP2D: recommended Phase 2 dose in R/R CLL subjects.
  • immunoglobulin refers to a class of structurally related glycoproteins consisting of two pairs of polypeptide chains, one pair of light (L) low molecular weight chains and one pair of heavy (H) chains, all four inter-connected by disulfide bonds.
  • L light
  • H heavy
  • the structure of immunoglobulins has been well characterized (see, e.g., Fundamental Immunology Ch. 7 (Paul, W., ed., 2nd ed. Raven Press, N.Y. (1989)).
  • each heavy chain typically is comprised of a heavy chain variable region (abbreviated herein as VH or VH) and a heavy chain constant region (abbreviated herein as CH or C H ).
  • the heavy chain constant region typically is comprised of three domains, CH1, CH2, and CH3.
  • the hinge region is the region between the CH1 and CH2 domains of the heavy chain and is highly flexible. Disulfide bonds in the hinge region are part of the interactions between two heavy chains in an IgG molecule.
  • Each light chain typically is comprised of a light chain variable region (abbreviated herein as VL or V L ) and a light chain constant region (abbreviated herein as CL or C L ).
  • the light chain constant region typically is comprised of one domain, CL.
  • the VH and VL regions may be further subdivided into regions of hypervariability (or hypervariable regions which may be hypervariable in sequence and/or form of structurally defined loops), also termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FRs).
  • CDRs complementarity determining regions
  • FRs framework regions
  • Each VH and VL is typically composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 (see also Chothia and Lesk J Mol Biol 1987; 196: 90117).
  • CDR sequences herein are identified according to IMGT rules (Brochet X., Nucl Acids Res 2008; 36: W503-508; Lefranc M P., Nucl Acids Res 1999; 27:209-12; www.imgt.org/).
  • reference to amino acid positions in the constant regions is according to the EU-numbering (Edelman et al., PNAS. 1969; 63:78-85; Kabat et al., Sequences of Proteins of Immunological Interest , Fifth Edition. 1991 NIH Publication No. 91-3242).
  • SEQ ID NO: 15 sets forth amino acids positions 118-447, according to EU numbering, of the IgG1 heavy chain constant region.
  • amino acid corresponding to position . . . refers to an amino acid position number in a human IgG1 heavy chain. Corresponding amino acid positions in other immunoglobulins may be found by alignment with human IgG1.
  • an amino acid or segment in one sequence that “corresponds to” an amino acid or segment in another sequence is one that aligns with the other amino acid or segment using a standard sequence alignment program such as ALIGN, ClustalW or similar, typically at default settings and has at least 50%, at least 80%, at least 90%, or at least 95% identity to a human IgG1 heavy chain. It is within the ability of one of ordinary skill in the art to align a sequence or segment in a sequence and thereby determine the corresponding position in a sequence to an amino acid position according to the present invention.
  • antibody refers to an immunoglobulin molecule which has the ability to specifically bind to an antigen under typical physiological conditions with a half-life of significant periods of time, such as at least about 30 minutes, at least about 45 minutes, at least about one hour, at least about two hours, at least about four hours, at least about 8 hours, at least about 12 hours, about 24 hours or more, about 48 hours or more, about 3, 4, 5, 6, 7 or more days, etc., or any other relevant functionally-defined period (such as a time sufficient to induce, promote, enhance, and/or modulate a physiological response associated with antibody binding to the antigen and/or time sufficient for the antibody to recruit an effector activity).
  • variable regions of the heavy and light chains of the immunoglobulin molecule contain a binding domain that interacts with an antigen.
  • the term antibody also encompasses polyclonal antibodies, monoclonal antibodies (mAbs), antibody-like polypeptides, chimeric antibodies and humanized antibodies. An antibody as generated can possess any isotype.
  • antibody fragment or “antigen-binding fragment” as used herein refers to a fragment of an immunoglobulin molecule which retains the ability to specifically bind to an antigen, and can be generated by any known technique, such as enzymatic cleavage, peptide synthesis, and recombinant techniques.
  • antibody fragments include (i) a Fab′ or Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains, or a monovalent antibody as described in WO2007059782 (Genmab); (ii) F(ab′) 2 fragments, bivalent fragments comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting essentially of the VH and CH1 domains; (iv) a Fv fragment consisting essentially of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al., Nature 1989; 341: 54446), which consists essentially of a VH domain and also called domain antibodies (Holt et al; Trends Biotechnol 2003; 21:484-90); (vi) camelid or nanobodies (Revets et al; Expert Opin Biol Ther 2005; 5:
  • the two domains of the Fv fragment, VL and VH are coded for by separate genes, they may be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain antibodies or single chain Fv (scFv), see, e.g., Bird et al., Science 1988; 242: 42326 and Huston et al., PNAS 1988; 85: 587983).
  • single chain antibodies are encompassed within the term antibody fragment unless otherwise noted or clearly indicated by context.
  • antibody-binding region or “antigen-binding region” as used herein refers to the region which interacts with the antigen and comprises both the VH and the VL regions.
  • antibody when used herein refers not only to monospecific antibodies, but also multispecific antibodies which comprise multiple, such as two or more, e.g., three or more, different antigen-binding regions.
  • antigen-binding region unless otherwise stated or clearly contradicted by context, includes fragments of an antibody that are antigen-binding fragments, i.e., retain the ability to specifically bind to the antigen.
  • the term “isotype” refers to the immunoglobulin class (for instance IgG1, IgG2, IgG3, IgG4, IgD, IgA, IgE, or IgM) that is encoded by heavy chain constant region genes.
  • IgG1 immunoglobulin class
  • the term is not limited to a specific isotype sequence, e.g., a particular IgG1 sequence, but is used to indicate that the antibody is closer in sequence to that isotype, e.g. IgG1, than to other isotypes.
  • an IgG1 antibody may be a sequence variant of a naturally-occurring IgG1 antibody, which may include variations in the constant regions.
  • bispecific antibody or “bs” or “bsAb” as used herein refers to an antibody having two different antigen-binding regions defined by different antibody sequences.
  • a bispecific antibody can be of any format.
  • Fab-arm half molecule
  • arm refers to one heavy chain-light chain pair.
  • bispecific antibody When a bispecific antibody is described as comprising a half-molecule antibody “derived from” a first parental antibody, and a half-molecule antibody “derived from” a second parental antibody, the term “derived from” indicates that the bispecific antibody was generated by recombining, by any known method, said half-molecules from each of said first and second parental antibodies into the resulting bispecific antibody.
  • recombining is not intended to be limited by any particular method of recombining and thus includes all of the methods for producing bispecific antibodies described herein, including for example recombining by half-molecule exchange (also known as “controlled Fab-arm exchange”), as well as recombining at nucleic acid level and/or through co-expression of two half-molecules in the same cells.
  • full-length indicates that the antibody is not a fragment but contains all of the domains of the particular isotype normally found for that isotype in nature, e.g., the VH, CH1, CH2, CH3, hinge, VL and CL domains for an IgG1 antibody.
  • a full-length antibody may be engineered.
  • An example of a “full-length” antibody is epcoritamab.
  • Fc region refers to an antibody region consisting of the Fc sequences of the two heavy chains of an immunoglobulin, wherein said Fc sequences comprise at least a hinge region, a CH2 domain, and a CH3 domain.
  • heterodimeric interaction between the first and second CH3 regions refers to the interaction between the first CH3 region and the second CH3 region in a first-CH3/second-CH3 heterodimeric protein.
  • homodimeric interactions of the first and second CH3 regions refers to the interaction between a first CH3 region and another first CH3 region in a first-CH3/first-CH3 homodimeric protein and the interaction between a second CH3 region and another second CH3 region in a second-CH3/second-CH3 homodimeric protein.
  • binding typically refers to binding with an affinity corresponding to a K D of about 10 ⁇ 6 M or less, e.g., 10 ⁇ 7 M or less, such as about 10 ⁇ 8 M or less, such as about 10 ⁇ 9 M or less, about 10 ⁇ 10 M or less, or about 10 ⁇ 11 M or even less, when determined by, e.g., BioLayer Interferometry (BLI) technology in a Octet HTX instrument using the antibody as the ligand and the antigen as the analyte, and wherein the antibody binds to the predetermined antigen with an affinity corresponding to a K D that is at least ten-fold lower, such as at least 100-fold lower, for instance at least 1,000-fold lower, such as at least 10,000-fold lower, for instance at least 100,000-fold lower than its K D of binding to a non-specific antigen (e.g., BSA, casein) other
  • the amount with which the K D of binding is lower is dependent on the K D of the antibody, so that when the K D of the antibody is very low, then the amount with which the K D of binding to the antigen is lower than the K D of binding to a non-specific antigen may be at least 10,000-fold (i.e., the antibody is highly specific).
  • K D refers to the dissociation equilibrium constant of a particular antibody-antigen interaction. Affinity, as used herein, and K D are inversely related, that is that higher affinity is intended to refer to lower K D , and lower affinity is intended to refer to higher K D .
  • isolated antibody refers to an antibody which is substantially free of other antibodies having different antigenic specificities.
  • an isolated bispecific antibody that specifically binds to CD20 and CD3 is in addition substantially free of monospecific antibodies that specifically bind to CD20 or CD3.
  • CD3 refers to the human Cluster of Differentiation 3 protein which is part of the T-cell co-receptor protein complex and is composed of four distinct chains. CD3 is also found in other species, and thus, the term “CD3” is not limited to human CD3 unless contradicted by context.
  • the complex contains a CD3 ⁇ (gamma) chain (human CD3 ⁇ chain UniProtKB/Swiss-Prot No P09693, or cynomolgus monkey CD3 ⁇ UniProtKB/Swiss-Prot No Q95LI7), a CD3 ⁇ (delta) chain (human CD3 ⁇ UniProtKB/Swiss-Prot No P04234, or cynomolgus monkey CD3 ⁇ UniProtKB/Swiss-Prot No Q95LI8), two CD3 ⁇ (epsilon) chains (human CD3 ⁇ UniProtKB/Swiss-Prot No P07766, SEQ ID NO: 28); cynomolgus CD3 ⁇ UniProtKB/Swiss-Prot No Q95LI5; or rhesus CD3 ⁇ UniProtKB/Swiss-Prot No G7NCB9), and a CD3 ⁇ -chain (zeta) chain (human CD3 ⁇ UniProtKB/S
  • CD3 antibody or “anti-CD3 antibody” as used herein refers to an antibody which binds specifically to the antigen CD3, in particular human CD3 ⁇ (epsilon).
  • human CD20 refers to human CD20 (UniProtKB/Swiss-Prot No P11836, SEQ ID NO: 29) and includes any variants, isoforms, and species homologs of CD20 which are naturally expressed by cells, including tumor cells, or are expressed on cells transfected with the CD20 gene or cDNA.
  • Species homologs include rhesus monkey CD20 (Macaca mulatta; UniProtKB/Swiss-Prot No H9YXP1) and cynomolgus monkey CD20 (Macaca fascicularis; UniProtKB No G7PQ03).
  • CD20 antibody or “anti-CD20 antibody” as used herein refers to an antibody which binds specifically to the antigen CD20, in particular to human CD20.
  • CD3 ⁇ CD20 antibody refers to a bispecific antibody which comprises two different antigen-binding regions, one of which binds specifically to the antigen CD20 and one of which binds specifically to CD3.
  • DuoBody-CD3 ⁇ CD20 refers to an IgG1 bispecific CD3 ⁇ CD20 antibody comprising a first heavy and light chain pair as defined in SEQ ID NO: 24 and SEQ ID NO: 25, respectively, and comprising a second heavy and light chain pair as defined in SEQ ID NO: 26 and SEQ ID NO: 27.
  • the first heavy and light chain pair comprises a region which binds to human CD3 ⁇ (epsilon)
  • the second heavy and light chain pair comprises a region which binds to human CD20.
  • the first binding region comprises the VH and VL sequences as defined by SEQ ID NOs: 6 and 7
  • the second binding region comprises the VH and VL sequences as defined by SEQ ID NOs: 13 and 14.
  • This bispecific antibody can be prepared as described in WO 2016/110576.
  • Antibodies comprising functional variants of the heavy chain, light chains, VL regions, VH regions, or one or more CDRs of the antibodies of the examples as also provided herein.
  • a functional variant of a heavy chain, a light chain, VL, VH, or CDRs used in the context of an antibody still allows the antibody to retain at least a substantial proportion (at least about 90%, 95% or more) of functional features of the “reference” and/or “parent” antibody, including affinity and/or the specificity/selectivity for particular epitopes of CD20 and/or CD3, Fc inertness and PK parameters such as half-life, Tmax, Cmax.
  • Such functional variants typically retain significant sequence identity to the parent antibody and/or have substantially similar length of heavy and light chains.
  • the percent identity between two nucleotide or amino acid sequences may e.g. be determined using the algorithm of E. Meyers and W. Miller, Comput. Appl. Biosci 4, 11-17 (1988) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4.
  • the percent identity between two amino acid sequences may be determined using the Needleman and Wunsch, J.
  • variants include those which differ from heavy and/or light chains, VH and/or VL, and/or CDR regions of the parent antibody sequences mainly by conservative substitutions; e.g., 10, such as 9, 8, 7, 6, 5, 4, 3, 2 or 1 of the substitutions in the variant may be conservative amino acid residue replacements.
  • substitution of an amino acid in a given position is written as, e.g., K409R which means a substitution of a Lysine in position 409 with an Arginine; and ii) for specific variants the specific three or one letter codes are used, including the codes Xaa and X to indicate any amino acid residue.
  • substitution of Lysine with Arginine in position 409 is designated as: K409R
  • substitution of Lysine with any amino acid residue in position 409 is designated as K409X.
  • deletion of Lysine in position 409 it is indicated by K409*.
  • humanized antibody refers to a genetically engineered non-human antibody, which contains human antibody constant domains and non-human variable domains modified to contain a high level of sequence homology to human variable domains. This can be achieved by grafting of the six non-human antibody CDRs, which together form the antigen binding site, onto a homologous human acceptor framework region (FR) (see WO92/22653 and EP0629240). In order to fully reconstitute the binding affinity and specificity of the parental antibody, the substitution of framework residues from the parental antibody (i.e., the non-human antibody) into the human framework regions (back-mutations) may be required.
  • FR human acceptor framework region
  • a humanized antibody may comprise non-human CDR sequences, primarily human framework regions optionally comprising one or more amino acid back-mutations to the non-human amino acid sequence, and fully human constant regions.
  • the VH and VL of the CD3 arm that is used herein in DuoBody-CD3 ⁇ CD20 represents a humanized antigen-binding region.
  • additional amino acid modifications which are not necessarily back-mutations, may be applied to obtain a humanized antibody with preferred characteristics, such as affinity and biochemical properties.
  • human antibody refers to antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Human antibodies may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). However, the term “human antibody”, as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.
  • the VH and VL of the CD20 arm that is used in DuoBody-CD3 ⁇ CD20 represents a human antigen-binding region.
  • Human monoclonal antibodies of the invention can be produced by a variety of techniques, including conventional monoclonal antibody methodology, e.g., the standard somatic cell hybridization technique of Kohler and Milstein, Nature 256: 495 (1975). Although somatic cell hybridization procedures are preferred, in principle, other techniques for producing monoclonal antibody can be employed, e.g., viral or oncogenic transformation of B-lymphocytes or phage display techniques using libraries of human antibody genes. A suitable animal system for preparing hybridomas that secrete human monoclonal antibodies is the murine system. Hybridoma production in the mouse is a very well-established procedure. Immunization protocols and techniques for isolation of immunized splenocytes for fusion are known in the art.
  • Fusion partners e.g., murine myeloma cells
  • Human monoclonal antibodies can thus be generated using, e.g., transgenic or transchromosomal mice or rats carrying parts of the human immune system rather than the mouse or rat system.
  • a human antibody is obtained from a transgenic animal, such as a mouse or a rat, carrying human germline immunoglobulin sequences instead of animal immunoglobulin sequences.
  • the antibody originates from human germline immunoglobulin sequences introduced in the animal, but the final antibody sequence is the result of said human germline immunoglobulin sequences being further modified by somatic hypermutations and affinity maturation by the endogenous animal antibody machinery (see, e.g., Mendez et al. Nat Genet 1997; 15:146-56).
  • the VH and VL regions of the CD20 arm that is used in DuoBody-CD3 ⁇ CD20 represents a human antigen-binding region.
  • biosimilar refers to a biologic product that is similar to the reference product based on data from (a) analytical studies demonstrating that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; (b) animal studies (including the assessment of toxicity); and/or (c) a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is approved and intended to be used and for which approval is sought (e.g., that there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product).
  • the biosimilar biological product and reference product utilizes the same mechanism or mechanisms of action for the condition or conditions of use prescribed, recommended, or suggested in the proposed labeling, but only to the extent the mechanism or mechanisms of action are known for the reference product.
  • the condition or conditions of use prescribed, recommended, or suggested in the labeling proposed for the biological product have been previously approved for the reference product.
  • the route of administration, the dosage form, and/or the strength of the biological product are the same as those of the reference product.
  • a biosimilar can be, e.g., a presently known antibody having the same primary amino acid sequence as a marketed antibody, but may be made in different cell types or by different production, purification, or formulation methods.
  • reducing conditions or “reducing environment” as used herein refers to a condition or an environment in which a substrate, here a cysteine residue in the hinge region of an antibody, is more likely to become reduced than oxidized.
  • Recombinant host cell (or simply “host cell”) as used herein is intended to refer to a cell into which an expression vector has been introduced, e.g., an expression vector encoding an antibody described herein.
  • Recombinant host cells include, for example, transfectomas, such as CHO, CHO-S, HEK, HEK293, HEK-293F, Expi293F, PER.C6 or NSO cells, and lymphocytic cells.
  • CLL chronic lymphocytic leukemia
  • CLL starts from lymphocytes in the bone marrow, and most commonly occurs in those aged >50 years. It is characterized by the clonal proliferation and accumulation of mature B lymphocytes, which ultimately leads to monoclonal B-cell lymphocytosis (reviewed in Uhm, Blood Res 2020; 55: S72-82).
  • Monoclonal B cells in CLL express several markers that are characteristic of mature activated B lymphocytes, including CD5, CD19, CD20 and CD23, as well as reduced expression of IgGM, IgGD, and CD79b (Chiorazzi et al., N Engl J Med 2005; 352-804-15).
  • Several prognostic markers have been reported for the disease, including mutations in the IGHV gene, mutations in TP53, del (17p), and del (11q) (Wierda et al., J Clin Oncol 2011; 29:4088-95; Rossi et al., Blood 2013-121:1403-12; CLL-IPI, Lancet Oncol 2016; 17:779-90).
  • Treatments for CLL include, for example, chemotherapy, BCL2 inhibitors, BTK inhibitors, PI3K6 inhibitors, alone or in combination with anti-CD20 antibodies, (Uhm, 2020, supra).
  • treatment refers to the administration of an effective amount of a therapeutically active antibody described herein for the purpose of easing, ameliorating, arresting or eradicating (curing) symptoms or disease states such as CLL.
  • Treatment may result in a complete response (CR), partial response (PR), or stable disease (SD), for example, as defined by iwCLL response criteria, as shown in Table 2.
  • Treatment may be continued, for example, until disease progression (PD) or unacceptable toxicity.
  • administering refers to the physical introduction of a composition (or formulation) comprising a therapeutic agent to a subject, using any of the various methods and delivery systems known to those skilled in the art.
  • Preferred routes of administration for antibodies described herein include intravenous, intraperitoneal, intramuscular, subcutaneous, spinal or other parenteral routes of administration, for example by injection or infusion.
  • parenteral administration means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intraperitoneal, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, as well as in vivo electroporation.
  • a therapeutic agent described herein can be administered via a non-parenteral route, such as a topical, epidermal or mucosal route of administration, for example, intranasally, orally, vaginally, rectally, sublingually or topically. Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods.
  • the bispecific antibody e.g., epcoritamab
  • Other agents used in combination with the bispecific antibody such as for cytokine release syndrome prophylaxis or tumor lysis syndrome (TLS) prophylaxis, may be administered via other routes, such as intravenously or orally.
  • an effective amount or “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result.
  • dosages as defined herein for the bispecific antibody e.g., epcoritamab
  • a therapeutically effective amount of an antibody may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the antibody to elicit a desired response in the individual.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of the antibody or antibody portion are outweighed by the therapeutically beneficial effects.
  • a therapeutically effective amount or dosage of a drug includes a “prophylactically effective amount” or a “prophylactically effective dosage”, which is any amount of the drug that, when administered alone or in combination with another therapeutic agent to a subject at risk of developing a disease or disorder (e.g., cytokine release syndrome) or of suffering a recurrence of disease, inhibits the development or recurrence of the disease.
  • a disease or disorder e.g., cytokine release syndrome
  • the term “inhibits growth” of a tumor as used herein includes any measurable decrease in the growth of a tumor, e.g., the inhibition of growth of a tumor by at least about 10%, for example, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 99%, or 100%.
  • subject refers to a human patient, for example, a human patient with CLL.
  • subject and patient are used interchangeably herein.
  • buffer as used herein denotes a pharmaceutically acceptable buffer.
  • the term “buffer” encompasses those agents which maintain the pH value of a solution, e.g., in an acceptable range and includes, but is not limited to, acetate, histidine, TRIS® (tris (hydroxymethyl)aminomethane), citrate, succinate, glycolate and the like.
  • the “buffer” as used herein has a pKa and buffering capacity suitable for the pH range of about 5 to about 6, preferably of about 5.5.
  • Disease progression refers to a situation in which one or more indices of CLL show that the disease is advancing despite treatment. In some embodiments, disease progression is defined based on iwCLL response criteria, as shown in Table 2.
  • a “surfactant” as used herein is a compound that is typically used in pharmaceutical formulations to prevent drug adsorption to surfaces and or aggregation. Furthermore, surfactants lower the surface tension (or interfacial tension) between two liquids or between a liquid and a solid.
  • an exemplary surfactant can significantly lower the surface tension when present at very low concentrations (e.g., 5% w/v or less, such as 3% w/v or less, such as 1% w/v or less such as 0.4% w/v or less, such as below 0.1% w/v or less, such as 0.04% w/v).
  • very low concentrations e.g., 5% w/v or less, such as 3% w/v or less, such as 1% w/v or less such as 0.4% w/v or less, such as below 0.1% w/v or less, such as 0.04% w/v).
  • Surfactants are amphiphilic, which means they are usually composed of both hydrophilic and hydrophobic or lipophilic groups, thus being capable of forming micelles or similar self-assembled structures in aqueous solutions.
  • Known surfactants for pharmaceutical use include glycerol monooleate, benzethonium chloride, sodium docusate, phospholipids, polyethylene alkyl ethers, sodium lauryl sulfate and tricaprylin (anionic surfactants); benzalkonium chloride, citrimide, cetylpyridinium chloride and phospholipids (cationic surfactants); and alpha tocopherol, glycerol monooleate, myristyl alcohol, phospholipids, poloxamers, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbintan fatty acid esters, polyoxyethylene sterarates, polyoxyl hydroxystearate, polyoxylglycerides, polysorbates such
  • a “diluent” as used herein is one which is pharmaceutically acceptable (safe and non-toxic for administration to a human) and is useful for the preparation of dilutions of the pharmaceutical composition or pharmaceutical formulation (the terms “composition” and “formulation” are used interchangeably herein).
  • dilutions of the composition dilute only the antibody concentration but not the buffer and stabilizer.
  • the diluent contains the same concentrations of the buffer and stabilizer as is present in the pharmaceutical composition of the invention.
  • exemplary diluents include sterile water, bacteriostatic water for injection (BWFI), a pH buffered solution which is preferably an acetate buffer, sterile saline solution, Ringer's solution or dextrose solution.
  • BWFI bacteriostatic water for injection
  • a pH buffered solution which is preferably an acetate buffer
  • sterile saline solution preferably a sterile saline solution
  • Ringer's solution or dextrose solution preferably acetate buffer
  • the diluent comprises or consists essentially of acetate buffer and sorbitol.
  • anti-CD3 ⁇ CD20 antibody an isolated anti-CD3 ⁇ CD20 antibody which binds to human CD3 and human CD20.
  • the methods are also useful for treating recurrent or refractory CLL (R/R CLL). It is understood that the methods of treating CLL with a bispecific antibody which binds to both CD3 and CD20 described herein also encompass corresponding uses of the bispecific antibody for treating CLL in a human subject.
  • a method of treating CLL in a human subject comprising administering (e.g., subcutaneously) to the subject an effective amount of a bispecific antibody comprising:
  • bispecific antibody is administered at a dose ranging from 12-60 mg in 28-days cycles.
  • the bispecific antibody is a full length antibody. In some embodiments, the bispecific antibody is an antibody with an inert Fc region. In some embodiments, the bispecific antibody is a full length antibody with an inert Fc region.
  • the bispecific antibody is administered at a dose of (or a dose of about) 12 mg. In some embodiments, the bispecific antibody is administered at a dose of (or a dose of about) 24 mg. In some embodiments, the bispecific antibody is administered at a dose of (or a dose of about) 48 mg. In some embodiments, the bispecific antibody is administered at a dose of (or a dose of about) 60 mg.
  • the dose of 12-60 mg of the bispecific antibody that is to be administered refers to the amount of a bispecific antibody representing a full-length antibody, such as epcoritamab as defined in the Examples section.
  • this amount refers to administering a dose of a bispecific antibody of 24 mg as administering a dose of a bispecific antibody described herein, wherein the dose corresponds to a dose of 24 mg of epcoritamab.
  • the amount of antibody to be administered when, for example, the antibody used differs substantially in molecular weight from the molecular weight of a full-length antibody such as epcoritamab.
  • the amount of antibody can be calculated by dividing the molecular weight of the antibody by the weight of a full-length antibody such as epcoritamab and multiplying the outcome thereof with the specified dose as described herein.
  • the bispecific antibody e.g., a functional variant of DuoBody-CD3 ⁇ CD20
  • the bispecific antibody has highly similar features as DuoBody-CD3 ⁇ CD20, with regard to plasma half-life, Fc inertness, and/or binding characteristics for CD3 and CD20, i.e., with regard to CDRs and epitope binding features
  • such antibodies are suitable for use in the methods provided herein at a dose described for a full-length antibody such as epcoritamab.
  • the bispecific anti-CD3 ⁇ CD20 antibody is administered at a dose in the range of between 12 mg and 60 mg. In some embodiments, the bispecific antibody is administered at a dose of 12 mg or about 12 mg. In some embodiments, the bispecific antibody is administered at a dose of 24 mg or about 24 mg. In some embodiments, the bispecific antibody is administered at a dose of 48 mg or about 48 mg. In some embodiments, the bispecific antibody is administered at a dose of 60 mg or about 60 mg.
  • the dose of bispecific antibody is administered once every week (weekly administration) in 28-day cycles.
  • the weekly administration is performed for 2.5 28-day cycles (i.e., 10 times).
  • the dose is administered for 2.5 28-day cycles (i.e., 10 times; on days 15 and 22 of cycle 1, and days 1, 8, 15, and 22 of cycles 2 and 3).
  • one may reduce the interval of administrating the bispecfic antibody to an administration once every two weeks (biweekly administration).
  • such biweekly administration may be performed for six 28-day cycles (i.e., 12 times).
  • the interval of administrating the bispecfic antibody may be reduced further to once every four weeks.
  • the administration once every four weeks may be performed for an extended period, for example, for at least 1 cycle, at least 2 cycles, at least 3 cycles, at least 4 cycles, at least 5 cycles, at least 6 cycles, at least 7 cycles, at least 8 cycles, at least 9 cycles, at least 10 cycles, at least 11 cycles, at least 12 cycles, at least 13 cycles, at least 14 cycles, at least 15 cycles, at least 16 cycles, at least 17 cycles, or between 1-20 cycles, 1-19 cycles, 1-18 cycles, 1-17 cycles, 1-16 cycles, 1-15 cycles, 1-14 cycles, 1-13 cycles, 1-12 cycles, 1-10 cycles, 1-5 cycles, 5-20 cycles, 5-15 cycles, or 5-10 cycles of the 28-day cycles.
  • epcoritamab is administered once every four weeks until disease progression (e.g., as defined by the iwCLL response criteria, as shown in Table 2) or unacceptable toxicity.
  • the weekly dose is administered on cycles 1-3 (and may include priming and intermediate doses, as described below), the biweekly dose is administered on cycles 4-9, and the dose once every four weeks is administered from cycle 10 onward.
  • the doses referred to herein may also be referred to as a full or a flat dose in the scenarios above wherein, e.g., the weekly dose, the biweekly dose, and/or the dose every four weeks is administered is at the same level. Accordingly, when a dose of 48 mg is selected, preferably, at each weekly administration, each biweekly administration, and each administration every four weeks, the same dose of 48 mg is administered.
  • a priming or a priming and subsequent intermediate (second priming) dose may be administered prior to administering the dose. This may be advantageous as it may help mitigate cytokine release syndrome (CRS) risk and severity, a side-effect that can occur during treatment with the bispecific anti-CD3 ⁇ CD20 antibody described herein.
  • Such priming, or priming and intermediate doses are at a lower dose as compared with the flat or full dose.
  • a priming dose of the bispecific antibody prior to administering the weekly dose of 12-60 mg, may be administered prior to administering the weekly dose of 12-60 mg.
  • the priming dose is administered two weeks prior to administering the first weekly dose of 12-60 mg in cycle 1.
  • the priming dose may be in the range of 20-2000 ⁇ g (0.02 mg-2 mg), for example, in the range of 50-1000 ⁇ g (0.05 mg to 1 mg) or in the range of 70-350 ⁇ g (0.07 mg to 0.35 mg).
  • the priming dose can be, for example, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 350, 400, 450, 500, 600, 700, 800, 900, or 1000 ⁇ g, or about 80, about 100, about 120, about 140, about 160, about 180, about 200, about 220, about 240, about 260, about 280, about 300, about 320, about 350, about 400, about 450, about 500, about 600, about 700, about 800, about 900, or about 1000 ⁇ g.
  • the priming dose is in the range of 50 and 350 ⁇ g (0.05 and 0.35 mg, respectively).
  • the priming dose is 160 ⁇ g (0.16 mg) or about 160 ⁇ g (about 0.16 mg). In most preferred embodiments, the priming dose is 160 ⁇ g (0.16 mg) or about 160 ⁇ g (about 0.16 mg) of the full-length bispecific antibody.
  • an intermediate dose of said bispecific antibody is administered after administering the priming dose and prior to administering the first weekly dose of 12-60 mg.
  • the priming dose is administered on day 1 and the intermediate dose is administered on day 8 before the first weekly dose of 12-60 mg on days 15 and 22 of cycle 1 i.e. the priming dose is administered one week before the intermediate dose (i.e., day 1 of cycle 1), and the intermediate dose is administered one week before the first weekly dose of 12-60 mg (day 8 of cycle 1).
  • the intermediate dose is selected from a range in between the priming dose and the flat or full dose.
  • the intermediate dose may be in the range of 200-8000 ⁇ g (0.2-8 mg), e.g., in the range of 400-4000 ⁇ g (0.4-4 mg) or 600-2000 ⁇ g (0.6-2 mg).
  • the intermediate dose can be, for example, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, or 1600 ⁇ g, or about 200, about 300, about 400, about 500, about 600, about 700, about 800, about 900, about 1000, about 1100, about 1200, about 1300, about 1400, about 1500, or about 1600 ⁇ g.
  • the intermediate dose is in the range of 600 and 1200 ⁇ g (0.6 and 1.2 mg, respectively).
  • the intermediate dose is 800 ⁇ g (0.8 mg) or about 800 ⁇ g (0.8 mg).
  • the intermediate dose is 800 ⁇ g or about 800 ⁇ g (0.8 mg) of the full-length bispecific antibody.
  • the bispecific antibody is administered (e.g., subcutaneously) in 28-day cycles, wherein
  • the bispecific antibody is administered (e.g., subcutaneously) in 28-day cycles, wherein
  • the bispecific antibody is administered (e.g., subcutaneously) in 28-day cycles, wherein
  • the bispecific antibody is administered (e.g., subcutaneously) in 28-day cycles, wherein
  • the bispecific antibody is administered (e.g., subcutaneously) in 28-day cycles, wherein
  • the bispecific antibody is administered (e.g., subcutaneously) in 28-day cycles, wherein
  • the bispecific antibody is administered (e.g., subcutaneously) in 28-day cycles, wherein
  • the bispecific antibody is administered (e.g., subcutaneously) in 28-day cycles, wherein
  • the bispecific antibody is administered (e.g., subcutaneously) in 28-day cycles, wherein
  • the bispecific antibody is administered (e.g., subcutaneously) in 28-day cycles, wherein
  • the bispecific antibody is administered (e.g., subcutaneously) in 28-day cycles, wherein
  • the bispecific antibody is administered (e.g., subcutaneously) in 28-day cycles, wherein
  • the bispecific antibody is administered (e.g., subcutaneously) in 28-day cycles, wherein
  • the bispecific antibody is administered (e.g., subcutaneously) in 28-day cycles, wherein
  • the bispecific antibody is administered (e.g., subcutaneously) in 28-day cycles, wherein
  • the bispecific antibody is epcoritamab, which is administered subcutaneously in 28-day cycles, wherein
  • the bispecific antibody is epcoritamab, which is administered (e.g., subcutaneously) in 28-day cycles, wherein
  • the bispecific antibody is epcoritamab, which is administered subcutaneously in 28-day cycles, wherein
  • the bispecific antibody is epcoritamab, which is administered subcutaneously in 28-day cycles, wherein
  • the bispecific antibody is epcoritamab, which is administered (e.g., subcutaneously) in 28-day cycles, wherein
  • the bispecific antibody is epcoritamab, which is administered subcutaneously in 28-day cycles, wherein
  • the bispecific antibody is epcoritamab, which is administered subcutaneously in 28-day cycles, wherein
  • the bispecific antibody is epcoritamab, which is administered (e.g., subcutaneously) in 28-day cycles, wherein
  • the bispecific antibody is epcoritamab, which is administered subcutaneously in 28-day cycles, wherein
  • the bispecific antibody is epcoritamab, which is administered subcutaneously in 28-day cycles, wherein
  • the bispecific antibody is epcoritamab, which is administered (e.g., subcutaneously) in 28-day cycles, wherein
  • the bispecific antibody is epcoritamab, which is administered subcutaneously in 28-day cycles, wherein
  • the bispecific antibody is epcoritamab, which is administered subcutaneously in 28-day cycles, wherein
  • the bispecific antibody is epcoritamab, which is administered (e.g., subcutaneously) in 28-day cycles, wherein
  • the bispecific antibody is epcoritamab, which is administered subcutaneously in 28-day cycles, wherein
  • a priming dose of 80 ⁇ g and an intermediate dose of 800 ⁇ g, respectively is selected on days 1 and 8 of the first cycle. In some embodiments, on days 1 and 8 of the first cycle, a priming dose of 80 ⁇ g and an intermediate dose of 1200 ⁇ g, respectively, is selected on days 1 and 8 of the first cycle. In some embodiments, on days 1 and 8 of the first cycle, a priming dose of 80 ⁇ g and an intermediate dose of 1600 ⁇ g, respectively, is selected. In some embodiments, on days 1 and 8 of the first cycle, a priming dose of 160 ⁇ g and an intermediate dose of 1200 ⁇ g, respectively, is selected on days 1 and 8 of the first cycle. In some embodiments, on days 1 and 8 of the first cycle, a priming dose of 160 ⁇ g and an intermediate dose of 1600 ⁇ g, respectively, is selected.
  • the human subject has active CLL disease that needs treatment, meeting at least one of the following criteria: (1) evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia; (2) Massive (i.e., ⁇ 6 cm below the left costal margin) or progressive or symptomatic splenomegaly; (3) Massive nodes (i.e., ⁇ 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy; (4) Progressive lymphocytosis with an increase of ⁇ 50% over a 2-month period, or lymphocyte doubling time (LDT) ⁇ 6 months; (5) Autoimmune complications including anemia or thrombocytopenia poorly responsive to corticosteroids; (6) Symptomatic or functional extra nodal involvement (e.g., skin, kidney, lung, spine); and/or (7) Disease-related symptoms as defined by any of the following: unintentional weight loss ⁇ 10% within the previous 6 months, significant fatigue, fevers ⁇ 38.0
  • the CLL disease is relapsed and/or refractory CLL.
  • the CLL is refractory to a BTK inhibitor.
  • the CLL relapsed during treatment with a BTK inhibitor.
  • the human subject has received at least one line of treatment prior to being treated with the methods described herein.
  • the subject has received one prior line of treatment.
  • the subject has received two prior lines of treatment.
  • the subject has received two prior lines of systemic antineoplastic therapy.
  • the subject has received two prior lines of systemic antineoplastic therapy, wherein at least one of the at least two prior antineoplastic therapy comprises treatment with (or intolerance of) a BTK inhibitor (e.g., ibrutinib).
  • a BTK inhibitor e.g., ibrutinib
  • the subject has refractory and/or relapsed CLL after receiving the two prior antineoplastic therapies.
  • Relapse may be defined as evidence of disease progression in a subject who has previously achieved a CR or PR for at least 6 months.
  • Refractory disease may be defined as treatment failure (not achieving a CR or PR) or as progression within 6 months from the last dose of therapy.
  • the subject has received three prior lines of treatment. In some embodiments, the subject has received more than three prior lines of treatment. In some embodiments, the subject has received one, two, three, or more prior lines of treatment. In some embodiments, the subject has received at least two prior lines of treatment.
  • a prior line of treatment comprises systemic antineoplastic therapy. In one embodiment, the systemic antineoplastic therapy comprises treatment with a BTK inhibitor, e.g., ibrutinib.
  • a prior line of therapy comprises treatment with a BCL2 inhibitor, e.g. venetoclax.
  • a prior line of therapy comprises a treatment with a combination of a BTK inhibitor and a BCL2 inhibitor (e.g., ibrutinib and venetoclax).
  • the human subject has measurable disease meeting at least one of (a) ⁇ 5 ⁇ 10 9 /L (5,000/ ⁇ L) B lymphocytes in peripheral blood and (b) presence of measurable lymphadenopathy and/or organomegaly.
  • the human subject has an ECOG performance status score of 0 or 1.
  • Information regarding ECOG performance status scores can be found in, e.g., Oken et al, Am J Clin Oncol 1982 December; 5(6):649-55).
  • the human subject has acceptable laboratory parameters for (1) creatine clearance or serum creatine ( ⁇ 45 mL/min using Cockcroft-Gault formula or serum creatinine ⁇ 1.5 times the upper limit of normal ( ⁇ ULN)), (2) serum alanine transaminase ( ⁇ 2.5 ⁇ ULN), (3) serum aspartate transaminase ( ⁇ 2.5 ⁇ ULN), (4) bilirubin ( ⁇ 1.5 ⁇ ULN unless due to Gilbert syndrome), (5) hemoglobin ( ⁇ 9.0 g/dL unless anemia is due to marrow involvement of CLL), (6) absolute neutrophil count ( ⁇ 1.0 ⁇ 10 9 /L (1000/ ⁇ L) unless neutropenia is due to bone marrow involvement of CLL), platelet count ( ⁇ 30 ⁇ 10 9 /L (30,000/ ⁇ L)), and coagulation status (PT/INR/aPTT ⁇ 1.5 ⁇ ULN).
  • a human subject receiving a treatment described herein may be a patient having one or more of the inclusion criteria set forth in Example 2, or not having one or more of the exclusion criteria set forth in Example 2.
  • Human subjects with CLL are classified as having a CD20-positive cancer.
  • prior cancer treatments such human subjects may have received include anti-CD20 monoclonal antibodies (e.g., rituximab).
  • the CLL may be refractory or have relapsed to said treatment.
  • the subject has received prior to treatment with the bispecific antibody a treatment with an anti-CD20 monoclonal antibody, such as rituximab or obinutuzumab.
  • the CLL relapsed or was refractory to treatment.
  • one therapeutic agent e.g., venetoclax (a Bcl2 inhibitor
  • the methods described herein are advantageous for treating CLL, such as refractory or recurrent CLL.
  • the treatment is maintained continuously using, e.g., the treatment regimens described above. However, treatment may be terminated when progressive disease develops or unacceptable toxicity occurs.
  • the response of subjects with CLL to the methods described herein may be assessed according to the iwCLL response criteria, as shown in Table 2 (source: Hallek et al., Lancet 2018; 391:1524-1537).
  • Subjects treated according to the methods described herein preferably experience improvement in at least one sign of CLL.
  • improvement is measured by a reduction in the number of circulating lymphocytes.
  • improvement is measured by a reduction in the quantity and/or size of measurable tumor lesions.
  • lesions can be measured on CT or MRI films.
  • cytology or histology can be used to evaluate responsiveness to a therapy.
  • bone marrow aspirate and bone marrow biopsy can be used to evaluate response to therapy.
  • the subject treated exhibits a complete response (CR), a partial response (PR), or stable disease (SD), as defined by iwCLL response criteria (see, e.g., Table 2).
  • the methods described herein produce at least one therapeutic effect chosen from prolonged survival, such as progression-free survival or overall survival, optionally compared to another therapy or placebo.
  • the subjects are treated with the methods described herein until disease progression (PD) or unacceptable toxicity.
  • Cytokine release syndrome can occur when methods are used in human subjects that utilize immune cell- and bispecific antibody-based approaches that function by activation of immune effector cell, such as by engaging CD3 (Lee et al., Biol Blood Marrow Transplant 2019; 25:625-38, which is incorporated herein by reference).
  • CRS mitigation is performed together with the methods described herein.
  • the selection of a priming dose and/or intermediate dose is performed prior to administering the full dose (e.g., 12-60 mg), as described herein.
  • CRS can be classified in accordance with standard practice (e.g. as outlined in Lee et al., Biol Blood Marrow Transplant.
  • CRS may include excessive release of cytokines, for example of proinflammatory cytokines, e.g., IL-6, TNF-alpha or IL-8, that may result in adverse effects like fever, nausea, vomiting and chills.
  • cytokines for example of proinflammatory cytokines, e.g., IL-6, TNF-alpha or IL-8
  • proinflammatory cytokines e.g., IL-6, TNF-alpha or IL-8
  • patients may be further subjected to a concomitant treatment, prophylaxis, and/or premedication with, e.g., analgesics, antipyretics, and/or anti-inflammatory drugs to mitigate possible CRS symptoms.
  • a concomitant treatment e.g., analgesics, antipyretics, and/or anti-inflammatory drugs to mitigate possible CRS symptoms.
  • human subjects in the methods described herein are treated with prophylaxis for CRS.
  • the prophylaxis comprises the administration of a corticosteroid to the subject.
  • the prophylaxis e.g. corticosteroid
  • the prophylaxis can also be administered on the subsequent days as well.
  • the prophylaxix e.g. corticosteroid
  • days 2, 3 and 4 when relating to further medication, such as prophylaxis, is relative to the administration of the bispecific antibody which is administered on day 1.
  • the prophylaxis corresponding to days 2, 3 and 4 are days 16, 17, and 18 of the cycle.
  • the prophylaxis is administered on the day when the bispecific antibody is administered and on subsequent days 2-4.
  • the prophylaxis is preferably administered 30-120 minutes prior to said administration of the bispecific antibody.
  • An exemplary corticosteroid suitable for use in the methods and uses described herein is prednisolone. In some embodiments, the corticosteroid is prednisolone.
  • prednisolone is administered at an intravenous dose of 100 mg, or an equivalent thereof, including an oral dose.
  • exemplary corticosteroid equivalents of prednisolone, along with dosage equivalents, which can be used for CRS prophylaxis are shown in Table 6.
  • human subjects in the methods described herein are treated with premedication to reduce reactions to injections.
  • the premedication includes the administration of antihistamines.
  • the premedication includes the administration of antipyretics.
  • the premedication includes systemic administration of antihistamines and antipyretics.
  • An exemplary antihistamine suitable for use in premedication is diphenhydramine. In some embodiments, the antihistamine is diphenhydramine. In one embodiment, diphenhydramine is administered at an intravenous or oral dose 50 mg, or an equivalent thereof.
  • An exemplary antipyretic suitable for use in premedication is acetaminophen. In some embodiments, the antipyretic is acetaminophen. In one embodiment, acetaminophen is administered at an oral dose of 560-1000 mg, such as 650-1000 mg, or equivalent thereof.
  • the premedication is administered on the same day as the bispecific antibody. In some embodiments, the premedication is administered on the same day as the bispecific antibody prior to the injection with the bispecific antibody, e.g., 30-120 minutes prior to administration of the bispecific antibody.
  • Premedication and/or prophylaxis can be administered at least in the initial phase of the treatment.
  • premedication and/or prophylaxis is administered during the first four administrations of the bispecific antibody.
  • the premedication and/or prophylaxis can be administered as described herein, during the first 28 day cycle of the bispecific antibody administration.
  • the premedication is administered during cycle 1.
  • the prophylaxis is administered during cycle 1.
  • risk of reactions during the initial treatment subsides after a few administrations, e.g., after the first four administrations (first cycle).
  • prophylaxis for CRS may be stopped.
  • CRS prophylaxis may continue.
  • premedication may also optionally continue.
  • CRS grading can be performed as described in Tables 7 and 8.
  • the prophylaxis is administered during the second 28-day cycle i.e cycle 2, when the human subject experiences CRS greater than grade 1 after the fourth i.e. last administration of the bispecific antibody in cycle 1.
  • the prophylaxis can be continued during a subsequent cycle, when in the last administration of the bispecific antibody of the previous cycle, the human subject experiences CRS greater than grade 1.
  • Any premedication may be optionally administered during the second cycle.
  • the premedication is administered during cycle 2. Further premedication may be optionally administered during subsequent cycles as well.
  • the premedication is administered during subsequent cycles (after cycle 2).
  • premedication and prophylaxis for CRS is administered, wherein the premedication comprises an antihistamine such as diphenhydramine (e.g., at an intravenous or oral dose 50 mg, or an equivalent thereof) and the prophylaxis comprises an antipyretic such as acetaminophen (e.g., at an oral dose of 650-1000 mg, or an equivalent thereof), and a corticosteroid such as prednisolone (e.g., at an intravenous dose of 100 mg, or an equivalent thereof).
  • the premedication and prophylaxis is administered 30-120 minutes prior to administration of the bispecific antibody.
  • further prophylaxis is administered comprising the systemic administration of a corticosteroid such as prednisolone (e.g., at an intravenous dose of 100 mg, or an equivalent thereof).
  • a corticosteroid such as prednisolone
  • the premedication and prophylaxis schedule preferably is administered during the first four administrations of the bispecific antibody, e.g., during the first 28-day cycle of bispecific antibody administration described herein.
  • subsequent cycles in case of, e.g., CRS greater than grade 1 occurring during the last administration of the prior cycle, can include the same administration schedule, wherein the premedication as part of the administration schedule is optional.
  • CRS can be well managed while at the same time effectively controlling and/or treating CLL.
  • subjects treated with the methods described herein may experience manageable CRS.
  • subjects receiving the treatment described herein may develop CRS of grade 1 as defined in accordance with standard practice.
  • subjects may develop manageable CRS of grade 2 as defined in accordance with standard practice.
  • subjects receiving the treatments described herein may have manageable CRS of grade 1 or grade 2 during as defined in accordance with standard practice.
  • a grade 1 CRS includes a fever to at least 38° C., no hypotension, no hypoxia, and a grade 2 CRS includes a fever to at least 38° C. plus hypotension, not requiring vasopressors and/or hypoxia requiring oxygen by low flow nasal cannula or blow by.
  • Such manageable CRS can occur during cycle 1.
  • Human subjects receiving the treatments described herein may also have CRS greater than grade 2 during the treatments as defined in accordance with standard practice.
  • human subjects receiving the treatments described herein may also have CRS of grade 3 during said treatments as defined in accordance with standard practice.
  • Such manageable CRS may further occur during cycle 1 and subsequent cycles.
  • Human subjects treated according to the methods described herein may also experience pyrexia, fatigue, and injection site reactions. They may also experience neurotoxicity, partial seizures, agraphia related to CRS, or confusional state related to CRS.
  • CRS grading criteria are described in Tables 7 and 8.
  • subject is administered antibiotics if the subject develops Grade 1 CRS i.e. subjects who develop Grade 1 CRS are treated with antibiotics if they present with infection. In some embodiments, the antibiotics are continued until neutropenia, if present, resolves. In some embodiments, subjects with Grade 1 CRS who exhibit constitutional symptoms are treated with NSAIDs.
  • subjects who develop Grade 2 CRS are treated with intravenous fluid boluses and/or supplemental oxygen.
  • subjects who develop Grade 2 CRS are treated with a vasopressor.
  • subjects with Grade 2 CRS with comorbidities are treated with tocilizumab (a humanized antibody against IL-6 receptor, commercially available as, e.g., ACTEMRA®) and/or steroids (e.g., dexamethasone or its equivalent of methylprednisolone).
  • a subject who presents with concurrent ICANS is administered dexamethasone.
  • a second dose of tocilizumab is administered together with a dose of corticosteroids.
  • additional cytokine therapy e.g., an anti-IL-6 antibody (e.g., siltuximab) or an IL-1R antagonist (e.g., anakinra) is administered to the subject.
  • subjects who develop Grade 3 CRS are treated with vasopressor (e.g., norepinephrine) support and/or supplemental oxygen.
  • subjects with Grade 3 CRS are treated with tocilizumab, or tocilizumab in combination with steroids (e.g., dexamethasone or its equivalent of methylprednisolone).
  • steroids e.g., dexamethasone or its equivalent of methylprednisolone.
  • a subject who presents with concurrent ICANS is administered dexamethasone.
  • cytokine therapy e.g., an anti-IL-6 antibody (e.g., siltuximab) or an IL-1R antagonist (e.g., anakinra) is administered to the subject.
  • an anti-IL-6 antibody e.g., siltuximab
  • an IL-1R antagonist e.g., anakinra
  • subjects who develop Grade 4 CRS are treated with vasopressor support and/or supplemental oxygen (e.g., via positive pressure ventilation, such as CPAP, BiPAP, intubation, or mechanical ventilation).
  • the subject is administered at least two vasopressors if the subject develops Grade 4 CRS.
  • the subject is further administered a steroid i.e. the subject is administered tocilizumab and a steroid.
  • the steroid is dexamethasone.
  • the steroid is methylprednisolone.
  • a subject who presents with concurrent ICANS is administered dexamethasone.
  • cytokine therapy e.g., an anti-IL-6 antibody (e.g., siltuximab) or an IL-1R antagonist (e.g., anakinra) is administered to the subject.
  • administration of tocilizumab is switched to administration of an anti-IL-6 antibody (e.g., siltuximab) if the subject is refractory to tocilizumab.
  • tocilizumab is switched to an IL-1R antagonist (e.g., anakinra) if the subject is refractory to tocilizumab.
  • the human subject receives prophylactic treatment for tumor lysis syndrome (TLS) i.e. the subject is treated with prophylaxis for tumor lysis syndrome (TLS).
  • TLS tumor lysis syndrome
  • Classification and grading of tumor lysis syndrome can be performed using methods known in the art, for example, as described in Howard et al. N Engl J Med 2011; 364:1844-54, and Coiffier et al., J Clin Oncol 2008; 26:2767-78.
  • prophylactic treatment of TLS comprises administering one or more uric acid reducing agents prior to administering the bispecific antibody i.e. the prophylaxis for TLS comprises administering one or more uric acid reducing agents prior to administration of the bispecific antibody.
  • Exemplary uric acid reducing agents include allopurinol and rasburicase.
  • the prophylactic treatment of TLS comprises administering allopurinol and/or rasburicase.
  • the prophylactic treatment of TLS comprises administering allopurinol and/or rasburicase prior to administering the bispecific antibody.
  • allopurinol is administered 72 hours prior to the bispecific antibody.
  • rasburicase is initiated after administering allopurinol but prior to administering the bispecific antibody. Reassessment of the subject's TLS risk category can be performed prior to subsequent doses of the bispecific antibody.
  • a subject is considered to be at low risk of TLS if all measurable lymph nodes have a largest diameter ⁇ 5 cm and ALC ⁇ 25 ⁇ 10 9 /L.
  • a subject is considered to be at medium risk of TLS if any measurable lymph node has a largest diameter ⁇ 5 cm but ⁇ 10 cm or ALC ⁇ 25 ⁇ 10 9 /L.
  • a subject is considered to be at high risk of TLS if (a) any measurable lymph node has a largest diameter ⁇ 10 cm, or (b) ALC ⁇ 25 ⁇ 10 9 /L and any measurable lymph node has a largest diameter ⁇ 5 cm but ⁇ 10 cm.
  • Subjects with a lymphocyte count >100 ⁇ 10 9 /L are considered as high risk.
  • supportive therapy such as rasburicase and/or allopurinol, may be used.
  • the bispecific antibody used in the methods described herein is administered subcutaneously, and thus is formulated in a pharmaceutical composition such that it is compatible with subcutaneous (s.c.) administration, i.e., having a formulation and/or concentration that allows pharmaceutical acceptable s.c. administration at the doses described herein.
  • subcutaneous administration is carried out by injection.
  • formulations for DuoBody-CD3 ⁇ CD20 that are compatible with subcutaneous formulation and can be used in the methods described herein have been described previously (see, e.g., WO2019155008, which is incorporated herein by reference).
  • the bispecific antibody may be formulated using sodium acetate trihydrate, acetic acid, sodium hydroxide, sorbitol, polysorbate 80, and water for injection, and have a pH of 5.5 or about 5.5.
  • the bispecific antibody is provided as a 5 mg/mL or 60 mg/mL concentrate.
  • the desired dose of the bispecific antibody is reconstituted to a volume of about 1 mL for subcutaneous injection.
  • a suitable pharmaceutical composition for the bispecific antibody can comprise the bispecific antibody, 20-40 mM acetate, 140-160 mM sorbitol, and a surfactant, such as polysorbate 80, and having a pH of 5.3-5.6.
  • the pharmaceutical formulation may comprise an antibody concentration in the range of 5-100 mg/mL, e.g., 48 or 60 mg/mL of the bispecific antibody, 30 mM acetate, 150 mM sorbitol, 0.04% w/v polysorbate 80, and have a pH of 5.5.
  • Such a formulation may be diluted with, e.g., the formulation buffer to allow proper dosing and subcutaneous administration.
  • the volume of the pharmaceutical composition is appropriately selected to allow for subcutaneous administration of the antibody.
  • the volume to be administered is in the range of about 0.3 mL to about 3 mL, such as from 0.3 mL to 3 mL.
  • the volume to be administered can be 0.5 mL, 0.8 mL, 1 mL, 1.2 mL, 1.5 ml, 1.7 mL, 2 mL, or 2.5 mL, or about 0.5 mL, about 0.8 mL, about 1 mL, about 1.2 mL, about 1.5 ml, about 1.7 mL, about 2 mL, or about 2.5 mL.
  • the volume to be administered is 0.5 mL or about 0.5 mL.
  • the volume to be administered is 0.8 mL or about 0.8 mL.
  • the volume to be administered is 1 mL or about 1 mL. In some embodiments, the volume to be administered is 1.2 mL or about 1.2 mL. In some embodiments, the volume to be administered is 1.5 mL or about 1.5 mL. In some embodiments, the volume to be administered is 1.7 mL or about 1.7 mL. In some embodiments, the volume to be administered is 2 mL or about 2 mL. In some embodiments, the volume to be administered is 2.5 mL or about 2.5 mL.
  • the methods (or uses of CD3 ⁇ CD20 antibodies) described herein are for the treatment of human patients with CLL. It is understood that the methods described herein may be the first, or part of the first, treatment provided to such patients. However, patients may have been subjected to prior treatments for CLL. Prior treatments may include, but are not limited to, one or more of chemotherapy, immunotherapy, and targeted therapy, or combinations thereof. Most commonly, the standard of care comprises treatments with a combination of cytotoxic chemotherapy and anti-CD20 monoclonal antibodies. It is understood that the methods described herein may also be used in combination with other treatments.
  • the bispecific antibody used in the methods described herein comprises:
  • CDR1, CDR2 and CDR3 regions can be identified from variable heavy and light chain regions using methods known in the art.
  • the CDR regions from said variable heavy and light chain regions can be annotated according to IMGT (see Lefranc et al., Nucleic Acids Research 1999; 27:209-12 and Brochet. Nucl Acids Res 2008; 36: W503-8).
  • the bispecific antibody comprises:
  • the bispecific antibody comprises:
  • the bispecific antibody is a full-length antibody. In some embodiments, the bispecific antibody comprises an inert Fc region. In one embodiment, the bispecific antibody is a full-length antibody and have an inert Fc region.
  • the first binding arm for CD3 is derived from a humanized antibody, e.g., from a full-length IgG1, ⁇ (lambda) antibody such as H1L1 described in WO2015001085, which is incorporated herein by reference, and/or the second binding arm for CD20 is derived from a human antibody, e.g., from a full-length IgG1, ⁇ (kappa) antibody such as clone 7D8 as described in WO2004035607, which is incorporated herein by reference.
  • the bispecific antibody may be produced from two half molecule antibodies, wherein each of the two half molecule antibodies comprises, e.g., the respective first and second binding arms set forth in SEQ ID NOs: 24 and 25, and SEQ ID NOs: 26 and 27.
  • the half-antibodies may be produced in CHO cells and the bispecific antibodies generated by, e.g., Fab-arm exchange.
  • the bispecific antibody is a functional variant of DuoBody-CD3 ⁇ CD20.
  • the bispecific antibody comprises (i) a first binding arm comprising a first antigen-binding region which binds to human CD3 ⁇ (epsilon) and comprises a VH region comprising an amino acid sequence which is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 6 or a VH region comprising the amino acid sequence of SEQ ID NO: 6, but with 1, 2, or 3 mutations (e.g., amino acid substitutions), and a VL region comprising an amino acid sequence which is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 7 or a VL region comprising the amino acid sequence of SEQ ID NO: 7, but with 1, 2, or 3 mutations (e.g., amino acid substitutions); and
  • the bispecific antibody comprises:
  • the bispecific antibody comprises (i) a first binding arm comprising a first antigen-binding region which binds to human CD3 ⁇ (epsilon) and comprises a heavy chain comprising an amino acid sequence which is at least 85%, 90%, 95%, 98%, or 99% identical to SEQ ID NO: 24 or a heavy chain comprising the amino acid sequence of SEQ ID NO: 24, but with 1, 2, or 3 mutations (e.g., amino acid substitutions), and a light chain comprising an amino acid sequence which is at least 85%, 90%, 95%, 98%, or 99% identical to SEQ ID NO: 25 or a light chain region comprising the amino acid sequence of SEQ ID NO: 25, but with 1, 2, or 3 mutations (e.g., amino acid substitutions); and
  • the antibody comprises an IgG constant region, such as a human IgG1 constant region, e.g., a human IgG1 constant region as defined in SEQ ID NO: 15, or any other suitable IgG1 allotype.
  • the bispecific antibody is a full-length antibody with a human IgG1 constant region.
  • the first binding arm of the bispecific antibody is derived from a humanized antibody, preferably from a full-length IgG1, ⁇ (lambda) antibody.
  • the first binding arm of the bispecific antibody is derived from a humanized antibody, e.g., from a full-length IgG1, ⁇ (lambda) antibody, and thus comprises a ⁇ light chain constant region. In some embodiments, the first binding arm comprises a ⁇ light chain constant region as defined in SEQ ID NO: 22.
  • the second binding arm of the bispecific antibody is derived from a human antibody, preferably from a full-length IgG1, ⁇ (kappa) antibody. In some embodiments the second binding arm of the bispecific antibody is derived from a human antibody, preferably from a full-length IgG1, ⁇ (kappa) antibody, and thus may comprise a ⁇ light chain constant region.
  • the second binding arm comprises a ⁇ light chain constant region as defined in SEQ ID NO: 23.
  • the first binding arm comprises a ⁇ light chain constant region as defined in SEQ ID NO: 22 and the second binding arm comprises a ⁇ light chain constant region as defined in SEQ ID NO: 23.
  • the constant region portion of the bispecific antibody may comprise modifications that allow for efficient formation/production of bispecific antibodies and/or provide for an inert Fc region. Such modifications are well known in the art.
  • bispecific antibodies may include, but are not limited to, bispecific antibodies with complementary CH3 domains to force heterodimerization, Knobs-into-Holes molecules (Genentech, WO9850431), CrossMAbs (Roche, WO2011117329), or electrostatically-matched molecules (Amgen, EP1870459 and WO2009089004; Chugai, US201000155133; Oncomed, WO2010129304).
  • the bispecific antibody comprises an Fc-region comprising a first heavy chain with a first Fc sequence comprising a first CH3 region, and a second heavy chain with a second Fc sequence comprising a second CH3 region, wherein the sequences of the first and second CH3 regions are different and are such that the heterodimeric interaction between said first and second CH3 regions is stronger than each of the homodimeric interactions of said first and second CH3 regions.
  • WO2011131746 and WO2013060867 Genemab
  • the bispecific antibody comprises in the first heavy chain (i) the amino acid L in the position corresponding to F405 in the human IgG1 heavy chain constant region of SEQ ID NO: 15, and comprises in the second heavy chain the amino acid R in the position corresponding to K409 in the human IgG1 heavy chain constant region of SEQ ID NO: 15, or vice versa.
  • Bispecific antibodies may comprise modifications in the Fc region to render the Fc region inert, or non-activating.
  • one or both heavy chains may be modified so that the antibody induces Fc-mediated effector function to a lesser extent relative to the bispecific antibody which does not have the modification.
  • Fc-mediated effector function may be measured by determining Fc-mediated CD69 expression on T cells (i.e. CD69 expression as a result of CD3 antibody-mediated, Fc ⁇ receptor-dependent CD3 crosslinking), by binding to Fc ⁇ receptors, by binding to C1q, or by induction of Fc-mediated cross-linking of Fc ⁇ Rs.
  • the heavy chain constant region sequence may be modified so that Fc-mediated CD69 expression is reduced by at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 99% or 100% when compared to a wild-type (unmodified) antibody, wherein said Fc-mediated CD69 expression is determined in a PBMC-based functional assay, e.g. as described in Example 3 of WO2015001085. Modifications of the heavy and light chain constant region sequences may also result in reduced binding of C1q to said antibody.
  • the reduction may be by at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, or 100%, and C1q binding may be determined, e.g., by ELISA.
  • the Fc region which may be modified so that the antibody mediates reduced Fc-mediated T-cell proliferation compared to an unmodified antibody by at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 99% or 100%, wherein said T-cell proliferation is measured in a PBMC-based functional assay.
  • amino acid positions that may be modified, e.g., in an IgG1 isotype antibody, include positions L234 and L235.
  • the bispecific antibody may comprises a first heavy chain and a second heavy chain, and wherein in both the first heavy chain and the second heavy chain, the amino acid residues at the positions corresponding to positions L234 and L235 in a human IgG1 heavy chain according to Eu numbering are F and E, respectively.
  • a D265A amino acid substitution can decrease binding to all Fc ⁇ receptors and prevent ADCC (Shields et al., JBC 2001; 276:6591-604).
  • the bispecific antibody may comprise a first heavy chain and a second heavy chain, wherein in both the first heavy chain and the second heavy chain, the amino acid residue at the position corresponding to position D265 in a human IgG1 heavy chain according to Eu numbering is A.
  • the amino acids in the positions corresponding to positions L234, L235, and D265 in a human IgG1 heavy chain are F, E, and A, respectively.
  • An antibody having these amino acids at these positions is an example of an antibody having an inert Fc region, or a non-activating Fc region.
  • the bispecific antibody comprises a first heavy chain and a second heavy chain, wherein in both the first and second heavy chains, the amino acids in the positions corresponding to positions L234, L235, and D265 in the human IgG1 heavy chain constant region of SEQ ID NO: 15 are F, E, and A, respectively.
  • the bispecific antibody comprises a first heavy chain and a second heavy chain, wherein in the first heavy chain, the amino acid in the position corresponding to F405 in the human IgG1 heavy chain constant region of SEQ ID NO: 15 is L, and wherein in the second heavy chain, the amino acid in the position corresponding to K409 in the human IgG1 heavy chain constant region of SEQ ID NO: 15 is R, or vice versa.
  • the bispecific antibody comprises a first heavy chain and a second heavy chain, wherein (i) in both the first and second heavy chains, the amino acids in the positions corresponding to positions L234, L235, and D265 in the human IgG1 heavy chain constant region of SEQ ID NO: 15 are F, E, and A, respectively, and (ii) in the first heavy chain, the amino acid in the position corresponding to F405 in the human IgG1 heavy chain constant region of SEQ ID NO: 15 is L, and wherein in the second heavy chain, the amino acid in the position corresponding to K409 in the human IgG1 heavy chain constant region of SEQ ID NO: 15 is R, or vice versa.
  • bispecific antibodies those which have the combination of three amino acid substitutions L234F, L235E and D265A and in addition the K409R or the F405L mutation, as described above, may be referred to with the suffix “FEAR” or “FEAL”, respectively.
  • an amino acid sequence of a wild type IgG1 heavy chain constant region may be identified herein as SEQ ID NO: 15.
  • the bispecific antibody may comprise an IgG1 heavy chain constant region carrying the F405L substitution and may have the amino acid sequence set forth in SEQ ID NO: 17 and/or an IgG1 heavy chain constant region carrying the K409R substitution and may have the amino acid sequence set forth in SEQ ID NO: 18, and have further substitutions that render the Fc region inert or non-activating.
  • the bispecific antibody comprises a combination of IgG1 heavy chain constant regions, with the amino acid sequence of one of the IgG1 heavy chain constant regions carrying the L234F, L235E, D265A and F405L substitutions (e.g., as set forth in SEQ ID NO: 19) and the amino acid sequence of the other IgG1 heavy chain constant region carrying the L234F, L235E, D265A and K409R substitutions (e.g., as set forth in SEQ ID NO: 20).
  • the bispecific antibody comprises heavy chain constant regions comprising the amino acid sequences of SEQ ID NOs: 19 and 20.
  • the bispecific antibody used in the methods and uses described herein comprises a first binding arm comprising a heavy chain and a light chain as defined in SEQ ID NOs: 24 and 25, respectively, and a second binding arm comprising a heavy chain and a light chain as defined in SEQ ID NOs: 26 and 27, respectively.
  • a first binding arm comprising a heavy chain and a light chain as defined in SEQ ID NOs: 24 and 25, respectively
  • a second binding arm comprising a heavy chain and a light chain as defined in SEQ ID NOs: 26 and 27, respectively.
  • Such an antibody can also be referred to herein as DuoBody-CD3 ⁇ CD20.
  • variants of such antibodies are contemplated use in the methods and uses as described herein.
  • the bispecific antibody comprising a heavy chain and a light chain consisting of the amino acid sequences set forth in SEQ ID NOs: 24 and 25, respectively, and a heavy chain and a light chain consisting of the amino acid sequences set forth in SEQ ID NOs: 26 and 27, respectively.
  • the bispecific antibody is epcoritamab (CAS 2134641-34-0), or a biosimilar thereof.
  • kits which include a pharmaceutical composition containing a bispecific antibody which binds to CD3 and CD20 in accordance with the invention, such as DuoBody-CD3 ⁇ CD20 or epcoritamab, and a pharmaceutically-acceptable carrier, in a therapeutically effective amount adapted for use in the methods described herein.
  • the kits optionally also can include instructions, e.g., comprising administration schedules, to allow a practitioner (e.g., a physician, nurse, or patient) to administer the composition contained therein to administer the composition to a patient with CLL.
  • the kit also can include a syringe.
  • kits include multiple packages of the single-dose (e.g., a dose between 12-60 mg, such as 12 mg, 24 mg, 36 mg, 48 mg, or 60 mg) pharmaceutical compositions each containing an effective amount of the bispecific antibody for a single administration in accordance with the methods described herein.
  • Instruments or devices necessary for administering the pharmaceutical composition(s) also may be included in the kits.
  • a kit may provide one or more pre-filled syringes containing an amount of the bispecific antibody.
  • DuoBody-CD3 ⁇ CD20 is a bsAb recognizing the T-cell antigen CD3 and the B-cell antigen CD20.
  • DuoBody-CD3 ⁇ CD20 triggers potent T-cell-mediated killing of CD20-expressing cells.
  • DuoBody-CD3 ⁇ CD20 has a regular IgG1 structure.
  • IgG1-CD3-FEAL Two parental antibodies, IgG1-CD3-FEAL, a humanized IgG11, CD3E-specific antibody having heavy and light chain sequences as listed in SEQ ID NOs: 24 and 25, respectively, and IgG1-CD20-FEAR, derived from human IgG1 ⁇ CD20-specific antibody 7D8 having heavy and light chain sequences as listed in SEQ ID NOs: 26 and 27, respectively, were manufactured as separate biological intermediates.
  • Each parental antibody contains one of the complementary mutations in the CH3 domain required for the generation of DuoBody molecules (F405L and K409R, respectively).
  • the parental antibodies comprised three additional mutations in the Fc region (L234F, L235E and D265A; FEA).
  • the parental antibodies were produced in mammalian Chinese hamster ovary (CHO) cell lines using standard suspension cell cultivation and purification technologies.
  • DuoBody-CD3 ⁇ CD20 was subsequently manufactured by a controlled Fab-arm exchange (cFAE) process (Labrijn et al. 2013, Labrijn et al. 2014, Gramer et al. 2013).
  • the parental antibodies are mixed and subjected to controlled reducing conditions. This leads to separation of the parental antibodies that, under re-oxidation, re-assemble. This way, highly pure preparations of DuoBody-CD3 ⁇ CD20 ( ⁇ 93-95%) were obtained. After further polishing/purification, final product was obtained, close to 100% pure.
  • the product has received the international proprietary name of epcoritamab.
  • Epcoritamab is prepared (5 mg/mL or 60 mg/mL) as a sterile clear colorless to slightly yellow solution supplied as concentrate for solution for subcutaneous (SC) injection.
  • Epcoritamab contains buffering and tonicifying agents. All excipients and amounts thereof in the formulated product are pharmaceutically acceptable for subcutaneous injection products. Appropriate doses are reconstituted to a volume of about 1 mL for subcutaneous injection.
  • Example 1 Epcoritamab-Induced Activation of CD4+ and CD8+ T Cells and Cytotoxicity of B Cells Obtained from CLL Patients
  • CLL patient PBMCs were co-cultured with healthy donor (HD) PBMCs (ratio patient:healthy donor cells 1:5) and epcoritamab, or with bispecific antibodies containing either the CD3 arm, or the CD20 arm, and a non-binding control arm (bsIgG1-CD3 ⁇ ctrl, and bsIgG1-ctrl ⁇ CD20, respectively, wherein controls have the same format as epcoritamab (i.e. having an inert Fc), for 24 hours.
  • the HD PBMCs were added to improve viability of the CLL patient-derived PBMCs and were labeled with CFSE to be able to distinguish them from the CLL patient-derived PBMCs.
  • CD69 expression was used to evaluate (A) CD4+ and (B) CD8+ T-cell activation.
  • B-cell viability (% CD4-CD8-CD22+ cells left) was analyzed as a measure for cytotoxicity induced by epcoritamab.
  • epcoritamab induced the activation of both CLL and HD CD4+ and CD8+ T cells (See panels A and B).
  • CD4+ T cells For CD4+ T cells, HD T cells were more efficiently activated than CLL T cells (see panel A, compare the left graph with the right graph, wherein epcoritamab induced CD4+ T cell activation to a higher % of CD69 in healthy donor derived PBMCs as compared to CLL patient derived PBMCs).
  • Epcoritamab activated both CLL and HDD CD8+ T cells to a similar degree (see panel B, the upper line of both graphs represents epcoritamab).
  • Epcoritamab induced T-cell-mediated cytotoxicity of both CLL and HD B cells, indicating that CLL B cells are susceptible to T-cell-mediated cytotoxicity (see panel C, wherein epcoritamab reduced the viability of B cells following a dose response curve). These data demonstrate that epcoritamab activates both CD4+ and CD8+ T cells, and induces killing of B cells, from CLL patients.
  • Epcoritamab is currently in a clinical trial for the treatment of R/R B-NHL (ClinicalTrials.gov Identifier: NCT03625037). Preliminary data suggest that the drug is tolerated at doses up to at least 48 mg, including 60 mg in R/R B-NHL patients, with a favourable safety profile, with no dose-limiting toxicities reported.
  • the primary objective of the dose escalation part is to identify the recommended phase 2 dose (RP2D) and maximum tolerated dose (MTD) (endpoint: incidence of dose limiting toxicities (DLTs)), and evaluate the safety and tolerability (endpoints: incidence and severity of adverse events (AEs), serious adverse events (SAEs), CRS, ICANs, and TLS, and incidence of dose interruption, dose delay, and dose intensity), of epcoritamab in subjects with R/R CLL.
  • R2D phase 2 dose
  • MTD maximum tolerated dose
  • DLTs dose limiting toxicities
  • Secondary objectives of the dose escalation part include characterizing the PK properties of epcoritamab (endpoints: PK parameters, including clearance, volume of distribution and AUC0-last and AUC0-x, Cmax, Tmax, predose values, and half-life), evaluating pharmacodynamic markers linked to efficacy and the mechanism of action of epcoritamab (endpoints: pharmacodynamic markers in blood samples), evaluating the immunogenicity of epcoritamab (endpoint: incidence of anti-drug antibodies (ADAs) to epcoritamab), and assessing the preliminary anti-tumor activity of epcoritamab (endpoints: overall response rate (ORR), duration of response (DOR), time to response (TTR), progression free survival (PFS), and overall survival (OS)).
  • endpoints PK parameters, including clearance, volume of distribution and AUC0-last and AUC0-x, Cmax, Tmax, predose values, and half-life
  • endpoints pharmacodynamic markers linked to
  • Exploratory objectives of the dose escalation part include evaluating biomarkers predictive of clinical response to epcoritamab (endpoints: CD20 expression, evaluation of immune populations, phenotype and function and blood) and assessing the minimal residual disease (MRD) status in peripheral blood and bone marrow (endpoint: incidence of undetectable MRD).
  • endpoints CD20 expression
  • MRD minimal residual disease
  • the primary objective of the expansion part is to assess the preliminary efficacy of epcoritamab (endpoint: ORR).
  • Secondary objectives of the expansion part include evaluating the preliminary efficacy of epcoritamab (endpoints: DOR, TTR, PFS, and OS), assessing the MRD status in peripheral blood and bone marrow (endpoint: incidence of undetectable MRD), evaluating the safety and tolerability of epcoritamab (endpoints: endpoints: incidence and severity of AEs, SAEs, CRS, ICANs, and TLS, and incidence of dose interruption, dose delay, and dose intensity), establishing the PK and pharmacodynamic profiles of epcoritamab (endpoints: PK parameters and pharmacodynamic parameters), and evaluating immunogenicity of epcoritamab (endpoint: incidence of ADAs to epcoritamab).
  • Exploratory objectives of the expansion part include evaluating biomarkers predictive of clinical response to epcoritamab (endpoints: expression of CD20 and evaluation of immune populations, phenotype, and function, and blood).
  • the trial is conducted in 2 parts: dose escalation (Part 1) and expansion (Part 2).
  • Part 1 dose escalation
  • Part 2 expansion
  • Both parts consist of a screening period (up to 21 days prior to Cycle 1 Day 1), a treatment period (Cycle 1 Day 1 until epcoritamab discontinuation), a safety follow-up (60 days after the last dose of epcoritamab), and a survival status follow-up.
  • epcoritamab is administered as a subcutaneous (SC) injection in 4-week cycles (i.e., 28 days), as shown below, until one or more of the discontinuation criteria are met:
  • a step-up dosing method is used to mitigate the potential for CRS: priming dose on Cycle 1 Day 1, followed by intermediate dose on Cycle 1 Day 8, then full dose on Cycle 1 Day and Day 22, and full dose in subsequent cycles.
  • epcoritamab is tested in subjects with R/R CLL using the modified 3+3 design. DLTs are evaluated during the first treatment cycle (i.e., 28 days). After identifying the RP2D, the preliminary efficacy of single agent epcoritamab is assessed together with safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and biomarkers in Part 2 (Expansion).
  • the dose escalation part implements a modified 3+3 design.
  • Epcoritamab is studied at 2 full dose levels: 24 mg and 48 mg.
  • a step-up dosing regimen is applied: 0.16 mg/0.8 mg/24 mg and 0.16 mg/0.8 mg/48 mg (priming/intermediate/full dose). Additional doses including intermediate doses and dosing regimens may be explored based on emerging data.
  • 3 subjects are initially treated. Based on the escalation rules specified following Table 3, 3 additional subjects may be needed at the current dose level or 3 subjects are treated at a different dose level. At least 6 subjects will be enrolled in Part 1. Subjects are monitored for DLTs during the first treatment cycle (i.e., 28 days).
  • Subjects who are not DLT evaluable may be replaced, and at least 6 subjects are needed for a dose level to be identified as RP2D. Additional full dose levels, either lower than 24 mg (e.g., 12 mg) or higher than 48 mg (e.g., 60 mg), may be investigated.
  • the MTD is defined as the highest investigated dose level with DLT observed in at most one-third of subjects.
  • the RP2D for R/R CLL will be set at 48 mg if the dose level is found to be safe and tolerable.
  • the totality of data including safety (e.g., adverse events (AEs) and safety laboratory values, and observations made after the end of the DLT evaluation period), pharmacokinetics, pharmacodynamics, and preliminary efficacy, will guide further development for expansion.
  • safety e.g., adverse events (AEs) and safety laboratory values, and observations made after the end of the DLT evaluation period
  • pharmacokinetics e.g., pharmacodynamics, and preliminary efficacy
  • the expansion part enrolls approximately 20 subjects with R/R CLL previously treated with 2 prior lines of systemic antineoplastic therapy, including a BTK inhibitor (e.g., ibrutinib) or are otherwise intolerant of a BTK inhibitor.
  • R/R CLL subjects are treated at the RP2D identified in Part 1.
  • the primary efficacy endpoint of the expansion part is ORR as assessed using the iwCLL 2018 criteria (Table 2).
  • ORR is a widely accepted response endpoint to evaluate the efficacy for subjects with R/R CLL.
  • Secondary efficacy endpoints include DOR, TTR, PFS, and OS. Incidence of MRD negative status is also evaluated as a secondary efficacy endpoint.
  • MRD assessment indicates how many cancer cells still remain in a subject who is in remission either during or after treatment has been implemented.
  • Safety endpoints in the expansion part include the incidence and severity of AEs/SAEs, incidence and severity of tumor lysis syndrome (TLS), immune effector cell-associated neurotoxicity syndrome (ICANS) and CRS, and incidence of treatment interruption and delay.
  • Blood transfusion may be administered during screening to meet this requirement
  • Growth factor support is allowed in case of bone marrow involvement.
  • g. Platelet count ⁇ 30 ⁇ 10 9 /L (30,000/ ⁇ L)
  • Transfusion may be administered during screening to meet this requirement.
  • Coagulation status PT/INR/aPTT ⁇ 1.5 ⁇ ULN
  • corticosteroids for four days is performed to reduce/prevent the severity of symptoms from potential CRS for each dose of epcoritamab in cycle 1.
  • CRS prophylaxis with corticosteroids is optional.
  • Corticosteroid administration can be either intravenous or oral route with recommended dose or equivalent.
  • CRS is graded according to the ASTCT grading for CRS (Tables 7 and 8), and for treatment of CRS, subjects should receive supportive care.
  • Supportive care can include, but is not limited to,
  • organ toxicities or constitutional symptoms associated with CRS may be graded according to CTCAE but they do not influence CRS grading.
  • Fever is defined as temperature ⁇ 38.0° C. not attributable to any other cause, with or without constitutional symptoms (eg, myalgia, arthralgia, malaise).
  • constitutional symptoms eg, myalgia, arthralgia, malaise.
  • CRS grading is driven by hypotension and/or hypoxia.
  • CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause.
  • a subject with temperature of 39.5° C., hypotension requiring 1 vasopressor, and hypoxia requiring low-flow nasal cannula is classified as grade 3 CRS.
  • Both systolic blood pressure and mean arterial pressure are acceptable for blood pressure measurement. No specific limits are required, but hypotension should be determined on a case-by-case basis, accounting for age and the subject’s individual baseline, i.e., a blood pressure that is below the normal expected for an individual in a given environment.
  • 3 Intubation of a subject without hypoxia for the possible neurologic compromise of a patent airway alone or for a procedure is not by definition grade 4 CRS.
  • vasopressor nodepinephrine
  • vasopressin a vasopressor
  • hypoxia Administer oxygen by high-flow nasal cannula (>6 L/min), facemask, non-breather mask, or Venturi mask.
  • Tocilizumab Yes ⁇ .
  • Steroids Consider ⁇ . 4 Fever: As per grade 1.
  • Hypotension Immediate clinical evaluation and intervention is warranted.
  • Hypoxia Positive pressure (e.g. CPAP, BiPAP, intubation, and mechanical ventilation).
  • Tocilizumab Yes ⁇ .
  • Steroids Yes ⁇ .
  • ⁇ Tocilizumab anti-IL-6R remains the only first-line anticytokine therapy approved for CRS. If there is no improvement in symptoms within 6 hours, or if the patient starts to deteriorate after initial improvement, a second dose of tocilizumab should be administered along with a dose of corticosteroids.
  • anticytokine therapy such as siltuximab (anti-IL-6) or anakinra (anti-IL-1R) may be considered.
  • anti-IL-6 siltuximab
  • anti-IL-1R anakinra
  • dexamethasone should be preferred.
  • Chimeric antigen receptor T-cell therapies for cancer (Chapter 5). Elsevier 2020)
  • subjects For prophylactic treatment of tumor lysis syndrome, subjects receive uric acid reducing agents prior to the administration of epcoritamab, with allopurinol given at least 72 hours prior to the first dose of epcoritamab and rasburicase initiated prior to starting epcoritamab. Increased oral hydration should be received prior to the first dose and is maintained during dosings. Reassessment of the subject's TLS risk category is performed prior to subsequent doses.
  • a fresh bone marrow aspirate is obtained at screening (i.e., within 21 days prior to Cycle 1 Day 1) and at the time of complete response (CR) or when clinically indicated.
  • a fresh bone marrow biopsy is obtained at screening and at the time of CR or nodular partial response (PR) (nPR) or when clinically indicated.
  • Bone marrow evaluations include morphological examination and either flow cytometry or immunohistochemistry.
  • a bone marrow biopsy with aspirate is obtained (a) to confirm a CR or nPR that is supported by physical examination findings, laboratory evaluations and radiographic evaluations according to iwCLL guidelines (Hallek et al, Lancet 2018; 391:1524-37), and (b) if progression is only shown in 1 parameter to confirm cytopenic progression (i.e., neutropenia, anemia, and/or thrombocytopenia and to distinguish from autoimmune and treatment-related cytopenias).
  • cytopenic progression i.e., neutropenia, anemia, and/or thrombocytopenia and to distinguish from autoimmune and treatment-related cytopenias.
  • Imaging scans of the neck, chest, abdomen and pelvis are performed at screening (i.e., within 3 weeks prior to the first dose of epcoritamab) and subsequent response assessments.
  • a CT scan with contrast is the recommended imaging modality.
  • MRI may be used only if CT with contrast is medically contraindicated or if the frequency of CT scans exceeds local standards. MRI studies do not replace the required neck, chest, abdomen, and pelvic CT scans. Additional imaging assessments may be performed to support the efficacy evaluations for a subject as necessary.
  • a fresh bone marrow aspirate is obtained at screening (i.e., within 21 days prior to Cycle 1 Day 1) and at the time of CR or as clinically indicated.
  • a fresh bone marrow biopsy is obtained at screening and at the time of CR or nodular PR (nPR) or as clinically indicated.
  • Bone marrow evaluations include a morphological examination and either flow cytometry or immunohistochemistry.
  • a bone marrow biopsy with aspirate is obtained (a) to confirm a CR or nPR according to iwCLL guidelines (Hallek et al., supra) that is supported by physical examination findings, laboratory evaluations and radiographic evaluations, and (b) if progression is only shown in 1 parameter to confirm cytopenic progression (i.e., neutropenia, anemia, and/or thrombocytopenia and to distinguish from autoimmune and treatment-related cytopenias).
  • cytopenic progression i.e., neutropenia, anemia, and/or thrombocytopenia and to distinguish from autoimmune and treatment-related cytopenias.
  • MRD is assessed in the blood by flow cytometry and next generation sequencing. After start of treatment, blood samples are requested at the fixed time points and at time of CR. As an exploratory analysis, when a subject reaches a CR, a portion of the aspirate collected to confirm CR is used to assess MRD.
  • Tumor response according to imaging assessment is performed to inform decisions on continuation of treatment.
  • Response assessment is completed according to the revised iwCLL guidelines for diagnosis, indications for treatment, response assessment and supportive management of CLL, as described in Table 2. Endpoint definitions are as follows:
  • Safety will be assessed by measuring adverse events, laboratory test results, ECGs, vital sign measurements, physical examination findings, and ECOG performance status. Also assessed are immune effector cell-associated neurotoxicity syndrome (e.g., as described by Lee et al., Biol Blood Marrow Transplant 2019; 25:625-638), constitutional symptoms (B symptoms), tumor flare reaction, and survival.
  • immune effector cell-associated neurotoxicity syndrome e.g., as described by Lee et al., Biol Blood Marrow Transplant 2019; 25:625-638
  • constitutional symptoms B symptoms
  • tumor flare reaction e.g., as described by Lee et al., Biol Blood Marrow Transplant 2019; 25:625-638
  • Absolute B and T-cell counts are determined in fresh whole blood using flow cytometry to monitor changes associated with epcoritamab treatment.
  • the T-cell activation and exhaustion phenotype is evaluated using flow cytometry and markers in order to evaluate the association of such markers with drug target engagement, treatment efficacy, and/or safety of epcoritamab.
  • Additional immunophenotypes of circulating immune cells e.g., levels of regulatory T-cells which can suppress T-cell function
  • cytokine levels are closely monitored.
  • the levels of cytokines such as IL-2, IL15, IL-6, IL-8, IL-10, IFN ⁇ , and/or TNF ⁇ , are measured in plasma samples using an array based ligand binding assay. Additional cytokines may also be determined to evaluate the association of such markers with treatment-emergent AEs and outcome to epcoritamab.
  • the first patient was enrolled on Nov. 30, 2020 .
  • Six patients completed the dose limiting toxicity (DLT) evaluation period, and 5 patients had a response assessment.
  • Patients had received a median of 4 lines of prior therapy (range, 2-5).
  • Six of 7 patients had poor-risk features of del (17p), TP53 mutations, or both.
  • Three of 7 pts had bulky disease. No DLTs occurred at 24 or 48 mg.
  • CRS cytokine release syndrome
  • ICANS immune effector cell-associated neurotoxicity syndrome
  • TLS tumor lysis syndrome
  • Epcoritamab was well tolerated at both 24 mg and 48 mg with the most common treatment-emergent adverse events being CRS, fatigue, and injection site reaction. There was no immune effector cell-associated neurotoxicity syndrome (ICANS). Preliminary activity of epcoritamab in these heavily pretreated patients who had high-risk cytogenetics have been observed. Among 6 response-evaluable subjects, there were 1 non-confirmed partial response (nPR) at 24 mg and 2 partial responses (PR) at 48 mg. These data are preliminary and non-validated and unclean data and response data were not completely entered by site.
  • nPR non-confirmed partial response
  • PR partial responses
  • KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH CH3 region italics YTQKSLSLSPG 16 IgG1-LFLEDA heavy ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGA chain constant LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN region (amino acids TKVDKRVEPKSCDKTHTCPPCPAPE FE GGPSVFLFPPKPKDTLMIS positions 118-447 RTPEVTCVVV A VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS according to EU TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR numbering).
  • Bold and underlined are FE; A; L and R, corresponding to positions 234 and 235; 265; 405 and 409, respectively, said positions being in accordance with EU-numbering.
  • said CDR regions that were annotated in accordance with IMGT definitions are underlined.

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