Antibody-drug conjugates for targeting CD56-positive tumors
Inventors
Dimitrov, Dimiter S. • Feng, Yang • Maris, John M. • Zhu, Zhongyu • Sussman, Robyn Tovah
Assignees
Childrens Hospital of Philadelphia CHOP • US Department of Health and Human Services
Publication Number
US-10548987-B2
Publication Date
2020-02-04
Expiration Date
2036-07-29
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Abstract
The identification and characterization of two fully human CD56-specific monoclonal antibodies targeting spatially separated epitopes proximal and distal to the plasma membrane is described. Also described are antibody-drug conjugates (ADCs) of the identified antibodies and their use for targeting CD56-expressing tumor cells.
Core Innovation
The invention provides two fully human CD56-specific monoclonal antibodies, m900 and m906, which bind to spatially separated epitopes proximal and distal to the plasma membrane of CD56. These antibodies can be conjugated to cytotoxic drugs to form antibody-drug conjugates (ADCs) for the targeted treatment of CD56-expressing tumor cells.
The background identifies a significant medical need due to CD56 overexpression in various cancers including neuroblastoma, small cell lung cancer, and multiple myeloma. CD56's function in cell adhesion and tumor metastasis highlights it as a therapeutic target. Existing treatments lack fully human antibodies targeting distinct CD56 epitopes with effective internalization and cell-killing properties.
The summary discloses that the antibodies m900 and m906 bind to non-overlapping regions of CD56: m900 binds the membrane-proximal fibronectin type III domains, and m906 binds the distal N-terminal IgG-like domains. The m906 antibody induces down-regulation and internalization of CD56, making it suitable for ADC development. ADCs made with m906 conjugated to cytotoxic agents like pyrrolobenzodiazepine (PBD) exhibit potent killing of CD56-positive tumor cells. Conversely, m900 mediates antibody-dependent cellular cytotoxicity (ADCC) but does not promote internalization efficiently.
Claims Coverage
The claims define one independent claim directed to an antibody-drug conjugate comprising a CD56-specific monoclonal antibody with defined variable region complementarity determining regions and its therapeutic uses. The inventive features focus on antibody structure, drug conjugation, and therapeutic application.
Antibody structure comprising specific CD56-binding CDR sequences
The ADC comprises a drug conjugated to a CD56-specific monoclonal antibody or antigen-binding fragment comprising a variable heavy (VH) domain with the complementarity determining region (CDR) sequences of SEQ ID NO: 6 and a variable light (VL) domain with the CDR sequences of SEQ ID NO: 8, including CDRs defined by IMGT or Kabat.
Specific amino acid residues defining the VH and VL domains
The VH domain includes amino acid residues 26-33, 51-59, and 97-111 or residues 31-35, 50-66, and 99-110 of SEQ ID NO: 6; the VL domain includes residues 27-37, 55-57, and 94-103 or residues 24-39, 55-61, and 94-102 of SEQ ID NO: 8.
Antibody variants with high sequence identity
The VH domain and VL domain may have at least 90% sequence identity to SEQ ID NOs: 6 and 8 respectively, including the sequences themselves.
Cytotoxic drug conjugation
The drug conjugated to the antibody is a cytotoxic agent, specifically an interstrand crosslinking agent, anti-mitotic agent, or anti-microtubule agent such as a pyrrolobenzodiazepine (PBD).
Varied antigen-binding fragment formats
The antigen-binding fragment may be an Fab, Fab′, F(ab)′2, single chain variable fragment (scFv), or disulfide stabilized variable fragment (dsFv).
Antibody characteristics and therapeutic uses
The monoclonal antibody is an IgG and may be fully human, chimeric or synthetic. The ADC is used for treating CD56-positive cancers including neuroblastoma, multiple myeloma, ovarian cancer, acute myeloid leukemia, Wilms tumor or small cell lung cancer.
The claims collectively cover an ADC consisting of a fully human CD56-specific monoclonal antibody with defined CDR sequences conjugated to a cytotoxic drug such as PBD, antibody variants with high sequence homology, multiple antibody fragment formats, and methods for treating various CD56-positive cancers using the ADC.
Stated Advantages
The disclosed ADCs enable targeted killing of CD56-positive tumor cells due to selective binding and internalization via m906 antibody.
m900 antibody mediates efficient antibody-dependent cellular cytotoxicity (ADCC), providing complementary cancer cell targeting through immune effector functions.
Fully human antibodies reduce immunogenicity risks and potentially improve pharmacokinetic properties compared to humanized antibodies.
The use of two antibodies binding distinct CD56 epitopes allows combinational approaches enhancing therapeutic efficacy against CD56-expressing cancers.
Documented Applications
Treatment of CD56-positive cancers including neuroblastoma, multiple myeloma, ovarian cancer, acute myeloid leukemia, Wilms tumor and small cell lung cancer by administration of the disclosed ADCs.
Inhibition of tumor growth or metastasis in subjects with CD56-positive cancers using the disclosed ADCs.
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