Antibody targeting cell surface deposited complement protein C3d and use thereof
Inventors
Wiestner, Adrian U. • Skarzynski, Martin W. • Lindorfer, Margaret A. • Taylor, Ronald P. • Rader, Christoph • Vire, Berengere
Assignees
UVA Licensing and Ventures Group • US Department of Health and Human Services
Publication Number
US-10035848-B2
Publication Date
2018-07-31
Expiration Date
2035-01-08
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Abstract
An anti-C3d antibody or antibody fragment; method for use thereof to kill cancer cells; and related methods and compositions.
Core Innovation
The invention provides an antibody or antibody fragment immunospecific for complement protein C3d and methods of using the antibody or antibody fragment to kill cells having C3d deposited on their surface. The complement system is activated upon binding of a monoclonal antibody to target cells, resulting in complement components deposited on the cell surface, including the stable C3d protein, which remains for days to weeks. The antibodies bind C3d on the surface of target cells, thereby targeting the cells for immune system destruction.
The problem addressed by the invention is that existing antibody therapies for cancer, such as anti-CD20 monoclonal antibodies (e.g., rituximab and ofatumumab), can be ineffective due to loss of the target surface antigen, CD20, by a process called trogocytosis. This antigen loss allows cancer cells to escape immune effector mechanisms. The invention aims to overcome limitations posed by antigen loss by targeting the stable complement protein C3d deposited on the cell surface after complement activation, providing an alternative antigenic target for antibody-mediated killing.
Claims Coverage
The patent includes multiple independent claims focused on anti-C3d antibodies or antibody fragments with specific complementary determining regions (CDRs), methods of killing cancer cells bearing C3d on their surface, compositions including such antibodies, and nucleic acids encoding them. Key inventive features relate to antibody structure and methods of use.
Anti-C3d antibody with specific heavy and light chain variable regions
An anti-C3d antibody or antibody fragment comprising heavy chain variable region CDRs SEQ ID NO: 1 (CDRH1), SEQ ID NO: 2 (CDRH2), and SEQ ID NO: 3 or 4 (CDRH3), and light chain variable region CDRs SEQ ID NO: 5 (CDRL1), SEQ ID NO: 6 (CDRL2), and SEQ ID NO: 7 (CDRL3).
Anti-C3d antibody with heavy and light chains of specific sequences
Antibodies comprising a heavy chain of SEQ ID NO: 8 or 10 and a light chain of SEQ ID NO: 9 or 11, or with at least about 50% sequence identity thereto, retaining the stated CDR regions.
Binding specificity to epitope comprising SEQ ID NO: 16
Antibody or antibody fragment binds to an epitope comprising SEQ ID NO: 16 or within SEQ ID NO: 16 on C3d protein.
Method of killing cancer cells bearing C3d on their surface
A method comprising administering to a subject an anti-C3d antibody or antibody fragment of the invention to kill cancer cells that have C3d complement protein on the surface.
Combination therapy inducing C3d formation and subsequent targeting
Methods that further include inducing C3d formation on the cancer cell surface by contacting or administering an antibody or fragment to a cell-surface protein other than C3d, such as an anti-CD20 antibody, optionally as a multi-specific antibody that targets both C3d and another cell-surface protein.
The claims cover anti-C3d antibodies with defined CDR sequences and specific heavy and light chain variants, antibodies binding a defined C3d epitope, methods of targeting and killing cancer cells bearing C3d, and pharmaceutical compositions and nucleic acids encoding the antibodies, including therapies combining induction of C3d and targeting C3d.
Stated Advantages
The anti-C3d antibodies can target and kill cancer cells that have escaped killing due to antigen loss caused by trogocytosis, overcoming a limitation of conventional antibody therapies.
Anti-C3d antibodies bind a stable antigen (C3d) that remains on the cell surface for extended periods, allowing durable targeting of opsonized cells.
The antibodies mediate killing through complement dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC), enhancing immune effector functions.
The anti-C3d antibody effectively decreases disease burden in vivo in xenograft mouse models of chronic lymphocytic leukemia.
Documented Applications
Use of anti-C3d antibodies to label or deliver therapeutic agents to cells bearing C3d on their surfaces, such as opsonized cancer cells.
Treatment of cancer, specifically chronic lymphocytic leukemia (CLL), including B-cell malignancies expressing CD20.
Treatment of cancer cells that have lost therapeutic target antigens (e.g., CD20) due to trogocytosis during monoclonal antibody therapy by targeting deposited C3d.
Combination therapy wherein an antibody or agent induces C3d formation on cancer cells followed by administration of anti-C3d antibody to kill the cells.
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