Antibody molecules to CD138 and uses thereof
Inventors
Chaganty, Bharat • Ramakrishnan, Boopathy • Adari-Hall, Hedy • Viswanathan, Karthik • Myette, James R. • Shriver, Zachary
Assignees
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Publication Number
US-11945868-B2
Publication Date
2024-04-02
Expiration Date
Abstract
Antibody molecules that specifically bind to CD138 are disclosed. The antibody molecules can be used to treat, prevent, and/or diagnose disorders, such as multiple myeloma.
Core Innovation
The invention relates to anti-CD138 antibody molecules defined by specified heavy chain variable region (VH) and light chain variable region (VL) complementarity determining regions, including a defined LCDR1 conservative amino-acid substitution variant. The disclosure also includes radiolabeled anti-CD138 antibody molecules and antibody-drug conjugates, with antibody formats that comprise an optional cytotoxic agent and/or linker as part of ADC compositions.
The document further describes cytotoxic payload options for antibody-drug conjugates directed to CD138, including duocarmycin analogues, maytansine and maytansinoids, monomethyl auristatin E (MMAE/vedotin), monomethyl auristatin F (MMAF), and pyrrolobenzodiazepines (PBDs). It also describes linker types that couple an antibody to a cytotoxic agent, including hydrazone, disulfide, peptide, thioether, β-glucuronide, and PEG linkers.
The disclosure further defines preferential targeting of membrane-associated CD138 over soluble CD138 by locating epitopes extracellularly proximal to the transmembrane domain, including the BB4/B-B4 epitope region around Gly217–Glu251. Functional properties referenced in the disclosure include high-affinity binding and effector-associated activities such as ADCC, complement-dependent cytotoxicity, ADCP, homotypic adhesion modulation, protease-shedding inhibition, and reduced proliferation.
The disclosed antibody molecules are encompassed in multiple formats and embodiments, including Fc receptor binding through FcγRI/II/III and Fc engineering concepts for FcRn binding, half-life, and effector enhancement. The invention also encompasses nucleic acids encoding the antibodies, expression vectors, host cells, pharmaceutical compositions and kits, and use contexts including cancer treatment/prevention and detection of CD138.
Claims Coverage
The consolidated claim coverage centers on an anti-CD138 antibody molecule defined by specific VH and VL CDR sequences. Across the items, six inventive features are recited, with dependent refinements concerning alternative CDR sequence choices, sequence-difference/homology constraints, Fc modifications, and therapeutic or effector-function use concepts involving CD138-expressing cells or cancers.
Specified VH and VL complementarity determining region sequences for an anti-CD138 antibody
An anti-CD138 antibody molecule comprising a VH with HCDR1, HCDR2, and HCDR3 defined by SEQ ID NO: 350, 355, or 356 for HCDR1, SEQ ID NO: 351 for HCDR2, and FVY for HCDR3, or alternatively HCDR1 as SEQ ID NO: 380, HCDR2 as SEQ ID NO: 381 or 382, and HCDR3 as FVY, and further comprising a VL with LCDR1 as SEQ ID NO: 352 or a sequence differing by 1 conservative amino-acid substitution, LCDR2 as SEQ ID NO: 353, and LCDR3 as SEQ ID NO: 354.
Alternative CDR sequence combinations via SEQ ID NO choices
The VH and/or VL CDR amino-acid sequences are further specified with alternative SEQ ID NO choices as dependent claim refinements.
Constrained sequence difference and homology to reference sequences
The VH and/or VL sequences have limited amino-acid differences versus specified reference sequences and/or specified sequence homology levels to those sequences.
Fc modifications for FcRn binding and antibody half-life
An antibody molecule with an Fc region defined by one or more mutations that increase binding affinity to FcRn and/or increase the half-life of the antibody molecule.
Treating a CD138-expressing cancer by administering the antibody molecule
A method of treating a CD138-expressing cancer in a subject by administering an effective amount of the antibody molecule.
Inducing ADCC by contacting CD138-expressing cells with the antibody molecule
A method that causes ADCC activity by contacting a CD138-expressing cell, including a cell in a subject, with the antibody molecule.
The claim coverage focuses on a CD138-binding antibody molecule defined by specific VH and VL CDR sequence selections, including a defined LCDR1 conservative substitution tolerance. Additional coverage narrows to Fc region mutations for FcRn binding and/or half-life, and to use concepts involving ADCC and treatment of CD138-expressing cancers.
Stated Advantages
High-affinity binding.
Effector-associated activities such as ADCC, complement-dependent cytotoxicity, and ADCP.
Homotypic adhesion modulation, protease-shedding inhibition, and reduced proliferation.
Preferential targeting of membrane-associated CD138 over soluble CD138.
Documented Applications
Treating a CD138-expressing cancer in a subject by administering the antibody molecule.
Causing ADCC activity by contacting a CD138-expressing cell or a subject comprising such a cell with the antibody molecule.
Treating or preventing multiple myeloma and related precancerous conditions, including smoldering myeloma and MGUS.
Using anti-CD138 antibody molecules in ADC compositions and pharmaceutical compositions or kits for cancer treatment/prevention and detection of CD138.
Evaluation of anti-CD138 antibodies in vivo in animal models for myeloma models.
Radiolabeling of anti-CD138 antibody molecules using a chelating agent and radioisotopes, including Indium-111, Yttrium-90, and/or Lutetium-177.
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