ANTICORPOS MULTIESPECÍFICOS CD19 / CD38

Abstract

Described herein are multispecific binding antibodies with reduced isoelectric focusing point.

Description

1 / 58 Multispecific Antibodies CD19 / CD38 Cross-reference with Related Requests

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 491,441, filed March 21, 2023, and U.S. Provisional Application No. 63 / 590,886, filed October 17, 2023, each of which is incorporated herein by reference. SEQUENCE LISTING

[0002] This application contains a Sequence Listing that was submitted electronically in XML format and is incorporated herein by reference in its entirety. The said XML copy, created on March 18, 2024, is named 51527716601_SEQ.xml and is 19,873 bytes in size. BACKGROUND

[0003] Immunosuppressive B cell populations (i.e., regulatory B cells or Bregs) are those B cell populations that suppress an individual's antitumor immune response. Therapies that effectively and specifically target immunosuppressive B cells can therefore be used to prevent and / or remove immunosuppression, thus providing effective treatments for different types of cancer. SUMMARY

[0004] In addition to binding to the intended target molecule, antibodies must also meet specific criteria related to manufacturability, storage stability, and absence of off-target binding. This set of characteristics is commonly referred to as “developability.” Unfortunately, there is no single parameter (e.g., assay property) that can definitively predict developability and development challenges based on the universe of antibodies that have reached the clinic.

[0005] Multispecific antibodies having modifications that allow are exemplified and provided in this document. Petition 870250105621, dated 11 / 18 / 2025, page 9 / 71 2 / 58 greater development and manufacturing capacity. This document provides, in one aspect, a multispecific antibody comprising: (a) a CD38-binding moiety comprising: (i) a first polypeptide comprising a variable region of the immunoglobulin heavy chain comprising the amino acid sequence presented in SEQ ID NO: 1 and a constant region of the heavy chain wherein the constant region of the heavy chain does not have a C-terminal lysine residue; and (ii) a second polypeptide comprising a variable region of the light chain comprising the amino acid sequence presented in SEQ ID NO: 3; and (b) a CD19-binding moiety comprising: (i) a third polypeptide comprising a variable region of the immunoglobulin heavy chain comprising the amino acid sequence presented in SEQ ID NO: 2 and a constant region of the heavy chain wherein the constant region of the heavy chain does not have a C-terminal lysine residue; and (ii) a fourthA polypeptide comprising a variable light chain region comprising the amino acid sequence shown in SEQ ID NO: 3. In certain embodiments, the constant region of the heavy chain of the first polypeptide, the third polypeptide, or both the first and third polypeptides, comprises a constant region of human IgG1 or human IgG4. In certain embodiments, the polypeptide comprising a variable light chain region additionally comprises a constant light chain region. In certain embodiments, the second polypeptide, the fourth polypeptide, or both the second and fourth polypeptides, comprise the amino acid sequence shown in SEQ ID NO: 6. In certain embodiments, the CD38-binding moiety comprises one or more amino acid substitutions that inhibit(s) the homodimerization of the CD38-binding moiety. In certain embodiments, the CD38-binding moiety comprises a T366W substitution, according to theEU numbering, or a replacement T366S / L368A / Y407V, of Petition 870250105621, dated 11 / 18 / 2025, page 10 / 71 3 / 58 according to EU numbering. In certain embodiments, the CD19-binding moiety comprises one or more amino acid substitutions that inhibit(s) the homodimerization of the CD19-binding moiety. In certain embodiments, the CD19-binding moiety comprises a T366W substitution, according to EU numbering, or a T366S / L368A / Y407V substitution, according to EU numbering. In certain embodiments, the first polypeptide consists of the amino acid sequence shown in SEQ ID NO: 4. In certain embodiments, the third polypeptide consists of the amino acid sequence shown in SEQ ID NO: 5. In certain embodiments, a pharmaceutical composition comprises the multispecific antibody, a pharmaceutically acceptable excipient, diluent, or carrier. In certain embodiments, a nucleic acid encodes the multispecific antibody.This document also describes a method for treating cancer in an individual in need thereof, comprising administering to the individual a multispecific antibody. In certain embodiments, the cancer or tumor is a solid tissue cancer. In certain embodiments, solid tissue cancer includes breast cancer, prostate cancer, pancreatic cancer, lung cancer, kidney cancer, stomach cancer, esophageal cancer, skin cancer, colorectal cancer, or head and neck cancer. In certain embodiments, breast cancer is triple-negative breast cancer, lung cancer is non-small cell lung cancer, head and neck cancer is squamous cell carcinoma of the head and neck, kidney cancer is renal cell carcinoma, brain cancer is glioblastoma multiforme, or skin cancer is melanoma. In certain embodiments, the cancer or tumor is a blood cancer.In certain forms, blood cancer is diffuse large B-cell lymphoma. In certain forms, blood cancer is myeloma. In certain forms, blood cancer is Burkitt lymphoma. In certain forms, blood cancer is aggressive lymphoma. Petition 870250105621, dated 11 / 18 / 2025, page 11 / 71 4 / 58 B cells. In certain modalities, aggressive B-cell lymphoma comprises double-impact lymphoma, double-expressor lymphoma, or triple-impact lymphoma. In certain modalities, blood cancer is relapsed or refractory. In certain modalities, cancer or tumor associated with CD19-positive, high-CD38-expressing, and immunosuppressive B cells is a cancer or tumor comprising infiltrates of CD19-positive, high-CD38-expressing B cells. In certain modalities, CD19-positive, high-CD38-expressing, and immunosuppressive B cells express a B-cell activation marker. In certain modalities, the B-cell activation marker comprises CD30. In certain modalities, cancer or tumor associated with CD19-positive, high-CD38-expressing B cells expresses PD-L1. In certain modalities, cancer or tumor associated with CD19-positive, high-CD38-expressing B cells is associated with low-CD20 or CD20-negative B cells.In certain modalities, B cells with high CD38 expression express at least approximately 30,000 CD38 proteins on the cell surface. In certain modalities, B cells with high CD38 expression express at least approximately 35,000 CD38 proteins on the cell surface. In certain modalities, B cells with high CD38 expression express at least approximately 40,000 CD38 proteins on the cell surface.

[0006] In one aspect, a common light chain bispecific antibody is provided in this document comprising: a variable anti-CD38 heavy chain region and a constant anti-CD38 heavy chain region, wherein the variable anti-CD38 heavy chain region comprises: (a) a heavy chain complementarity-determining region 1 (HCDR1) comprising an amino acid sequence presented in SEQ ID NO: 7, (b) a heavy chain complementarity-determining region 2 (HCDR2) comprising an amino acid sequence presented in SEQ ID NO: 8, (c) a complementarity-determining region Petition 870250105621, dated 11 / 18 / 2025, page 12 / 71 5 / 58 of the heavy chain 3 (HCDR3) comprising an amino acid sequence presented in SEQ ID NO: 9, and a negatively charged amino acid at the position of the variable region of the heavy chain 1 by Kabat numbering, a variable region of the anti-CD19 heavy chain and a constant region of the anti-CD19 heavy chain, wherein the variable region of the human anti-CD19 heavy chain comprises: (a) a complementarity-determining region of the heavy chain 1 (HCDR1) comprising an amino acid sequence presented in SEQ ID NO: 10, (b) a complementarity-determining region of the heavy chain 2 (HCDR2) comprising an amino acid sequence presented in SEQ ID NO: 11, (c) a complementarity-determining region of the heavy chain 3 (HCDR3) comprising an amino acid sequence presented in SEQ ID NO: 12, and a negatively charged amino acid at the position of the variable region of the heavy chain 1 by Kabat numbering,a variable region of the common light chain comprising: (a) a complementarity-determining region of light chain 1 (LCDR1) comprising an amino acid sequence presented in SEQ ID NO: 13, (b) a complementarity-determining region of light chain 2 (LCDR2) comprising an amino acid sequence presented in SEQ ID NO: 14 (AAS), and (c) a complementarity-determining region of light chain 3 (LCDR3) comprising an amino acid sequence presented in SEQ ID NO: 15, wherein: each of the constant region of the anti-CD38 heavy chain and the constant region of the anti-CD19 heavy chain lacks a C-terminal lysine residue (e.g., K447 per EU numbering); and the common light chain bispecific antibody comprises an experimental isoelectric point (pI) less than 9. In certain embodiments,The common light chain bispecific antibody additionally comprises a hydrophobicity retention time (HIC) of less than about 10 minutes. In certain embodiments, the terminal lysine residue is K447, according to, Petition 870250105621, dated 11 / 18 / 2025, p. 13 / 71 6 / 58 EU numbering. In certain embodiments, the variable region of the anti-CD19 heavy chain comprises a serine at position 84 and / or a leucine at position 108, according to Kabat numbering. In certain embodiments, the variable region of the common light chain comprises a histidine at position 32, according to Kabat numbering. In certain embodiments, the negatively charged amino acid is glutamic acid. In certain embodiments, the pI is between 8 and 9. In certain embodiments, a pharmaceutical composition comprises the common light chain bispecific antibody and a pharmaceutically acceptable excipient, diluent, or carrier. In certain embodiments, a nucleic acid encodes the bispecific antibody. A method for treating cancer in an individual in need thereof, comprising administering the common light chain bispecific antibody to the individual, is also provided herein. In certain embodiments, the cancer or tumor is a solid tissue cancer.In certain modalities, solid tissue cancer includes breast cancer, prostate cancer, pancreatic cancer, lung cancer, kidney cancer, stomach cancer, esophageal cancer, skin cancer, colorectal cancer, or head and neck cancer. In certain modalities, breast cancer is triple-negative breast cancer, lung cancer is non-small cell lung cancer, head and neck cancer is squamous cell carcinoma of the head and neck, kidney cancer is renal cell carcinoma, brain cancer is glioblastoma multiforme, or skin cancer is melanoma. In certain modalities, the cancer or tumor is blood cancer. In certain modalities, blood cancer is diffuse large B-cell lymphoma. In certain modalities, blood cancer is myeloma. In certain modalities, blood cancer is Burkitt lymphoma. In certain modalities, blood cancer is aggressive B-cell lymphoma.In certain forms, aggressive B-cell lymphoma includes dual-impact lymphoma and dual-expressor lymphoma. Petition 870250105621, dated 11 / 18 / 2025, page 14 / 71 7 / 58 or triple-impact lymphoma. In certain modalities, the blood cancer is recurrent or refractory. In certain modalities, the cancer or tumor associated with CD19-positive B cells with high CD38 expression and immunosuppression is a cancer or tumor comprising infiltrates of CD19-positive B cells with high CD38 expression. In certain modalities, the CD19-positive B cells with high CD38 expression and immunosuppression express a marker of B cell activation. In certain modalities, the marker of B cell activation comprises CD30. In certain modalities, the cancer or tumor associated with CD19-positive B cells with high CD38 expression expresses PD-L1. In certain modalities, the cancer or tumor associated with CD19-positive B cells with high CD38 expression is associated with low CD20 or CD20-negative B cells. In certain modalities, B cells with high CD38 expression express at least approximately 30,000 CD38 proteins on their cell surface.In certain modes, B cells with high CD38 expression express at least approximately 35,000 CD38 proteins on their cell surface. In certain modes, B cells with high CD38 expression express at least approximately 40,000 CD38 proteins on their cell surface.

[0007] In another aspect, a method is provided in this document for reducing an experimental isoelectric point of an antibody, the method comprising: (a) mutating a glutamine to a negatively charged amino acid at position 1 of a variable region of the heavy chain by Kabat numbering; and (b) removing a lysine at the C-terminal position of a constant region of the heavy chain. In certain embodiments, the negatively charged amino acid is glutamic acid. In certain embodiments, the antibody is a common light chain bispecific antibody comprising: an anti-CD38 heavy chain variable region, wherein the anti-CD38 heavy chain variable region comprises: (a) a heavy chain complementarity-determining region 1 (HCDR1) comprising an amino acid sequence presented in SEQ ID Petition 870250105621, dated 11 / 18 / 2025, page 15 / 71 8 / 58 NO: 7, (b) a heavy chain complementarity-determining region 2 (HCDR2) comprising an amino acid sequence presented in SEQ ID NO: 8, and (c) a heavy chain complementarity-determining region 3 (HCDR3) comprising an amino acid sequence presented in SEQ ID NO: 9, a variable region of the anti-CD19 heavy chain, wherein the variable region of the human anti-CD19 heavy chain comprises: (a) a heavy chain complementarity-determining region 1 (HCDR1) comprising an amino acid sequence presented in SEQ ID NO: 10, (b) a heavy chain complementarity-determining region 2 (HCDR2) comprising an amino acid sequence presented in SEQ ID NO: 11, and (c) a heavy chain complementarity-determining region 3 (HCDR3) comprising an amino acid sequence presented in SEQ ID NO: 12,a variable region of the common light chain comprising: (a) a complementarity-determining region of light chain 1 (LCDR1) comprising an amino acid sequence presented in SEQ ID NO: 13, (b) a complementarity-determining region of light chain 2 (LCDR2) comprising an amino acid sequence presented in SEQ ID NO: 14 (AAS), and (c) a complementarity-determining region of light chain 3 (LCDR3) comprising an amino acid sequence presented in SEQ ID NO: 15.

[0008] Also provided in this document is a method for producing an antibody, the method comprising collecting a bispecific antibody of this disclosure from the supernatant of a cell line comprising a nucleic acid encoding the antibody and subjecting the supernatant to one or more purification steps. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Figures 1A, 1B and 1C show polyreactivity profiles for BSM-001F (BSM-001.1). Petition 870250105621, dated 11 / 18 / 2025, page 16 / 71 9 / 58

[00010] FIG. 2 shows hydrophobicity chromatography (HIC) profiles for BSM-001F (BSM-001.1).

[00011] FIG. 3 shows B-cell binding data for BSM-001F (BSM-001.1).

[00012] FIG. 4 shows ADCC cell death data for BSM-001F (BSM-001.1).

[00013] FIG. 5 shows apoptosis cell death data for BSM-001F (BSM-001.1). DETAILED DESCRIPTION

[00014] The term immunosuppression or immunodepression or “negative or regulatory immune modulation,” in reference to specific cell populations, as used in this document, refers to processes or cells that are responsible for reducing or suppressing the function of the immune system. Immunosuppression generally indicates a state in which the function of the immune system is reduced or absent with respect to one or more functions, such as cellular immunity, antibody-based immunity, or innate immune function. In certain cases, immunosuppression generally indicates a state in which the function of the immune system against a tumor or within, around, or adjacent to the tumor microenvironment is reduced or absent. The entire immune response may be depressed, the immune response within a local or specific region may be reduced, or a particular population of immunologically active lymphocytes may be selectively affected.Antigen-specific immunosuppression can result from the exclusion or suppression of a particular population of antigen-specific cells, or from the enhanced regulation of the immune response by antigen-specific suppressor cells. References to immunosuppressive B cells refer to B cells or populations of B cells that exert negative modulation on the immune response and can be identified by specific surface markers associated with them. Petition 870250105621, dated 11 / 18 / 2025, page 17 / 71 10 / 58 populations, such as CD38. In certain cases, immunosuppression can be identified by the presence or release of IL-10, IL-35, TGF-beta, or a combination thereof. In certain cases, immunosuppression can be identified by the presence or release of IL-10, IL-35, TGF-beta, or a combination thereof by B cells.

[00015] As used in this document, the term cancer may refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Cancer may also include solid tumors. Cancer may refer to diseases of the blood, bones, organs, skin tissues, and vascular system, including but not limited to the bladder, blood, bones, brain, breast, cervix, chest, colon, endometrium, esophagus, eyes, head, kidneys, liver, lungs, lymph nodes, mouth, neck, ovaries, pancreas, prostate, rectum, kidney, skin, stomach, testicles, throat, and uterus. Specific cancers include, but are not limited to, gastrointestinal tumor (e.g., gastrointestinal stromal tumor (GIST)), follicular lymphoma, mantle cell lymphoma / leukemia, diffuse B-cell lymphoma, mediastinal (thymus) large B-cell lymphoma, intravascular large B-cell lymphoma, primary exudative lymphoma, and Burkitt lymphoma.Mature T-cell and natural killer (NK) cell tumors (prelymphocytic leukemia, T-cell large lymphocytic leukemia, invasive NK-cell leukemia, adult T-cell leukemia / lymphoma, extranodal NK / T-cell lymphoma, enteropathic T-cell lymphoma, hepatosplenic T-cell lymphoma, NK-cell blastic lymphoma, mycosis fungoides (Sézary syndrome), primary degenerative large cell lymphoma of the skin, lymphomatoid papulosis, angioimmunoblastic T-cell lymphoma, peripheral lymphoma not otherwise specified, T-cell lymphoma and degenerative large cell lymphoma, Hodgkin lymphoma (nodular sclerosis, type of, Petition 870250105621, dated 11 / 18 / 2025, page 18 / 71 11 / 58 mixed cells, lymphocyte-rich type, lymphocyte-depleted or non-reduced type, nodular lymphocyte type), myeloma (multiple myeloma, inert myeloma, latent multiple myeloma), chronic myeloproliferative diseases, myelodysplasia / myeloproliferative diseases, myelodysplastic syndromes, immunodeficiency-associated lymphoproliferative disorders, histiocytic and dendritic cell tumors, hypercytosis, chondrosarcoma, Ewing's sarcoma, fibrosarcoma, malignant giant cell tumor, myeloma bone disease, osteosarcoma, breast cancer (hormone-dependent, hormone-non-hormone-dependent), gynecological cancer (child's cervix, endometrium, fallopian tube, gestational trophoblastic disease, ovary, peritoneum, uterus, vagina and vulva), basal cell carcinoma (BCC), squamous cell carcinoma (SCC), malignant melanoma, cutaneous protuberant fibrosarcoma, Merkel cell carcinoma, Kaposi's sarcoma, astrocytoma, hair cell astrocytoma,Embryonic capillary-growing neuroepithelial neoplasm, oligodendroglioma, ependymoma, glioblastoma multiforme, mixed glioma, oligodendrocyte astrocytoma, medulloblastoma, retinoblastoma, neuroblastoma, embryonal tissue tumor, teratoma, malignant mesothelioma (peritoneal mesothelioma, pericardial mesothelioma, pleural mesothelioma), gastric-intestinal-pancreatic or gastrointestinal pancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor, pancreatic endocrine tumor (PET), colorectal adenocarcinoma, rectal cancer with nodule, invasive neuroendocrine tumor, leiomyosarcoma, mucinous adenocarcinoma, signet ring cell adenocarcinoma, hepatocellular carcinoma, hepatobiliary liver cancer, hepatic blastoma, hemangioma, hepatic adenoma, focal nodular hyperplasia (regenerative nodular hyperplasia, hamartoma), non-small cell lung cancer (NSCLC) (squamous cell lung cancer, adenocarcinoma, large cell lung cancer), cancer of, Petition 870250105621, dated 11 / 18 / 2025, page 19 / 71 12 / 58 small cell lung cancer, thyroid cancer, prostate cancer (hormone-refractory, non-androgen-dependent, androgen-dependent, hormone-insensitive), renal cell carcinoma and soft tissue sarcoma (fibrosarcoma, malignant fibrous histiocytoma, cutaneous fibrosarcoma, liposarcoma, rhabdomyosarcoma, leiomyosarcoma, angiosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumor / neurofibrosarcoma, extraosseous osteosarcoma).

[00016] The term CD19 or “Cluster of Differentiation 19” (also known as B4, Leu-12 T-cell surface antigen, and CVID3) refers to a B cell lineage surface biomarker or transmembrane protein that, in humans, is encoded by the CD19 gene. CD19 can function as a co-receptor for the B cell antigen receptor (BCR) complex on B lymphocytes, which lowers the threshold for activation of downstream signaling pathways and for triggering B cell responses to antigens. Structurally, a CD19 amino acid sequence has at least approximately 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence, for example, of Gene Bank accession number NM_001178098.2 ^NP_001171569.1 or NM_001770.6 ^ NP_001761.3 in a sequence length of at least 50, 100, 150, 200, 250, 300, 350, 400, 450, 500 amino acids or more throughout the length of the polypeptide.Structurally, a CD19 nucleic acid sequence has at least approximately 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the nucleic acid sequence, for example, from Gene Bank accession number NG_007275.1 or NCBI Gene ID 930, in a sequence length of at least 300, 500, 750, 1000, 1250, 1500 nucleic acids or the entire polynucleotide length. Sequence alignments can be performed using any known alignment algorithm. Petition 870250105621, dated 11 / 18 / 2025, page 20 / 71 13 / 58 technique, for example, BLAST, ALIGN, defined as default settings.

[00017] The term CD38 or Cluster of Differentiation 38 (also known as ADPRC1) refers to a B cell surface biomarker or transmembrane protein that, in humans, is encoded by the CD38 gene. CD38 may act in B cell signaling leading to cell activation and proliferation. Structurally, a CD38 amino acid sequence exhibits at least approximately 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence, for example, of the Gene Bank accession number NM_001775.4 ^ NP_001766.2, in a sequence length of at least 50, 100, 150, 200, 250 amino acids or the entire length of the polypeptide. There is a second CD38 isoform with a premature stop codon that can be expressed at low levels in some cells.Structurally, a CD19 nucleic acid sequence has at least approximately 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the nucleic acid sequence, for example, of Gene Bank accession number NC_000004.12 or NCBI Gene ID 952, in a sequence length of at least 300, 500, 750 nucleic acids or in the entire polynucleotide length. Sequence alignments can be performed using any alignment algorithm known in the art, for example, BLAST, ALIGN, defined with the default settings.

[00018] The term CD20” or Cluster of Differentiation 20” (also known as B lymphocyte surface antigen B1) refers to a B cell lineage surface biomarker or transmembrane protein that, in humans, is encoded by the CD20 gene. Structurally, a CD20 amino acid sequence has at least approximately 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of, for example, the Uniprot entry. Petition 870250105621, dated 11 / 18 / 2025, page 21 / 71 14 / 58 P11836, in a sequence length of at least 50, 100, 150, 200, 250 amino acids or the entire length of the polypeptide.

[00019] As described in this document, with reference to binding molecules, such as antibodies and bispecific antibodies, binding refers to the specific interaction of a target antigen with one or more amino acid residues of a variable region of the complementarity-determining region. Such specific binding will generally result in a dissociation constant less than about 1x10-6M, and such affinity can be determined by a skilled technician using techniques known in the art, such as surface plasmon resonance.

[00020] The term antibody in this document is used in the broadest sense and includes multivalent or bispecific antibodies and monoclonal antibodies, including intact antibodies and functional antibody fragments (antigen-binding) thereof, including antigen-binding fragments (Fab), F(ab')2 fragments, Fab' fragments, Fv fragments, recombinant IgG (rIgG) fragments, single-chain antibody fragments, including variable single-chain fragments (sFv or scFv) and single-domain antibody fragments (e.g., sdAb, sdFv, nanobodies). The term encompasses forms of genetically engineered and / or otherwise modified immunoglobulins, such as intracorporeal, pepticorpial, chimeric antibodies, fully human antibodies, humanized antibodies and heteroconjugated, multispecific antibodies, for example, bispecific antibodies, diacorporeal, triacorporeal and tetracorporeal, tandem di-scFv, tandem tri-scFv.Unless otherwise indicated, the term antibody should be understood to encompass functional fragments of antibodies. The term also encompasses intact or full-length antibodies, including antibodies of any class or subclass, including IgG and its subclasses, IgM, IgE, IgA, and IgD. The antibody may... Petition 870250105621, dated 11 / 18 / 2025, p. 22 / 71 15 / 58 comprise a constant region of human IgG1. The antibody may comprise a constant region of human IgG4.

[00021] Among the antibodies provided are multispecific or multivalent antibodies (e.g., bispecific antibodies and polyreactive antibodies) and fragments thereof. Antibodies include antibody conjugates and molecules comprising antibodies, such as chimeric molecules. Thus, an antibody includes, but is not limited to, full-length and native antibodies, as well as fragments and portions thereof that retain their binding specificities, such as any specific binding portion thereof, including those possessing any number of immunoglobulin classes and / or isotypes (e.g., IgG1, IgG2, IgG3, IgG4, IgM, IgA, IgD, IgE, and IgM); and biologically relevant (antigen-binding) fragments or specific binding portions thereof, including, but not limited to, Fab, F(ab')2, Fv, and scFv (single chain or related entity).A monoclonal antibody is generally one within a composition of substantially homogeneous antibodies; thus, any individual antibodies comprised in the monoclonal antibody composition are identical except for possible naturally occurring mutations that may be present in small quantities. A monoclonal antibody may comprise a constant region of human IgG1 or a constant region of human IgG4.

[00022] The terms “complementarity-determining region” and “CDR” include the amino acid positions / residues (contiguous or non-contiguous) that confer antigenic specificity and / or binding affinity. In general, there are three CDRs in each variable region of the heavy chain (CDR-H1, CDR-H2, CDR-H3) and three CDRs in each variable region of the light chain (CDRL1, CDR-L2, CDR-L3). “Structural regions” and “FR” are known in the art to refer to the non-CDR portions of the regions. Petition 870250105621, dated 11 / 18 / 2025, p. 23 / 71 16 / 58 variables of the heavy and light chains. In general, there are four FRs in each variable region of the full-length heavy chain (FRH1, FR-H2, FR-H3, and FR-H4) and four FRs in each variable region of the full-length light chain (FR-L1, FR-L2, FR-L3, and FRL4). The precise amino acid sequence boundaries of a given CDR or FR can be easily determined using any of several well-known schemes, including those described by Kabat et al. (1991), “Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (numbering scheme “Kabat”), Al-Lazikani et al., (1997) JMB 273,927-948 (numbering scheme “Chothia”); MacCallum et al., J. Mol. Biol. 262:732-745 (1996), “Antibody Interactions: Contact Analysis and Topography of Binding Sites,” J. Mol Biol. (numbering scheme “Contact”); Lefranc MP et al., “Unique IMGT numbering scheme for immunoglobulin receptor variable domains and T and similar domains of the Ig superfamily,” Dev Comp Immunol, 2003 Jan;27(1):55-77 (numbering scheme “IMGT”); Honegger A and Plückthun A, “Another numbering scheme for immunoglobulin variable domains: an automated modeling and analysis tool,” J Mol Biol, 2001 June 8;309(3):657-70, (numbering scheme “Aho”); and Whitelegg NR and Rees AR, “WAM: an improved algorithm for modeling antibodies on the WEB,” Protein Eng. 2000 Dec;13(12):819-24 (Numbering scheme “AbM”). In certain embodiments, the CDRs of the antibodies described in this document may be defined by a method selected from Kabat, Chothia, IMGT, Aho, AbM, or combinations thereof.

[00023] The limits of a given CDR or FR may vary depending on the scheme used for identification. For example, the Kabat scheme is based on structural alignments, while the Chothia scheme is based on structural information. The numbering for the Kabat and Chothia schemes is based on the most common sequence lengths of the antibody region, Petition 870250105621, dated 11 / 18 / 2025, page 24 / 71 17 / 58 with insertions accommodated by insertion letters, for example, 30a, and exclusions appearing in some antibodies. The two schemes place certain insertions and exclusions (indels) in different positions, resulting in differential numbering. The Contact scheme is based on the analysis of complex crystal structures and is similar in many respects to the Chothia numbering scheme.

[00024] The term variable region or variable domain refers to the domain of an antibody heavy or light chain that is involved in antibody binding to the antigen. The variable domains of the heavy chain and light chain (VH and VL, respectively) of a native antibody generally have similar structures, with each domain comprising four conserved structural regions (FRs) and three CDRs (See, for example, Kindt et al. Kuby Immunology, 6th ed., W.H. Freeman and Co., page 91 (2007)). A single Vh or Vl domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind to a specific antigen can be isolated using a Vh or Vl domain from an antigen-binding antibody to screen a library of complementary Vl or Vh domains, respectively (See, for example, Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991)).

[00025] The term constant region can refer to a constant region of the light chain or the heavy chain. Light chain constant regions have two main isotypes: kappa and lambda (sometimes abbreviated as CK or CL, respectively). Heavy chain constant regions can comprise any of the 5 isotypes: IgA, IgD, IgG, IgE, or IgM. The IgG isotype is additionally comprised of subclasses IgG1, IgG2, IgG3, and IgG4. Heavy chain constant regions comprise a CH1, hinge, CH2, and / or CH3 domain. Residues of light and heavy chain constant regions can be numbered from Petition 870250105621, dated 11 / 18 / 2025, page 25 / 71 18 / 58 according to the EU numbering scheme (Edelman, GM et al., Proc. Natl. Acad. USA, 63, 78-85 (1969) .) or the Kabat numbering scheme (Kabat, EA et al., Sequences of proteins of immunological interest. 5th Edition - U.S. Department of Health and Human Services, NIH Publication No. 913242, pp. 662, 680, 689 (1991)). An “Fc Region,” as described in this document, generally refers to the CH2 and CH3 domains of the constant region of the heavy chain.

[00026] Among the antibodies supplied are antibody fragments. An “antibody fragment” may refer to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds to the antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv or sFv); and multispecific antibodies formed from antibody fragments. In particular embodiments, antibodies are single-chain antibody fragments comprising a variable region of the heavy chain and / or a variable region of the light chain, such as scFvs. Antibody fragments may be produced by various techniques, including, but not limited to, proteolytic digestion of an intact antibody, as well as production by recombinant host cells.In some embodiments, the antibodies are recombinantly produced fragments, such as fragments comprising arrangements that do not occur naturally, such as those with two or more antibody regions or chains joined by synthetic linkers, for example, polypeptide linkers, and / or those that are not produced by enzymatic digestion of an intact naturally occurring antibody.

[00027] In this document, a molecule, a peptide, a polypeptide, an antibody, or an antibody fragment may be Petition 870250105621, dated 11 / 18 / 2025, page 26 / 71 19 / 58 termed bispecific or dual-specific”, including grammatical equivalents. A bispecific molecule has the ability to bind specifically to at least two structurally distinct targets. The specific binding may be the result of two distinct binding moieties that are structurally distinct at the molecular level, including, but not limited to, distinct non-identical amino acid sequences; or a single binding moiety that is capable of specifically binding to two structurally distinct targets with high affinity (e.g., with a KD less than about 1x10-6). A molecule, peptide, polypeptide, antibody, or antibody fragment termed multispecific refers to a molecule that has the ability to bind specifically to at least two or more structurally distinct targets.A bispecific antibody, including grammatical equivalents, refers to a bispecific molecule that preserves at least one fragment of an antibody capable of specifically binding to a target, for example, a variable region, heavy or light chain, or one or more complementarity-determining regions of an antibody molecule. A multispecific antibody, including grammatical equivalents, refers to a multispecific molecule that preserves at least one fragment of an antibody capable of specifically binding to a target, for example, a variable region, heavy or light chain, or a complementarity-determining region of an antibody molecule.

[00028] A “linker” in this document is also referred to as a “linker sequence”, “spacer”, “tie sequence”, or grammatical equivalents thereof. A “linker”, as mentioned in this document, connects two distinct molecules that, by themselves, possess target binding, catalytic activity, or are naturally expressed and assembled as separate polypeptides. For example, two distinct linking moieties or a Petition 870250105621, dated 11 / 18 / 2025, p. 27 / 71 20 / 58 heavy chain / light chain pair. Several strategies can be used to covalently link molecules. These include, but are not limited to, polypeptide linkages between the N- and C-terminus of proteins or protein domains, linkage via disulfide bonds, and linkage via chemical crosslinking reagents. In one embodiment of this embodiment, the linker is a peptide bond, generated by recombinant techniques or peptide synthesis. The linker peptide may predominantly include the following amino acid residues: Gly, Ser, Ala, or Thr. The linker peptide must have a length that is suitable for linking two molecules in such a way that they assume the correct conformation relative to each other, so that they retain the desired activity. In one embodiment, the linker is 1 to 50 amino acids long or 1 to 30 amino acids long. In another embodiment, linkers of 1 to 20 amino acids in length may be used.Useful ligands include glycine-serine polymers, including, for example, (GS)n, (GSGGS)n, (GGGGS)ne (GGGS)n, where n is an integer of at least one, glycine-alanine polymers, alanine-serine polymers, and other flexible ligands. For example, ligands for binding antibody fragments or variable single-chain fragments may include AAEPKSS, AAEPKSSDKTHTCPPCP (SEQ ID NO: 19), GGGG (SEQ ID NO: 20), or GGGGDKTHTCPPCP (SEQ ID NO: 21). Alternatively, a variety of non-protein polymers, including but not limited to polyethylene glycol (PEG), polypropylene glycol, polyoxyalkylenes, or copolymers of polyethylene glycol and polypropylene glycol, may be used as ligands.

[00029] Bispecific antibodies “based on fragments” or bispecific antibodies comprising a “single-chain variable fragment” or “scFv” of this disclosure may refer to a single-chain antibody, or fragment thereof, comprising two binding moieties and a linker connecting the two binding moieties. The linker may be a polypeptide linker or other Petition 870250105621, dated 11 / 18 / 2025, page 28 / 71 21 / 58 ligand with adequate flexibility so as not to inhibit the binding of any of the targeting fractions. Bispecific fragment-based antibody formats include tandem Vhh antibodies, tandem scFvs, scFv-Fabs, F(ab)2, and dual-affinity targeting antibodies (DARTs). Such fragment-based antibodies can be further manipulated to comprise additional binding fractions with specificity for a given target, for example, A2:Bi, Ai:B2, or A2:B2, or with fragments of an Fc region to improve pharmacokinetics or promote ADCC, ADCP, or CDC.

[00030] A “binding fraction” refers to a portion of a molecule, a peptide, a polypeptide, an antibody, or an antibody fragment that mediates specific binding to a specific target, antigen, or epitope. As an example, the binding fraction of an antibody may comprise a pair of variable regions of the heavy chain / light chain or one or more complementarity-determining regions (CDRs).

[00031] A “target,” as referred to in this document, refers to the portion of a molecule that participates with a binding moiety of a molecule, a peptide, a polypeptide, an antibody, or an antibody fragment. A target may comprise an amino acid sequence and / or a carbohydrate, lipid, or other chemical entity. An “antigen” is a target comprising a portion that is capable of being bound by an adaptive immune molecule, such as an antibody or antibody fragment, B cell receptor, or T cell receptor.

[00032] In some embodiments, the bispecific antibodies provided in this document have a dissociation constant (Kd) of approximately 10 pM, 1 pM, 100 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 5 nM, 2 nM, 1 nM, 0.5 nM, 0.1 nM, 0.05 nM, 0.01 nM or 0.001 nM or less (e.g., 10⁻⁸ M or less, e.g., from 10⁻⁸ M to 10⁻¹³ M, e.g., from 10⁻⁹ M to 10⁻¹³ M) for the antibody target. The antibody target may be a CD19 target, a CD38 target, or a CD38 target. Petition 870250105621, dated 11 / 18 / 2025, p. 29 / 71 22 / 58 target or a target comprising CD19 and CD38. Kd can be measured by any suitable assay. In certain embodiments, Kd can be measured using surface plasmon resonance assays (e.g., using a BIACORE®-2000 or a BIACORE®3000 or Octet).

[00033] A humanized antibody is an antibody in which all or substantially all amino acid residues of the CDR are derived from non-human CDRs and all or substantially all amino acid residues of the FR are derived from human FRs. A humanized antibody may optionally include at least a portion of a constant region of the antibody derived from a human antibody. A humanized form of a non-human antibody refers to a variant of the non-human antibody that has undergone humanization, typically to reduce immunogenicity to humans while maintaining the specificity and affinity of the precursor non-human antibody. In some embodiments, some FR residues in a humanized antibody are replaced with corresponding residues from a non-human antibody (e.g., the antibody from which the CDR residues are derived), for example, to restore or improve the antibody's specificity or affinity.

[00034] Among the antibodies supplied are human antibodies. A human antibody is an antibody with an amino acid sequence corresponding to that of an antibody produced by a human being or a human cell, or a non-human source that utilizes human antibody repertoires or other human antibody-coding sequences, including human antibody libraries. The term excludes humanized forms of non-human antibodies that comprise non-human antigen-binding regions, such as those in which all or substantially all CDRs are non-human. Human antibodies can be prepared by administering an immunogen to a transgenic animal that has been modified to produce Petition 870250105621, dated 11 / 18 / 2025, page 30 / 71 23 / 58 intact human antibodies or intact antibodies with variable human regions in response to an antigenic challenge. Such animals typically contain all or part of the human immunoglobulin loci, which replace endogenous immunoglobulin loci, or which are present extrachromosomally or randomly integrated into the animal's chromosomes. In such transgenic animals, the endogenous immunoglobulin loci have usually been inactivated. Human antibodies can also be derived from human antibody libraries, including phage display and cell-free libraries, containing antibody-coding sequences derived from a human repertoire.

[00035] ADCC or antibody-dependent cell-mediated cytotoxicity, as used in this document, refers to the cell-mediated reaction in which nonspecific cytotoxic cells expressing FcyRs recognize antibodies bound to a target cell and subsequently cause lysis of the target cell. ADCC can be correlated with FcyRIIIa binding, where increased FcyRIIIa binding leads to increased ADCC activity. ADCP or antibody-dependent cell-mediated phagocytosis, as used in this document, can refer to the cell-mediated reaction in which nonspecific cytotoxic cells expressing FcyRs recognize antibodies bound to a target cell and subsequently cause phagocytosis of the target cell.

[00036] The terms “polypeptide” and “protein” are used interchangeably and refer to a polymer of amino acid residues, not limited to a minimum length. Polypeptides, including antibodies and supplied antibody chains and other peptides, for example, ligands and binding peptides, may include amino acid residues, including natural and / or non-natural amino acid residues. The terms also include post-expression modifications of Petition 870250105621, dated 11 / 18 / 2025, page 31 / 71 24 / 58 polypeptide, for example, glycosylation, sialylation, acetylation, phosphorylation, and the like. In some respects, polypeptides may contain modifications relative to a native or natural sequence, provided that the protein maintains the desired activity. These modifications may be deliberate, such as through site-directed mutagenesis, or accidental, such as through mutations in the hosts that produce the proteins or errors due to PCR amplification.

[00037] The percentage (%) of sequence identity with respect to a reference polypeptide sequence is the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues in the reference polypeptide sequence, after sequence alignment and the introduction of gaps, if necessary, to achieve the maximum percentage of sequence identity, without considering any conservative substitutions as part of the sequence identity. Alignment for the purpose of determining the percentage of amino acid sequence identity can be achieved in several known ways, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Appropriate parameters for sequence alignment can be determined, including algorithms needed to achieve maximum alignment across the entire length of the sequences being compared.For the purposes of this document, however, the amino acid sequence identity percentage values ​​are generated using the ALIGN-2 sequence comparison computer program. The ALIGN-2 sequence comparison computer program was created by Genentech, Inc., and the source code was filed with the user documentation at the U.S. Copyright Office, Washington DC, 20559, where it is registered under U.S. copyright registration number TXU510087. The ALIGN-2 program is... Petition 870250105621, dated 11 / 18 / 2025, page 32 / 71 25 / 58 is publicly available from Genentech, Inc., South San Francisco, California, or can be compiled from source code. The ALIGN-2 program must be compiled for use on a UNIX operating system, including Digital UNIX V4.0D. All sequence comparison parameters are defined by the ALIGN-2 program and do not vary.In situations where ALIGN-2 is used for amino acid sequence comparisons, the % amino acid sequence identity of a given amino acid sequence A with, including, or against a given amino acid sequence B (which may alternatively be expressed as a given amino acid sequence A that has or includes a given % amino acid sequence identity with or against a given amino acid sequence B) is calculated as follows: 100 times the fraction X / Y, where X is the number of amino acid residues classified as identical matches by the ALIGN-2 sequence alignment program in the alignment of A and B performed by that program, and where Y is the total number of amino acid residues in B.It should be noted that when the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity from A to B will not be equal to the % amino acid sequence identity from B to A. Unless specifically indicated otherwise, all % amino acid sequence identity values ​​used in this document are obtained as described in the immediately preceding paragraph, using the ALIGN-2 computer program.

[00038] Amino acid sequence variants of the antibodies provided in this document may be contemplated and designed. A variant typically differs from a polypeptide specifically disclosed in this document in one or more substitutions, deletions, additions, and / or insertions. Such variants may occur naturally or may be generated synthetically. Petition 870250105621, dated 11 / 18 / 2025, page 33 / 71 26 / 58 For example, by modifying one or more of the polypeptide sequences of the invention above and evaluating one or more of the polypeptide's biological activities as described in this document and / or using any of several known techniques. For example, it may be desirable to improve the binding affinity and / or other biological properties of antibody amino acid sequence variants, which can be prepared by introducing appropriate modifications to the nucleotide sequence encoding the antibody or by peptide synthesis. Such modifications include, for example, deletions and / or insertions and / or substitutions of residues within the antibody amino acid sequences. Any combination of deletion, insertion, and substitution can be made to arrive at the final construct, provided that the final construct possesses the desired characteristics, for example, antigen binding. Antibody variants having one or more amino acid substitutions can be provided.Sites of interest for substitution mutagenesis include CDRs and FRs. Amino acid substitutions can be introduced into an antibody of interest, and the products can be screened for a desired activity, for example, retained / enhanced antigen binding, decreased immunogenicity, or enhanced ADCC or CDC.

[00039] This disclosure also provides immunoconjugates or “antibody conjugates” or “antibody-drug conjugates” which refer to an antibody conjugated to one or more heterologous molecules. For example, an immunoconjugate may comprise an antibody conjugated to one or more cytotoxic agents, such as chemotherapeutic agents or drugs, growth-inhibiting agents, protein domains, toxins (e.g., protein toxins, enzymatically active toxins of bacterial, fungal, plant or animal origin, or fragments thereof) or radioactive isotopes. In some embodiments, a Petition 870250105621, dated 11 / 18 / 2025, pp. 34 / 71 27 / 58 Immunoconjugate may comprise the compound linker molecule disclosed in this document, or a fragment thereof (e.g., an scFv).

[00040] The antibodies described in this document may be encoded by a nucleic acid. A nucleic acid is a type of polynucleotide comprising two or more nucleotide bases. In certain embodiments, the nucleic acid is a component of a vector that can be used to transfer the polypeptide encoding the polynucleotide into a cell. As used in this document, the term vector refers to a nucleic acid molecule capable of carrying another nucleic acid to which it has been attached. One type of vector is an integrated genomic vector, or integrated vector, which can integrate into the chromosomal DNA of the host cell. Another type of vector is an episomal vector, for example, a nucleic acid capable of extrachromosomal replication. Vectors capable of directing the expression of genes to which they are operatively linked are referred to in this document as expression vectors.Suitable vectors include plasmids, bacterial artificial chromosomes, yeast artificial chromosomes, viral vectors, and the like. In expression vectors, regulatory elements, such as promoters, enhancers, and polyadenylation signals for use in transcriptional control, may be derived from mammalian, microbial, viral, or insect genes. The ability to replicate in a host, usually conferred by an origin of replication, and a selection gene to facilitate the recognition of transformants may be additionally incorporated. Vectors derived from viruses, such as lentiviruses, retroviruses, adenoviruses, adeno-associated viruses, and the like, may be employed. Plasmid vectors may be linearized for integration into a chromosomal locus. Vectors may comprise sequences that direct site-specific integration to a defined location or a restricted set. Petition 870250105621, dated 11 / 18 / 2025, page 35 / 71 28 / 58 of sites in the genome (e.g., AttP-AttB recombination). Additionally, vectors may comprise sequences derived from transposable elements.

[00041] As used in this document, the terms homologous, homology, or percent homology, when used in this document to describe an amino acid sequence or a nucleic acid sequence relative to a reference sequence, can be determined using the formula described by Karlin and Altschul (Proc. Natl. Acad. Sci. USA 87: 1564-2268, 1990, modified as in Proc. Natl. Acad. Sci. USA 90: 5873-5877, 1993). This formula is incorporated into the programs of the Basic Local Alignment Search Tool (BLAST) by Altschul et al. (J. Mol. Biol. 215: 403-410, 1990). The percent homology of sequences can be determined using the most recent version of BLAST at the date of filing of this application.

[00042] The nucleic acids encoding the antibodies described in this document can be used to infect, transfect, transform a cell, or otherwise make a suitable transgenic cell for the nucleic acid, thus enabling the production of antibodies for commercial or therapeutic uses. Standard cell lines and methods for producing antibodies from a large-scale cell culture are known in the art. See, for example, Li et al., Cell culture processes for monoclonal antibody production. Mabs. Sep-Oct 2010; 2(5): 466-477. In certain embodiments, the cell is a eukaryotic cell. In certain embodiments, the eukaryotic cell is a mammalian cell. In certain embodiments, the mammalian cell is a cell line useful for antibody production, such as a Chinese hamster ovary (CHO) cell, a murine myeloma NS0 cell, or a PER.C6® cell.In certain embodiments, the nucleic acid that encodes the antibody is integrated into a genomic locus of a... Petition 870250105621, dated 11 / 18 / 2025, pp. 36 / 71 29 / 58 useful cell for antibody production. In certain embodiments, a method for preparing an antibody is described in this document comprising culturing a cell comprising a nucleic acid encoding an antibody under in vitro conditions sufficient to permit the production and secretion of said antibody.

[00043] As used in this document, the term being, patient, or individual refers to individuals diagnosed with, suspected of having, or at risk of developing at least one disease for which the compositions and method described are useful for treatment. In certain embodiments, the individual is a mammal. In certain embodiments, the mammal is a mouse, rat, rabbit, dog, cat, horse, cow, sheep, pig, goat, llama, alpaca, or yak. ​​In certain embodiments, the individual is a human being.

[00044] As used in this document, the term about used to modify a specific number refers to that number plus or minus 10% of that number. The term about that modifies a range refers to that range minus 10% of its smallest value and plus 10% of its largest value.

[00045] As used in this document, the terms treatment or treating are used in reference to a pharmaceutical regimen or other intervention regimen used to achieve beneficial or desired results in the recipient. Beneficial or desired results include, but are not limited to, a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit may refer to the eradication or improvement of symptoms or of an underlying disorder being treated. Furthermore, a therapeutic benefit may be achieved by eradicating or improving one or more physiological symptoms associated with the underlying disorder, such that an improvement is observed in the individual, even though the individual may still be affected by the underlying disorder. A prophylactic effect includes Petition 870250105621, dated 11 / 18 / 2025, pp. 37 / 71 30 / 58 To delay, prevent, or eliminate the onset of a disease or condition, to delay or eliminate the onset of symptoms of a disease or condition, to delay, interrupt, or reverse the progression of a disease or condition, or any combination thereof. For prophylactic benefit, an individual at risk of developing a specific disease, or an individual reporting one or more physiological symptoms of a disease, may undergo treatment even if a diagnosis of that disease has not been made. Qualified technicians will recognize that, given a population of individuals potentially eligible for treatment, not all will respond to treatment or will respond equally to treatment. Such individuals are considered treated.

[00046] The section headings used in this document are for organizational purposes only and should not be interpreted as limiting the subject matter described.

[00047] Methods for preparing an antibody are also described in this document. Such methods comprise incubating a cell or cell line comprising a nucleic acid encoding the antibody in a cell culture medium under conditions sufficient to permit antibody expression and secretion, and subsequently collecting the antibody from the cell culture medium. Collection may further comprise one or more purification steps to remove live cells, cell debris, non-antibody proteins or polypeptides, unwanted salts, buffers, and medium components. In certain embodiments, the additional purification step(s) include centrifugation, ultracentrifugation, purification of protein A, protein G, protein A / G or protein L, and / or ion-exchange chromatography.

[00048] Treating, treatment or treating, as used in this document, refers to, for example, a deliberate intervention in a physiological disease state, resulting in a reduction in the severity of a disease or condition; in the reduction of Petition 870250105621, dated 11 / 18 / 2025, pp. 38 / 71 31 / 58 duration of the course of a condition; in the improvement or elimination of one or more symptoms associated with a disease or condition; or in providing beneficial effects to an individual with a disease or condition. Treatment does not require curing the underlying disease or condition.

[00049] A “therapeutically effective amount,” “effective dose,” “effective quantity,” or “therapeutically effective dosage” of a drug or therapeutic agent is any amount of the drug that, when used alone or in combination with another therapeutic agent, protects an individual against the onset of a disease or promotes disease regression, evidenced by a decrease in the severity of disease symptoms, an increase in the frequency and duration of symptom-free periods, or a prevention of disability or incapacity due to the condition. The ability of a therapeutic agent to promote disease regression can be assessed using a variety of methods known to the qualified professional, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the agent's activity in in vitro assays.

[00050] As used in this document, “pharmaceutically acceptable” with reference to a carrier, “excipient” or “diluent” includes any and all solvents, dispersing media, coatings, antibacterial and antifungal agents, isotonic agents and absorption retardants and the like that are physiologically compatible. In some respects, the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion). Depending on the route of administration, the active compound, i.e., the antibody, may be coated with a material to protect the compound from the action of acids and other natural conditions that may inactivate it. Petition 870250105621, dated 11 / 18 / 2025, pp. 39 / 71 32 / 58

[00051] The bispecific and multispecific antibodies described in this document may include one or more pharmaceutically acceptable salts. A “pharmaceutically acceptable salt” refers to a salt that retains the desired biological activity of the precursor compound and does not confer any undesirable toxicological effects (see, for example, Berge, SM, et al. (1977) J. Pharm. Sci. 66: 1-19). Examples of such salts include acid addition salts and base addition salts. Acid addition salts include those derived from non-toxic inorganic acids, such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous and the like, as well as from non-toxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenylsubstituted alkanoic acids, hydroxyalkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like.Base addition salts include those derived from alkaline earth metals, such as sodium, potassium, magnesium, calcium and the like, as well as from non-toxic organic amines, such as N,N'-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine and the like.

[00052] This document describes, in one aspect, a multispecific antibody comprising: (a) a CD38-binding moiety comprising: (i) a first polypeptide comprising a variable region of the immunoglobulin heavy chain comprising the amino acid sequence presented in SEQ ID NO: 1, and a constant region of the heavy chain wherein the constant region of the heavy chain lacks a C-terminal lysine residue; and (ii) a second polypeptide comprising a variable region of the light chain comprising the amino acid sequence presented in SEQ ID NO: 3; and (b) a CD19-binding moiety comprising: (i) a third polypeptide comprising a variable region of the immunoglobulin heavy chain comprising the amino acid sequence Petition 870250105621, dated 11 / 18 / 2025, pp. 40 / 71 33 / 58 presented in SEQ ID NO: 2, and a constant region of the heavy chain wherein the constant region of the heavy chain does not have a C-terminal lysine residue; and (ii) a fourth polypeptide comprising a variable region of the light chain comprising the amino acid sequence presented in SEQ ID NO: 3. In certain embodiments, the constant region of the heavy chain of the first polypeptide, the third polypeptide, or both the first and third polypeptides, comprises a constant region of human IgG1 or human IgG4. In certain embodiments, the polypeptide comprising a variable region of the light chain additionally comprises a constant region of the light chain. In certain embodiments, the second polypeptide, the fourth polypeptide, or both the second and fourth polypeptides, comprise the amino acid sequence presented in SEQ ID NO: 6.In certain embodiments, the CD38-binding moiety comprises one or more amino acid substitutions that inhibit(s) the homodimerization of the CD38-binding moiety. In certain embodiments, the CD38-binding moiety comprises a T366W substitution, according to EU numbering, or a T366S / L368A / Y407V substitution, according to EU numbering. In certain embodiments, the CD19-binding moiety comprises one or more amino acid substitutions that inhibit(s) the homodimerization of the CD19-binding moiety. In certain embodiments, the CD19-binding moiety comprises a T366W substitution, according to EU numbering, or a T366S / L368A / Y407V substitution, according to EU numbering. In certain embodiments, the first polypeptide consists of the amino acid sequence shown in SEQ ID NO: 4. In certain embodiments, the third polypeptide consists of the amino acid sequence shown in SEQ ID NO: 5.In certain embodiments, a pharmaceutical composition comprises the multispecific antibody, an excipient, diluent, or carrier. Petition 870250105621, dated 11 / 18 / 2025, pp. 41 / 71 34 / 58 pharmaceutically acceptable. In certain embodiments, a nucleic acid encodes the multispecific antibody.

[00053] Bispecific antibodies, according to this disclosure, comprise intact antibody molecules or substantially fully intact antibody molecules and may be asymmetric or symmetric.

[00054] Asymmetric bispecific antibodies generally comprise a heavy chain / light chain (HC / LC) pair from an antibody specific for target A and an HC / LC pair from an antibody specific for target B, creating a heterobifunctional antibody. Heterobifunctional antibodies such as these face the problem of unproductive molecule formation during their production. HC / LC-A:HC / LC-B is desirable, but is generally thermodynamically or statistically unfavorable among all possible combinations. Several schemes have been introduced to circumvent this problem. In some cases, the HC / LC pair of an antibody specific for A and the HC / LC pair of an antibody specific for B additionally comprise mutations in the FC region to increase the probability of forming an antibody with HC / LC-A:HC / LC-B.This can be achieved through genetic engineering of structural features, such as knobs in the FC region for HC-A and holes in HC-B, or vice versa, which promote the formation of heterodimers between HC-A and HC-B. Another scheme to promote HCA:HC-B heterodimers is to genetically engineer amino acid residues in the FC portion of HC-A and HC-B to understand charge pairs that favor electrostatic interactions between HC-B and HC-A. Another scheme to address the chain association problem is to replace the variable regions of one of the HC / LC pairs with single-chain linking molecules (e.g., Vhh or scFv). So that half of the molecule comprises a classic HC / LC pair and the other half comprises a constant region of HC fused or otherwise connected to the linking molecule. Petition 870250105621, dated 11 / 18 / 2025, pp. 42 / 71 35 / 58 single chain. Other modifications can be made to promote proper HC / LC pairing and include genetically engineered mutations in HC and LC to A or B to favor the formation of the proper HC / LC pair; CrossMab technology, which involves exchanging the corresponding constant regions of the HC / LC pair. Symmetric bispecific antibodies circumvent the chain association problem by not depending on the formation of a heterobifunctional molecule. Examples include: the double variable domain molecule, which comprises stacked variable regions of different specificity; the IgG-scFv molecule, which comprises an scFv of different specificity fused to the c-terminus of the heavy chain of a classical antibody molecule; the (scFV)4FC, which comprises two scFvs connected by an Fc region of an Ig (the Fcs dimerize, creating a bispecific and tetravalent molecule); the DART-Fc and the two-in-one, among others.

[00055] The structure of multispecific antibodies or bispecific antibodies can be engineered and engineered to alter the functionality or binding properties of compound binding molecules or bispecific antibodies (see, for example, “Bispecific antibodies: a pipeline mechanics review.” Nat Rev Drug Discovery. August 2019;18(8):585-608) (see, for example, “The making of bispecific antibodies” MAbs. Feb-Mar 2017; 9(2):112-212). For example, the bispecific antibody can be selected from one of the following formats: a common light chain bispecific IgG, a Fab-Fc:scFv-Fc bispecific IgG, a Fab-Fc-Fab:Fc bispecific IgG, a Fab-Fc-scFv:Fab-Fc-scFv bispecific IgG, a Fab-Fc-scFv:Fc bispecific IgG, a Fab-FcFab:Fab-Fc bispecific IgG, a scFv-Fab-Fc:scFv-Fab-Fc bispecific IgG, a Fab-Fab-Fc:Fab-Fab-Fc bispecific IgG, a Fab-Fc-Fab:Fab-Fc-Fab bispecific IgG, and a Fab-Fc-scFv:FabFc bispecific IgG. Petition 870250105621, dated 11 / 18 / 2025, pp. 43 / 71 36 / 58

[00056] Example “knob into hole” mutations for use with the antibodies described in this document may comprise T366W (EU numbering) in one heavy chain and T366S / L368A / Y407V (EU numbering) in a second heavy chain. Example mutations that facilitate the coupling of a first and a second heavy chain molecule are disclosed, for example, in WO2009089004, US 8,642,745, US PG-PUB: US20140322756 and “The making of bispecific antibodies” MAbs. 2017 Feb-Mar; 9(2): 112-212.

[00057] In some embodiments, common bispecific light chain antibodies are provided in this document comprising: (1) an anti-CD38 heavy chain variable region and an anti-CD38 heavy chain constant region, wherein the anti-CD38 heavy chain variable region comprises: (i) a heavy chain complementarity-determining region 1 (HCDR1) comprising an amino acid sequence presented in SEQ ID NO: 7, (ii) a heavy chain complementarity-determining region 2 (HCDR2) comprising an amino acid sequence presented in SEQ ID NO: 8, (iii) a heavy chain complementarity-determining region 3 (HCDR3) comprising an amino acid sequence presented in SEQ ID NO: 9, and (iv) a Kabat numbering Q1E heavy chain variable region mutation, (2) an anti-CD19 heavy chain variable region and an anti-CD19 heavy chain constant region,wherein the variable region of the human anti-CD19 heavy chain comprises: (i) a heavy chain complementarity-determining region 1 (HCDR1) comprising an amino acid sequence presented in SEQ ID NO: 10, (ii) a heavy chain complementarity-determining region 2 (HCDR2) comprising an amino acid sequence presented in SEQ ID NO: 11, (iii) a heavy chain complementarity-determining region 3 (HCDR3) comprising an amino acid sequence presented in SEQ ID NO: 12, and (iv) a, Petition 870250105621, dated 11 / 18 / 2025, pp. 44 / 71 37 / 58 mutation of the Q1E heavy chain variable region by Kabat numbering, (3) a common light chain variable region comprising: (i) a complementarity-determining region of light chain 1 (LCDR1) comprising an amino acid sequence presented in SEQ ID NO: 13, (ii) a complementarity-determining region of light chain 2 (LCDR2) comprising an amino acid sequence presented in SEQ ID NO: 14 (AAS), and (iii) a complementarity-determining region of light chain 3 (LCDR3) comprising an amino acid sequence presented in SEQ ID NO: 15, wherein: the anti-CD38 heavy chain constant region and the anti-CD19 heavy chain constant region lack a C-terminal lysine residue (e.g., K478 by Kabat numbering); and the common light chain bispecific antibody comprises an experimental isoelectric point (pI) less than about 9.In certain cases, the variable region of the anti-CD38 heavy chain may comprise a complementarity-determining region of heavy chain 2 (HCDR2) comprising an amino acid sequence presented in SEQ ID NO: 8 or 16-18.

[00058] In certain embodiments, the common light chain bispecific antibody additionally comprises a hydrophobicity retention time (HIC) of less than about 10 minutes. In certain embodiments, the variable region of the anti-CD19 heavy chain comprises a serine at position 84 and / or a leucine at position 108, according to Kabat numbering. In certain embodiments, the variable region of the common light chain comprises a histidine at position 32, according to Kabat numbering. In certain embodiments, the pI is less than 9. In certain embodiments, the pI is between 8 and 9. In certain embodiments, the pI is between 8.5 and 9.0. In certain embodiments, the pI is between 8.7 and 9.0. In certain embodiments, the pI is between 8.8 and 9.0. In certain embodiments, the pI is 8.9. Therapeutic methods Petition 870250105621, dated 11 / 18 / 2025, pp. 45 / 71 38 / 58

[00059] In certain modalities, antibodies useful for the treatment of a cancer or tumor are disclosed in this document. Treatment refers to a method that seeks to improve or alleviate the condition being treated. With respect to cancer, treatment includes, but is not limited to, reducing tumor volume, reducing tumor volume growth, increasing progression-free survival or overall life expectancy. In certain modalities, treatment will effect remission of a cancer being treated. In certain modalities, treatment encompasses use as a prophylactic or maintenance dose intended to prevent recurrence or progression of a previously treated cancer or tumor. It is understood by those skilled in the art that not all individuals will respond equally or not at all to an administered treatment; however, such individuals are considered treated.

[00060] Also described in this document is a method for treating cancer in a person in need thereof, comprising administering to the person a multispecific antibody. In certain embodiments, the cancer or tumor is a solid tissue cancer. In certain embodiments, solid tissue cancer includes breast cancer, prostate cancer, pancreatic cancer, lung cancer, kidney cancer, stomach cancer, esophageal cancer, skin cancer, colorectal cancer, or head and neck cancer. In certain embodiments, breast cancer is triple-negative breast cancer, lung cancer is non-small cell lung cancer, head and neck cancer is squamous cell carcinoma of the head and neck, kidney cancer is renal cell carcinoma, brain cancer is glioblastoma multiforme, or skin cancer is melanoma. In certain embodiments, the cancer or tumor is a blood cancer.In certain forms, blood cancer is diffuse large B-cell lymphoma. In certain forms, blood cancer is myeloma. In certain forms, blood cancer is lymphoma. Petition 870250105621, dated 11 / 18 / 2025, pp. 46 / 71 39 / 58 of Burkitt. In certain modalities, blood cancer is an aggressive B-cell lymphoma. In certain modalities, aggressive B-cell lymphoma comprises double-impact lymphoma (e.g., defined by mutations and / or rearrangements within the MYC gene and the BCL2 gene or the BCL6 gene), double-expressor lymphoma (e.g., defined by co-expression of cMYC and BCL-2), or triple-impact lymphoma (e.g., defined as having morphological, biological, and cytogenetic properties similar to diffuse large B-cell lymphoma and Burkitt lymphoma, but possessing three, instead of two, gene rearrangements: c-MYC, BCL-2, and BCL-6 genes). In certain modalities, blood cancer is relapsed (e.g., the cancer has returned after a period of remission) or refractory (e.g., the cancer has stopped responding to previous treatment with a different therapy / treatment).In certain modalities, CD19-positive, high-expression, immunosuppressive B-cell-associated cancer or tumor is a cancer or tumor comprising infiltrates of CD19-positive, high-expression CD38 B cells. In certain modalities, the immunosuppressive CD19-positive, high-expression CD38 B cells express a B cell activation marker. In certain modalities, the B cell activation marker comprises CD30. In certain modalities, CD19-positive, high-expression CD38 B-cell-associated cancer or tumor expresses PD-L1. In certain modalities, CD19-positive, high-expression CD38 B-cell-associated cancer or tumor is associated with low-CD20 or CD20-negative B cells. In certain modalities, high-expression CD38 B cells express at least approximately 30,000 CD38 proteins on the cell surface. In certain modalities, high-expression CD38 B cells express at least approximately 35.000 CD38 proteins on the cell surface. In certain modalities, B cells with high CD38 expression express at least approximately 40,000 CD38 proteins on their surface. Petition 870250105621, dated 11 / 18 / 2025, pp. 47 / 71 40 / 58 cellular. In certain embodiments, the multispecific antibody comprises: (a) a CD38-binding moiety comprising: (i) a first polypeptide comprising a variable region of the immunoglobulin heavy chain comprising the amino acid sequence presented in SEQ ID NO: 1 and a constant region of the heavy chain wherein the constant region of the heavy chain lacks a C-terminal lysine residue; and (ii) a second polypeptide comprising a variable region of the light chain comprising the amino acid sequence presented in SEQ ID NO: 3; and (b) a CD19-binding moiety comprising: (i) a third polypeptide comprising a variable region of the immunoglobulin heavy chain comprising the amino acid sequence presented in SEQ ID NO: 2 and a constant region of the heavy chain wherein the constant region of the heavy chain lacks a C-terminal lysine residue;and (ii) a fourth polypeptide comprising a variable region of the light chain comprising the amino acid sequence presented in SEQ ID NO: 3.;

[00061] In certain embodiments, the cancer or tumor is a solid cancer or tumor. In certain embodiments, the cancer or tumor is a blood cancer or tumor. In certain embodiments, the cancer or tumor comprises tumors of the breast, heart, lung, small intestine, colon, spleen, kidney, bladder, head, neck, ovary, prostate, brain, pancreas, skin, bone, bone marrow, blood, thymus, uterus, testicle, and liver. In certain embodiments, the tumors that can be treated with the antibodies of the invention comprise adenoma, adenocarcinoma, angiosarcoma, astrocytoma, epithelial carcinoma, germinoma, glioblastoma, glioma, hemangioendothelioma, hemangiosarcoma, hematoma, hepatoblastoma, leukemia, lymphoma, medulloblastoma, melanoma, neuroblastoma, osteosarcoma, retinoblastoma, rhabdomyosarcoma, sarcoma, and / or teratoma. In certain modalities, the tumor / cancer is selected from the acral lentiginous melanoma group, keratosis Petition 870250105621, dated 11 / 18 / 2025, pp. 48 / 71 41 / 58 actinic, adenocarcinoma, adenoid cystic carcinoma, adenomas, adenosarcoma, adenosquamous carcinoma, astrocytic tumors, Bartholin's gland carcinoma, basal cell carcinoma, bronchial gland carcinoma, capillary carcinoid, carcinoma, carcinosarcoma, cholangiocarcinoma, chondrosarcoma, cystadenoma, endodermal sinus tumor, endometrial hyperplasia, endometrial stromal sarcoma, endometrioid adenocarcinoma, ependymal sarcoma, Swing sarcoma, focal nodular hyperplasia, gastronoma, germline tumors, glioblastoma, glucagonoma, hemangioblastoma, hemangioendothelioma, hemangioma, hepatic adenoma, hepatic adenomatosis, hepatocellular carcinoma, insulinitis, intraepithelial neoplasia, squamous cell intraepithelial neoplasia, invasive squamous cell carcinoma, large cell carcinoma, liposarcoma, lung carcinoma, lymphoblastic leukemia, lymphocytic leukemia, leiomyosarcoma, melanoma, malignant melanoma, malignant mesothelial tumornerve sheath tumor, medulloblastoma, medulloepithelioma, mesothelioma, mucoepidermoid carcinoma, myeloid leukemia, neuroblastoma, neuroepithelial adenocarcinoma, nodular melanoma, osteosarcoma, ovarian carcinoma, papillary serous adenocarcinoma, pituitary tumors, plasmacytoma, pseudosarcoma, prostate carcinoma, pulmonary blastoma, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, serous carcinoma, squamous cell carcinoma, small cell carcinoma, soft tissue carcinoma, somatostatin-secreting tumor, squamous cell carcinoma, squamous cell carcinoma, undifferentiated carcinoma, uveal melanoma, verrucous carcinoma, carcinoma of the vagina / vulva, VIPpoma and Wilm's tumor. In certain embodiments, the tumor / cancer to be treated with one or more antibodies of the invention includes brain cancer, head and neck cancer, colorectal carcinoma, acute myeloid leukemia, pre-B cell acute lymphoblastic leukemia, bladder cancer, astrocytoma,preferably grade II, III or IV astrocytoma, Petition 870250105621, dated 11 / 18 / 2025, pp. 49 / 71 42 / 58 glioblastoma, glioblastoma multiforme, small cell lung cancer and non-small cell lung cancer, preferably non-small cell lung cancer, lung adenocarcinoma, metastatic melanoma, androgen-independent metastatic prostate cancer, androgen-dependent metastatic prostate cancer, prostate adenocarcinoma and breast cancer, preferably ductal breast cancer and / or breast carcinoma. In certain embodiments, the cancer treated with the antibodies of this disclosure includes glioblastoma. In certain embodiments, the cancer treated with one or more antibodies of this disclosure includes pancreatic cancer. In certain embodiments, the cancer treated with one or more antibodies of this disclosure includes ovarian cancer. In certain embodiments, the cancer treated with one or more antibodies of this disclosure includes lung cancer. In certain embodiments, the cancer treated with one or more antibodies of this disclosure includes prostate cancer.In certain modalities, the cancer treated with one or more antibodies from this disclosure includes colon cancer. In certain modalities, the cancer treated includes glioblastoma, pancreatic cancer, ovarian cancer, colon cancer, prostate cancer, or lung cancer. In a particular modality, the cancer is refractory to other treatments. In a particular modality, the cancer treated is recurrent.

[00062] In certain embodiments, antibodies may be administered to an individual in need of them by any route suitable for the administration of pharmaceutical compositions containing antibodies, such as, for example, subcutaneous, intraperitoneal, intravenous, intramuscular, intratumoral or intracerebral, etc. In certain embodiments, antibodies are administered intravenously. In certain embodiments, antibodies are administered subcutaneously. In certain embodiments, antibodies are administered intratumorally. In certain embodiments, antibodies are Petition 870250105621, dated 11 / 18 / 2025, pp. 50-71 43 / 58 administered in an appropriate dosing schedule, for example, weekly, twice weekly, monthly, twice monthly, once every two weeks, once every three weeks, or once a month, etc. In certain embodiments, the antibodies are administered once every three weeks. The antibodies may be administered in any therapeutically effective amount. In certain embodiments, the therapeutically acceptable amount is between about 0.1 mg / kg and about 50 mg / kg. In certain embodiments, the therapeutically acceptable amount is between about 1 mg / kg and about 40 mg / kg. In certain embodiments, the therapeutically acceptable amount is between about 1 mg / kg and about 20 mg / kg. In certain embodiments, the therapeutically acceptable amount is between about 1 mg / kg and about 10 mg / kg. In certain embodiments, the therapeutically acceptable amount is between about 5 mg / kg and about 30 mg / kg.In certain modalities, the therapeutically acceptable amount is between approximately 5 mg / kg and approximately 20 mg / kg. Therapeutically effective amounts include sufficient quantities to improve one or more of the symptoms associated with the disease or condition being treated. Methods for preparing antibodies with reduced pI

[00063] In some embodiments, methods are provided in this document for reducing an experimental isoelectric point of an antibody, the method comprising: (a) mutating a glutamine to a negatively charged amino acid at position 1 of a variable region of the heavy chain by Kabat numbering; and (b) removing a lysine at the C-terminal position of a constant region of the heavy chain. In some embodiments, the negatively charged amino acid is glutamic acid. In some embodiments, the negatively charged amino acid is aspartic acid. In some embodiments, the lysine at the C-terminal position of a constant region of the heavy chain is K447, according to EU numbering. Petition 870250105621, dated 11 / 18 / 2025, pp. 51 / 71 44 / 58

[00064] In some embodiments, the antibody is a common light chain bispecific antibody comprising: (1) an anti-CD38 heavy chain variable region, wherein the anti-CD38 heavy chain variable region comprises: (i) a heavy chain complementarity-determining region 1 (HCDR1) comprising an amino acid sequence presented in SEQ ID NO: 7, (ii) a heavy chain complementarity-determining region 2 (HCDR2) comprising an amino acid sequence presented in SEQ ID NO: 8, and (iii) a heavy chain complementarity-determining region 3 (HCDR3) comprising an amino acid sequence presented in SEQ ID NO: 9, (2) an anti-CD19 heavy chain variable region, wherein the human anti-CD19 heavy chain variable region comprises: (i) a heavy chain complementarity-determining region 1 (HCDR1) comprising an amino acid sequence presented in SEQ ID NO: 10,(ii) a heavy chain 2 (HCDR2) complementarity-determining region comprising an amino acid sequence presented in SEQ ID NO: 11, and (iii) a heavy chain 3 (HCDR3) complementarity-determining region comprising an amino acid sequence presented in SEQ ID NO: 12, and (3) a common light chain variable region comprising: (i) a light chain 1 (LCDR1) complementarity-determining region comprising an amino acid sequence presented in SEQ ID NO: 13, (ii) a light chain 2 (LCDR2) complementarity-determining region comprising an amino acid sequence presented in SEQ ID NO: 14 (AAS), and (iii) a light chain 3 (LCDR3) complementarity-determining region comprising an amino acid sequence presented in SEQ ID NO: 15.

[00065] In certain embodiments, the common light chain bispecific antibody additionally comprises a hydrophobicity retention time (HIC) of less than about 10 minutes. In certain embodiments, the variable region of the anti-CD19 heavy chain Petition 870250105621, dated 11 / 18 / 2025, pp. 52-71 45 / 58 comprises a serine at position 84 and / or a leucine at position 108, according to the Kabat numbering. In certain embodiments, the variable region of the common light chain comprises a histidine at position 32, according to the Kabat numbering. In certain embodiments, the pI is less than 9. In certain embodiments, the pI is between 8 and 9. In certain embodiments, the pI is between 8.5 and 9.0. In certain embodiments, the pI is between 8.7 and 9.0. In certain embodiments, the pI is between 8.8 and 9.0. In certain embodiments, the pI is 8.9. Pharmaceutically acceptable excipients, carriers and diluents

[00066] In certain embodiments, the multispecific antibodies of this disclosure are included in a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients, carriers, and diluents. Pharmaceutically acceptable excipients, carriers, and diluents may be included to increase the shelf life, stability, or administerability of the antibody. Such compounds include salts, pH buffers, detergents, anticoagulants, and preservatives. In certain embodiments, the antibodies of this disclosure are administered in suspension in a sterile solution. In certain embodiments, the solution comprises approximately 0.9% NaCl. In certain embodiments, the solution comprises approximately 5.0% dextrose.In certain embodiments, the solution additionally comprises one or more of the following: buffers, for example, acetate, citrate, histidine, succinate, phosphate, bicarbonate and hydroxymethylaminomethane (Tris); surfactants, for example, polysorbate 80 (Tween 80), polysorbate 20 (Tween 20) and poloxamer 188; polyol / disaccharide / polysaccharides, for example, glucose, dextrose, mannose, mannitol, sorbitol, sucrose, trehalose and dextran 40; amino acids, for example, glycine or arginine. Petition 870250105621, dated 11 / 18 / 2025, pp. 53 / 71 46 / 58 antioxidants, for example, ascorbic acid, methionine; or chelating agents, for example, EDTA or EGTA.

[00067] In certain embodiments, the antibodies of this disclosure may be shipped / stored lyophilized and reconstituted before administration. In certain embodiments, the lyophilized antibody formulations comprise a bulking agent, such as mannitol, sorbitol, sucrose, trehalose, dextran 40, or combinations thereof. The lyophilized formulation may be packaged in a vial comprising glass or other suitable non-reactive material. The antibodies, when formulated, reconstituted or not, may be buffered to a specific pH, generally less than 7.0. In certain embodiments, the pH may be between 4.5 and 7.0, 4.5 and 6.5, 4.5 and 6.0, 4.5 and 5.5, 4.5 and 5.0, or 5.0 and 6.0.

[00068] Also described in this document are kits comprising one or more of the antibodies described in this document in a suitable container and one or more additional components selected from: instructions for use; a diluent, an excipient, a carrier and an administration device.

[00069] In certain embodiments, a method for preparing a cancer treatment is described in this document comprising mixing one or more pharmaceutically acceptable excipients, carriers or diluents and an antibody of this disclosure. In certain embodiments, a method for preparing a cancer treatment for storage or transport is described in this document comprising lyophilizing one or more antibodies of this disclosure. Examples of Additional Embodiments

[00070] Example of Embodiment 1. A bispecific common light chain antibody comprising: a variable anti-CD38 heavy chain region and a constant anti-CD38 heavy chain region, wherein the variable anti-CD38 heavy chain region comprises: a complementarity-determining region of Petition 870250105621, dated 11 / 18 / 2025, pp. 54 / 71 47 / 58 heavy chain 1 (HCDR1) comprising an amino acid sequence presented in SEQ ID NO: 7, a complementarity-determining region of heavy chain 2 (HCDR2) comprising an amino acid sequence presented in SEQ ID NO: 8, a complementarity-determining region of heavy chain 3 (HCDR3) comprising an amino acid sequence presented in SEQ ID NO: 9 and a negatively charged amino acid in the variable region of heavy chain 1, according to Kabat numbering, a variable region of the anti-CD19 heavy chain and a constant region of the anti-CD19 heavy chain, wherein the variable region of the human anti-CD19 heavy chain comprises: a complementarity-determining region of heavy chain 1 (HCDR1) comprising an amino acid sequence presented in SEQ ID NO: 10, a complementarity-determining region of heavy chain 2 (HCDR2) comprising an amino acid sequence presented in SEQ ID NO: 11,a complementarity-determining region of heavy chain 3 (HCDR3) comprising an amino acid sequence presented in SEQ ID NO: 12, and a negatively charged amino acid in the variable region of heavy chain 1, as per Kabat numbering; a common light chain variable region comprising: a complementarity-determining region of light chain 1 (LCDR1) comprising an amino acid sequence presented in SEQ ID NO: 13, a complementarity-determining region of light chain 2 (LCDR2) comprising an amino acid sequence presented in SEQ ID NO: 14, and a complementarity-determining region of light chain 3 (LCDR3) comprising an amino acid sequence presented in SEQ ID NO: 15.wherein: each of the constant regions of the anti-CD38 heavy chain and the constant region of the anti-CD19 heavy chain lacks a C-terminal lysine residue; and the common bispecific light chain antibody comprises an experimental isoelectric point (pI) less than 9.0, preferably wherein the bispecific light chain antibody, Petition 870250105621, dated 11 / 18 / 2025, pp. 55 / 71 Common 48 / 58 also comprises a hydrophobicity retention time (HIC) of less than about 10 minutes (e.g., as tested in Example 2).

[00071] Example of embodiment 2. The common light chain bispecific antibody of embodiment 1, wherein the common light chain bispecific antibody additionally comprises a Hydrophobicity Retention Time (HIC) of less than about 10 minutes (e.g., as assayed in Example 2).

[00072] Example of embodiment 3. The common light chain bispecific antibody of any of embodiments 1-2, in which the terminal lysine residue is K447, as per EU numbering.

[00073] Example of embodiment 4. The common light chain bispecific antibody of any of embodiments 1 to 3, wherein the variable region of the anti-CD19 heavy chain comprises a serine at position 84 and / or a leucine at position 108, according to Kabat numbering.

[00074] Example of embodiment 5. The common light chain bispecific antibody of any of embodiments 1 to 4, wherein the common light chain variable region comprises a histidine at position 32, according to Kabat numbering.

[00075] Example of embodiment 6. The common light chain bispecific antibody of any of embodiments 1 to 5, in which the negatively charged amino acid is glutamic acid.

[00076] Example of embodiment 7. The common bispecific light chain antibody of any of embodiments 1 to 6, where the pI is between 8.7 and 9.0.

[00077] Example of embodiment 8. The common light chain bispecific antibody of any of embodiments 1 to 7, wherein the constant region of the anti-CD19 heavy chain comprises a T366W substitution, according to EU numbering, or a T366S / L368A / Y407V substitution, according to EU numbering.

[00078] Example of embodiment 9. The common bispecific light chain antibody of any of embodiments 1 to 8, where Petition 870250105621, dated 11 / 18 / 2025, pp. 56 / 71 49 / 58 The constant region of the anti-CD38 heavy chain comprises a T366W replacement according to EU numbering or a T366S / L368A / Y407V replacement according to EU numbering.

[00079] Example of embodiment 10. The common light chain bispecific antibody of any of embodiments 1 to 9, wherein the common light chain bispecific antibody additionally comprises a constant region of the light chain.

[00080] Example of embodiment 11. The common light chain bispecific antibody of any of embodiments 1 to 10, wherein: (i) the variable region of the anti-CD38 heavy chain and the constant of the anti-CD38 heavy chain comprise the amino acid sequence of SEQ ID NO: 4; (ii) the variable region of the anti-CD19 heavy chain and the constant of the anti-CD38 heavy chain comprise the amino acid sequence of SEQ ID NO: 5; (iii) the variable region of the common light chain and the constant region of the light chain comprise the amino acid sequence of SEQ ID NO: 6.

[00081] Example of embodiment 12. A composition comprising one or more nucleic acid molecules encoding the common light chain bispecific antibody of any of embodiments 1 to 11.

[00082] Example of embodiment 13. A cell comprising one or more nucleic acid molecules encoding the common light chain bispecific antibody of any of embodiments 1 to 11.

[00083] Example of embodiment 14. A method for treating cancer in a being in need thereof, comprising administering to the being the common light chain bispecific antibody of any of embodiments 1 to 11.

[00084] Modality Example 15. The modality example 14 method, in which cancer comprises a solid tumor. Petition 870250105621, dated 11 / 18 / 2025, pp. 57 / 71 50 / 58

[00085] Example of modality 16. The method of modality 14, in which the cancer is a hematological cancer.

[00086] Example of modality 17. The method of modality 16, in which hematologic cancer is a B-cell malignancy.

[00087] Example of embodiment 18. A method for reducing an experimental isoelectric point of an antibody, the method comprising: (a) the mutation of a glutamine to a negatively charged amino acid at position 1 of a variable region of the heavy chain by Kabat numbering; and (b) the removal of a lysine at the C-terminal position of a constant region of the heavy chain, wherein the antibody is a common bispecific light chain antibody comprising: an anti-CD38 variable region of the heavy chain and an anti-CD38 constant region of the heavy chain, wherein the anti-CD38 variable region of the heavy chain comprises: a heavy chain complementarity-determining region 1 (HCDR1) comprising an amino acid sequence presented in SEQ ID NO: 7, a heavy chain complementarity-determining region 2 (HCDR2) comprising an amino acid sequence presented in SEQ ID NO: 8 and a heavy chain complementarity-determining region 3 (HCDR3) comprising an amino acid sequence presented in SEQ ID NO: 9,a variable region of the anti-CD19 heavy chain and a constant region of the anti-CD19 heavy chain, wherein the variable region of the human anti-CD19 heavy chain comprises: a complementarity-determining region of heavy chain 1 (HCDR1) comprising an amino acid sequence presented in SEQ ID NO: 10, a complementarity-determining region of heavy chain 2 (HCDR2) comprising an amino acid sequence presented in SEQ ID NO: 11 and a complementarity-determining region of heavy chain 3 (HCDR3) comprising an amino acid sequence presented in SEQ ID NO: 12, a variable region of the common light chain comprising: a, Petition 870250105621, dated 11 / 18 / 2025, pp. 58 / 71 51 / 58 Light chain complementarity determining region 1 (LCDR1) comprising an amino acid sequence presented in SEQ ID NO: 13, a light chain complementarity determining region 2 (LCDR2) comprising an amino acid sequence presented in SEQ ID NO: 14 and a light chain complementarity determining region 3 (LCDR3) comprising an amino acid sequence presented in SEQ ID NO: 15. EXAMPLES Example 1

[00088] Polyspecificity was measured using ELISA (BVP, PSR HEK293, PSR CHO). Plates (3) were coated with Baculovirus (BVP), HEK293 and CHO particles at 4 °C overnight. Antibody concentrations of 150, 50, 16.7 and 5.6 μg / mL were tested in triplicate. Plates were blocked (blocking buffer: PBS + 2% BSA). Background signal was measured in wells coated only with secondary antibody (2°). A cutoff point of 5 x background signal was used. The positive control (PC) included MEDNA Bio #H1308 and the negative control (NC) included MEDNA Bio #H1314.

[00089] BSM-001F (BSM-001.1) is a common light chain antibody comprising: (1) a variable region of the anti-CD38 heavy chain and a constant region of the anti-CD38 heavy chain, wherein the variable region of the anti-CD38 heavy chain comprises (i) a complementarity-determining region of the heavy chain 1 (HCDR1) comprising an amino acid sequence presented in SEQ ID NO: 7, (ii) a complementarity-determining region of the heavy chain 2 (HCDR2) comprising an amino acid sequence presented in SEQ ID NO: 8, (iii) a complementarity-determining region of the heavy chain 3 (HCDR3) comprising an amino acid sequence presented in SEQ ID NO: 9, (2) a variable region of the anti-CD19 heavy chain and a constant region of the anti-CD19 heavy chain, wherein Petition 870250105621, dated 11 / 18 / 2025, pp. 59 / 71 52 / 58 the variable region of the human anti-CD19 heavy chain comprises (i) a heavy chain complementarity-determining region 1 (HCDR1) comprising an amino acid sequence presented in SEQ ID NO: 10, (ii) a heavy chain complementarity-determining region 2 (HCDR2) comprising an amino acid sequence presented in SEQ ID NO: 11, and (iii) a heavy chain complementarity-determining region 3 (HCDR3) comprising an amino acid sequence presented in SEQ ID NO: 12, (3) a common light chain variable region comprising: (i) a light chain complementarity-determining region 1 (LCDR1) comprising an amino acid sequence presented in SEQ ID NO: 13, (ii) a light chain complementarity-determining region 2 (LCDR2) comprising an amino acid sequence presented in SEQ ID NO: 14 (AAS),and (iii) a complementarity-determining region of light chain 3 (LCDR3) comprising an amino acid sequence presented in SEQ ID NO: 15. BSM-001F includes a variable region mutation of the heavy chain Q1E by Kabat numbering in each heavy chain, each of the anti-CD38 heavy chain constant region and the anti-CD19 heavy chain constant region lacks a C-terminal lysine residue (e.g., K447 as per EU numbering).

[00090] For data analysis, a BVP / HEK / CHO score was determined, where the BVP / HEK / CHO Score = (Average OD450 value of triplicate sample) / (Average OD450 value of background signal). Figures 1A-C show the OD450 readings from the ELISA for guselkumab, BSM-001F (BSM-001.1), NC, and PC. BSM001F (BSM001.1) showed substantially lower polyreactivity when compared to guselkumab and PC. Example 2

[00091] To determine the experimental isoelectric point, the sample was diluted in a matrix of methylcellulose, 4 M urea, 3-10 pharmalytes (4%), 5 mM arginine and pI markers (pI 4.22 Petition 870250105621, dated 11 / 18 / 2025, pages 60 / 71 53 / 58 and pI 10.10). The mixture was subjected to an IEF iCE3 Analyzer (ProteinSimple) and pre-focused at 1,500 V, followed by focusing at 3,000 V. The isoelectric points of each peak were calculated from the cluster pI markers. The experimental isoelectric point of BSM-001F (BSM-001.1) was measured as 8.9. Unmodified BSM-001 (i) without a negatively charged amino acid in the variable region of heavy chain 1, as per Kabat numbering, and (ii) having constant regions of the heavy chain that include a terminal lysine residue (e.g., K447, as per EU numbering) showed a pI of 9.1. The experimental isoelectric point of BSM-001F (BSM-001.1) was reduced to below 9 (8.9).

[00092] Hydrophobic Interaction Chromatography (HIC) of Curia (Curia) was also determined. For the HIC protocol, the sample was titrated with 1 M (NH4)tSO4 prior to injection. 10 μL of the sample were injected onto a Sepax Proteomix HIC butyl-NP1.7, 4.6 x 35 mm column at a flow rate of 0.8 mL / min. The mobile phase started as 60% Buffer C (1.8 M (NH4)tSO4, 0.1 M NaHcPO4, pH 6.5) and 40% Buffer D (0.1 M NaHcPO4, pH 6.5) and changed in a linear gradient to 0% Buffer C and 100% Buffer D from 1 min to 16 min. The signal was measured at 280 nm. An HIC retention time of 9.9 was observed. FIG. 2 shows the HIC profiles of the BSM-001F (BSM001.1). Example 3

[00093] Cell binding to Daudi cells was measured. BSM-001F (BSM-001.1) showed equivalent binding to Daudi cells when compared to unmodified BSM-001 (i.e., without Q1E and terminal lysine modifications). Figure 3 shows the cell binding profiles.

[00094] ADCC elimination assays were also conducted using PBMC samples from human donors. For direct apoptosis assessment, cells were treated with the test articles and incubated for 48 hours at 37 °C / 5% CO2. For Petition 870250105621, dated 11 / 18 / 2025, pp. 61 / 71 54 / 58 evaluation of cross-linking-induced apoptosis: cells were incubated with the test articles on ice for 30 minutes before the addition of rabbit anti-human Fc gamma-specific F(ab')2. Cells were then incubated at 37 °C / 5% CO2. After incubation, cells were washed and stained with Annexin V, and then resuspended in Annexin V buffer containing a viability dye (propidium iodide; PI) before acquisition by flow cytometry. Early apoptotic cells were defined as single Annexin V+ / PI- cells, while late apoptotic / necrotic cells were defined as single Annexin V+ / PI+ cells. The sum of Annexin V+ / PI- and Annexin V+ / PI- cells was defined as total apoptotic / necrotic cells. The percentages of Annexin V+ / PI- or Annexin V+ / PI+ cells were plotted to compare the various apoptosis conditions. BSM-001F (BSM-001.1) showed equivalent ADCC-mediated elimination of Daudi cells when compared to unmodified BSM-001 (i.e., without Q1E and terminal lysine modifications). FIG. 4 shows the ADCC profiles.

[00095] For direct apoptosis assessment, cells were treated with test articles and incubated for 48 hours at 37 °C / 5% CO2. For cross-linking-induced apoptosis assessment, cells were incubated with test articles on ice for 30 minutes before the addition of rabbit anti-human Fc gamma-specific F(ab')2. Cells were then incubated for 48 hours at 37 °C / 5% CO2. After incubation, cells were washed and stained with Annexin V, then resuspended in Annexin V buffer containing a viability dye (propidium iodide; PI) before acquisition by flow cytometry. Early apoptotic cells were defined as single Annexin V+ / PI- cells, while late apoptotic / necrotic cells were defined as single Annexin V+ / PI+ cells. The sum of Annexin V+ / PI- and Annexin V+ / PI- was defined as the total number of apoptotic / necrotic cells. The percentages of cells Petition 870250105621, dated 11 / 18 / 2025, pp. 62 / 71 55 / 58 Annexin V+ / PI- or Annexin V+ / PI+ were plotted to compare the various apoptosis conditions. BSM-001F (BSM-001.1) showed equivalent apoptosis-mediated death of Daudi cells when compared to unmodified BSM-001 (i.e., without Q1E and terminal lysine modifications). Figure 5 shows the apoptosis profiles.

[00096] Although preferred embodiments of the present invention have been shown and described in this document, it will be obvious to those skilled in the art that such embodiments are provided only by way of example. Numerous variations, alterations, and substitutions will now occur for those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described in this document may be employed in the practice of the invention.

[00097] All publications, patent applications, issued patents, and other documents mentioned in this descriptive report are incorporated herein by reference, as if each individual publication, patent application, granted patent, or other document were specifically and individually designated to be incorporated by reference in its entirety. Definitions contained in text incorporated by reference are excluded to the extent that they contradict the definitions in this disclosure. Petition 870250105621, dated 11 / 18 / 2025, pp. 63 / 71 56 / 58 SEQUENCES Sequence listings provided here: SEQ ID NO: Sequence Origin 1 EVQL VQSGAEVKKPGS S VKVSCKASGGTFS S YAF SWVRQAP GQGLEWMGRVIPQLGIANSAQKFQGRVTITADKSTSTAYME LS SLRSEDTAVYYC ARDDIAALGPFDYWGQGTLVT VS S Knob anti-CD38 (variable region) 2 EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYTINWVRQAP GQGLEWMGGIIPIFGIPNYAQKFQGRVTITADESTNTAYMELS SLRSEDTAVYYCARASGGSADYSYGMDVWGQGTLVTVSS Hole anti-CD19 (variable region) 3 DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQKPEK APKSLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATY YCQQYNSYPRTFGQGTKVEIK AntiCD38 light chain (variable region) 4 EVQL VQSGAEVKKPGS S VKVSCKASGGTFS S YAF SWVRQAP GQGLEWMGRVIPQLGIANSAQKFQGRVTITADKSTSTAYME LS SLRSEDTAVYYC ARDDIAALGPFDYWGQGTLVT VS SASTK GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGAL TSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKD TLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK PREEQYNSTYRVVSVLTVLHQDWLNGI <EYI<CI<VSNI<ALPAP IEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG Bispecific Knob-type anti-CD38 arm 5 EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYTINWVRQAP GQGLEWMGGIIPIFGIPNYAQKFQGRVTITADESTNTAYMELS SLRSEDTAVYYCARASGGSADYSYGMDVWGQGTLVTVSSA STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVN HKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPK PKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA LPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLSCAVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG Bispecific Hole-type anti-CD19 arm 6 DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQKPEK APKSLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATY YCQQYNSYPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGT ASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GEC Anti-CD38 light chain Petition 870250105621, dated 11 / 18 / 2025, pp. 64 / 71 57 / 58 7 SYAFS Anti-CD38_VH_CD R1 _ 8 PQLGIA AntiCD38_VH_CD R2 9 DIAALGPFD Anti-CD38_VH_CD R3 _ 10 SYTIN Anti-CD19_VH_CD R1 _ 11 PIFG Anti-CD19_VH_CD R2 _ 12 SGGSADYSYGMD Anti-CD19_VH_CD R3 _ 13 SQGISSW Anti- CD38_VL_CDR 1 _ 14 AAS Anti- CD38_VL_CDR 2 _ 15 YNSYPR Anti- CD38_VH_CD R3 _ 16 PFLGIA AntiCD38_VH_CD R2 Petition 870250105621, dated 11 / 18 / 2025, pages 65 / 71 58 / 58 17 PHLGIA AntiCD38_VH_CD R2 18 PFLGTA AntiCD38_VH_CD R2 19 AAEPKSSDKTHTCPPCP 20 GGGG 21 GGGGDKTHTCPPCP Petition 870250105621, dated 11 / 18 / 2025, pp. 66 / 71

Claims

1 / 9 CLAIMS 1. Multispecific antibody, characterized in that it comprises: a) a CD38-binding moiety comprising: i) a first polypeptide comprising a variable region of the immunoglobulin heavy chain comprising the amino acid sequence shown in SEQ ID NO: 1 and a constant region of the heavy chain wherein the constant region of the heavy chain does not have a C-terminal lysine residue; and ii) a second polypeptide comprising a variable region of the light chain comprising the amino acid sequence shown in SEQ ID NO: 3; and b) a CD19-binding moiety comprising: i) a third polypeptide comprising a variable region of the immunoglobulin heavy chain comprising the amino acid sequence shown in SEQ ID NO: 2 and a constant region of the heavy chain wherein the constant region of the heavy chain does not have a C-terminal lysine residue;and ii) a fourth polypeptide comprising a variable region of the light chain comprising the amino acid sequence presented in SEQ ID NO: 3.; 2. Multispecific antibody, according to claim 1, characterized in that the constant region of the heavy chain of the first polypeptide, the third polypeptide, or both the first polypeptide and the third polypeptide, comprises a constant region of human IgG1 or human IgG4.

3. Multispecific antibody, according to claim 1, characterized in that the polypeptide comprising a variable light chain region additionally comprises a constant light chain region.

4. Multispecific antibody, according to any one of claims 1 to 3, characterized in that the second polypeptide, the fourth polypeptide, or both, the second polypeptide and the fourth polypeptide, comprise the amino acid sequence presented in SEQ ID NO:

6.

5. Multispecific antibody, according to any one of claims 1 to 4, characterized in that the CD38-binding moiety comprises one or more amino acid substitutions that inhibit homodimerization of the heavy chain of the CD38-binding moiety.

6. Multispecific antibody, according to claim 5, characterized in that the CD38-binding fraction comprises a T366W substitution according to the EU numbering, or a T366S / L368A / Y407V substitution in the heavy chain of the CD38-binding fraction according to the EU numbering.

7. Multispecific antibody, according to claim 1 or 2, characterized in that the CD19-binding moiety comprises one or more amino acid substitutions that inhibit homodimerization of the heavy chain of the CD19-binding moiety.

8. Multispecific antibody, according to claim 7, characterized in that the CD19-binding fraction comprises a T366W substitution according to EU numbering or a T366S / L368A / Y407V substitution in the heavy chain of the CD19-binding fraction according to EU numbering.

9. Multispecific antibody, according to any one of claims 1 to 8, characterized in that the first polypeptide consists of the amino acid sequence presented in SEQ ID NO:

4.

10. Multispecific antibody, according to any one of claims 1 to 8, characterized in that the third polypeptide consists of the amino acid sequence presented in SEQ ID NO:

5.

11. Bispecific common light chain antibody, characterized in that it comprises: Petition 870250105616, dated 11 / 18 / 2025, p. 19 / 26 3 / 9 a variable region of the anti-CD38 heavy chain and a constant region of the anti-CD38 heavy chain, wherein the variable region of the anti-CD38 heavy chain comprises: a complementarity-determining region of heavy chain 1 (HCDR1) comprising an amino acid sequence presented in SEQ ID NO: 7, a complementarity-determining region of heavy chain 2 (HCDR2) comprising an amino acid sequence presented in SEQ ID NO: 8, a complementarity-determining region of heavy chain 3 (HCDR3) comprising an amino acid sequence presented in SEQ ID NO: 9, and a negatively charged amino acid at the position of the variable region of heavy chain 1 by Kabat numbering, a variable region of the anti-CD19 heavy chain and a constant region of the anti-CD19 heavy chain,wherein the variable region of the human anti-CD19 heavy chain comprises: a heavy chain complementarity-determining region 1 (HCDR1) comprising an amino acid sequence presented in SEQ ID NO: 10, a heavy chain complementarity-determining region 2 (HCDR2) comprising an amino acid sequence presented in SEQ ID NO: 11, a heavy chain complementarity-determining region 3 (HCDR3) comprising an amino acid sequence presented in SEQ ID NO: 12, and a negatively charged amino acid at the position of the variable region of heavy chain 1, according to Kabat numbering, a common light chain variable region comprising: a light chain complementarity-determining region 1 (LCDR1) comprising an amino acid sequence presented in SEQ ID NO: 13, a complementary region of the chain Petition 870250105616, dated 11 / 18 / 2025,pg. 20 / 26 4 / 9 light chain 2 (LCDR2) comprising an amino acid sequence presented in SEQ ID NO: 14 (AAS), and a complementarity-determining region of light chain 3 (LCDR3) comprising an amino acid sequence presented in SEQ ID NO: 15, wherein: each of the constant region of the anti-CD38 heavy chain and the constant region of the anti-CD19 heavy chain lacks a C-terminal lysine residue (e.g., K447, as per EU numbering); and the common light chain bispecific antibody comprises an experimental isoelectric point (pI) less than 9.

12. Common light chain bispecific antibody, according to claim 11, characterized in that the common light chain bispecific antibody additionally comprises a hydrophobicity retention time (HIC) of less than about 10 minutes.

13. A bispecific common light chain antibody according to claim 11 or 12, characterized in that the terminal lysine residue is K447, as per EU numbering.

14. A bispecific common light chain antibody, according to any one of claims 11 to 13, characterized in that the variable region of the anti-CD19 heavy chain comprises a serine at position 84 and / or a leucine at position 108 according to Kabat numbering.

15. Bispecific common light chain antibody, according to any one of claims 11 to 14, characterized in that the variable region of the common light chain comprises a histidine at position 32 according to Kabat numbering.

16. A bispecific common light chain antibody, according to any one of claims 11 to 15, characterized in that the negatively charged amino acid is glutamic acid.

17. Common light chain bispecific antibody, according to Petition 870250105616, dated 11 / 18 / 2025, pp. 21 / 26 5 / 9 with any of claims 11 to 16, characterized in that the pI is between 8.7 and 9.

18. Pharmaceutical composition, characterized in that it comprises the multispecific antibody, as defined in any one of claims 1 to 10, or the common light chain bispecific antibody, as defined in any one of claims 11 to 17, and a pharmaceutically acceptable excipient, diluent or carrier.

19. Nucleic acid or plurality of nucleic acids, characterized (a) in that it encodes the common light chain bispecific antibody as defined in any one of claims 1 to 10, or the common light chain bispecific antibody as defined in any one of claims 11 to 17.

20. A method for treating cancer in an individual in need thereof, characterized in that it comprises administering to the individual the common bispecific light chain antibody, as defined in any one of claims 1 to 10, or the common bispecific light chain antibody, as defined in any one of claims 11 to 17, thereby treating the cancer in the individual in need thereof.

21. Method according to claim 20, characterized in that the cancer or tumor is a solid tissue cancer.

22. Method according to claim 21, characterized in that solid tissue cancer comprises breast cancer, prostate cancer, pancreatic cancer, lung cancer, kidney cancer, stomach cancer, esophageal cancer, skin cancer, colorectal cancer, or head and neck cancer.

23. Method, according to claim 22, characterized in that the breast cancer is a triple-negative breast cancer, the lung cancer is a non-small cell lung cancer, the head and neck cancer is a squamous cell carcinoma of the head and neck, the kidney cancer is a renal cell carcinoma, the brain cancer is a glioblastoma multiforme, or the skin cancer is a melanoma.

24. Method according to claim 20, characterized in that the cancer or tumor is a blood cancer.

25. Method, according to claim 24, characterized in that the blood cancer is a diffuse large B-cell lymphoma.

26. Method according to claim 24, characterized in that the blood cancer is a myeloma.

27. Method according to claim 24, characterized in that the blood cancer is Burkitt's lymphoma.

28. Method according to claim 24, characterized in that the blood cancer is B-cell lymphoma.

29. Method according to claim 28, characterized in that the B-cell lymphoma comprises double-impact lymphoma, double-expressor lymphoma, or triple-impact lymphoma.

30. A method, according to any one of claims 24 to 29, characterized in that the blood cancer is recurrent or refractory to treatment.

31. A method, according to any one of claims 20 to 30, characterized in that the cancer or tumor associated with CD19-positive B cells and with high CD38 immunosuppression is a cancer or tumor comprising infiltrates of CD19-positive B cells and with high CD38 immunosuppression.

32. Method according to claim 31, characterized in that CD38-positive and highly immunosuppressed CD19 B cells express a B cell activation marker.

33. Method according to claim 32, characterized in that the B cell activation marker comprises CD30.

34. Method, according to any of the claims in Petition 870250105616, dated 11 / 18 / 2025, pp. 23 / 26 7 / 9 to 33, characterized in that the cancer or tumor associated with CD19-positive B cells and with high immunosuppression of CD38 expresses PD-L1.

35. A method, according to any one of claims 22 to 34, characterized in that cancer or tumor associated with CD19-positive B cells and high immunosuppression of CD38 is associated with B cells with low CD20 expression or negative CD20.

36. Method according to claim 35, characterized in that B cells with high CD38 expression express at least about 30,000 CD38 proteins on the cell surface.

37. Method according to claim 35, characterized in that B cells with high CD38 expression express at least about 35,000 CD38 proteins on the cell surface.

38. Method according to claim 35, characterized in that B cells with high CD38 expression express at least about 40,000 CD38 proteins on the cell surface.

39. Method for reducing an experimental isoelectric point of an antibody, the method characterized in that it comprises: (a) mutating a glutamine to a negatively charged amino acid at position 1 of a variable region of the heavy chain according to Kabat numbering; and (b) removing a lysine at the C-terminal position of a constant region of the heavy chain.

40. Method according to claim 39, characterized in that the negatively charged amino acid is glutamic acid.

41. Method according to claim 39 or 40, characterized in that the antibody is a common light chain bispecific antibody comprising: Petition 870250105616, dated 11 / 18 / 2025, pp. 24 / 26 8 / 9 a variable region of the anti-CD38 heavy chain, wherein the variable region of the anti-CD38 heavy chain comprises: a heavy chain complementarity-determining region 1 (HCDR1) comprising an amino acid sequence presented in SEQ ID NO: 7, a heavy chain complementarity-determining region 2 (HCDR2) comprising an amino acid sequence presented in SEQ ID NO: 8, and a heavy chain complementarity-determining region 3 (HCDR3) comprising an amino acid sequence presented in SEQ ID NO: 9, a variable region of the anti-CD19 heavy chain,wherein the variable region of the human anti-CD19 heavy chain comprises: a heavy chain complementarity-determining region 1 (HCDR1) comprising an amino acid sequence presented in SEQ ID NO: 10, a heavy chain complementarity-determining region 2 (HCDR2) comprising an amino acid sequence presented in SEQ ID NO: 11, and a heavy chain complementarity-determining region 3 (HCDR3) comprising an amino acid sequence presented in SEQ ID NO: 12, a variable region of the common light chain comprising: a light chain complementarity-determining region 1 (LCDR1) comprising an amino acid sequence presented in SEQ ID NO: 13, a light chain complementarity-determining region 2 (LCDR2) comprising an amino acid sequence presented in SEQ ID NO: 14 (AAS),and a complementarity-determining region of light chain 3 (LCDR3) comprising an amino acid sequence presented in SEQ ID NO: 15., 42. Method for preparing an antibody, the method characterized by the fact that it comprises collecting the bispecific antibody, as defined in any one of claims 1 to 17, from the supernatant of a cell line comprising a nucleic acid encoding the antibody and subjecting the supernatant to one or more purification steps.

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