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-11384139-B2
Publication Date
2022-07-12
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, useful for killing cells having C3d deposited on their surface. These antibodies bind to C3d on the cell surface and thereby target the cell for destruction by the host's immune effector cells, such as monocytes, macrophages, natural killer cells, and neutrophils. The antibody or fragment comprises specific heavy and light chain variable regions, including complementary determining regions (CDRs) with defined sequences and can be humanized, chimeric, or fully human. The antibody can be engineered into various forms, including complete antibodies, antigen-binding fragments, multispecific antibodies, or chimeric antigen receptors (CARs) for T-cells.
The background establishes that existing monoclonal antibody therapies, such as anti-CD20 antibodies rituximab and ofatumumab, though effective by mediating immune effector mechanisms including complement dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC), face challenges from cancer cells losing target surface antigens due to trogocytosis. This antigen loss limits the efficacy of antibody therapies. The invention addresses the need for new antibody therapies that can overcome problems associated with the loss of targeted antigens by targeting the stable complement protein C3d deposited on the surface of antibody-opsonized cells.
Claims Coverage
The patent claims include one independent claim addressing a method of killing cancer cells using an anti-C3d antibody or fragment along with an antibody targeting a different cell surface protein. The main inventive features relate to the composition and use of the anti-C3d antibody, its specific CDR regions, and the combination therapy with other antibodies inducing C3d deposition.
Anti-C3d antibody with specific heavy and light chain CDR regions
An anti-C3d antibody or antibody fragment comprising heavy chain variable regions with SEQ ID NO: 1 (CDRH1), SEQ ID NO: 2 (CDRH2), and SEQ ID NO: 3 or 4 (CDRH3), and light chain variable regions with SEQ ID NO: 5 (CDRL1), SEQ ID NO: 6 (CDRL2), and SEQ ID NO: 7 (CDRL3).
Combination therapy with antibody to a non-C3d cell surface protein inducing C3d formation
A method comprising administering the anti-C3d antibody along with an antibody or antibody fragment to a cell surface protein other than C3d, including anti-CD33, anti-CD38, anti-EGFR, or anti-ERBB2 antibodies, wherein the other antibody induces formation of C3d on the cancer cell surface.
Anti-C3d antibody comprising specific heavy and light chain sequences
The anti-C3d antibody or fragment comprises a heavy chain comprising SEQ ID NO: 8 and a light chain comprising SEQ ID NO: 9, or alternatively a heavy chain comprising SEQ ID NO: 10 and a light chain comprising SEQ ID NO: 11, retaining the defined CDR regions.
Administration parameters
The anti-C3d antibody and the antibody to the different cell surface protein can be administered simultaneously or sequentially in any order.
Variable immunoglobulin types and antibody fragment forms
The anti-C3d antibody or fragment can be selected from various immunoglobulin classes and fragment types, including IgA1, IgA2, IgD, IgE, IgG1-4, IgM, and fragments such as scFv, F(ab'), diabodies, T-bodies, multispecific, and multivalent antibodies.
In conclusion, the claims cover a method using a specifically defined anti-C3d antibody with particular CDR sequences in combination with antibodies targeting other cell surface proteins to induce C3d formation and thereby kill cancer cells. The claims also address variations in antibody sequences, formats, and administration modes.
Stated Advantages
The anti-C3d antibody can target cancer cells that have lost therapeutic target antigens through trogocytosis, overcoming a major limitation of existing antibody therapies.
The method enables elimination of malignant cells resistant to anti-CD20 monoclonal antibody therapies by exploiting stable C3d deposition on cell surfaces.
The anti-C3d antibody mediates immune effector functions such as complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC).
The antibody binds with high specificity and affinity to C3d without cross-reacting with other complement proteins, allowing precise targeting.
The antibody's C3d epitopes are stable on cell surfaces over days to weeks, providing durable targeting capability.
The approach can be combined with existing therapies targeting cell surface proteins, providing a versatile and synergistic treatment modality.
Demonstrated efficacy in reducing chronic lymphocytic leukemia (CLL) disease burden in xenograft mouse models.
Documented Applications
Killing cancer cells that have C3d complement protein on their surface, notably cells resistant to anti-CD20 monoclonal antibody therapy such as chronic lymphocytic leukemia (CLL) cells.
Treatment of CD20-positive B-cell malignancies and cancers from various tissues including gut, colon, lung, breast, head, neck, pancreas, ovary, endometrium, or brain tissue.
Use in combination with antibodies targeting other cell surface proteins to induce complement deposition and subsequent targeting of cancer cells.
Labeling opsonized cells for diagnostic detection.
Delivering therapeutic agents specifically to cells with surface-deposited C3d.
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