Inhibitors of complement factor H
Inventors
Patz, JR., Edward F. • Campa, Michael J. • Gottlin, Elizabeth • Haynes, Barton F. • Liao, Hua-Xin • Moody, M. Anthony
Assignees
Publication Number
US-12286471-B2
Publication Date
2025-04-29
Expiration Date
2034-06-07
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Abstract
Disclosed herein are Complement factor H (CFH) inhibitors, such as anti-CFH antibodies and small molecules, and methods of using said inhibitors.
Core Innovation
The invention is directed to Complement Factor H (CFH) inhibitors, specifically isolated antibodies or antibody fragments that are capable of binding to an epitope within short consensus repeat (SCR) 19 of CFH protein, particularly the epitope comprising PIDNGDIT (SEQ ID NO: 3). These inhibitors include anti-CFH antibodies and small molecules designed to target reduced forms of CFH, which may represent tumor-bound or tumor-cell–specific conformations.
The problem addressed by the invention is the lack of effective therapies that exploit humoral immunity for cancer treatment, particularly for lung cancer where tumor cells develop resistance to existing treatments and utilize CFH to protect themselves from complement-mediated lysis. Tumor-associated CFH presents cryptic epitopes under reducing conditions prevalent in tumor microenvironments, limiting immune system recognition and attack.
By generating and utilizing antibodies that specifically recognize these exposed epitopes in the reduced form of CFH, particularly within SCR19, the invention provides new therapeutic strategies against cancer cells, enhancing complement-dependent cytotoxicity and C3b deposition on tumor cells. The invention further encompasses nucleic acids encoding such antibodies, cells expressing them, pharmaceutical compositions, diagnostic kits, and methods for both therapeutic intervention and detection of CFH or its reduced form.
Claims Coverage
The patent claims primarily cover a pharmaceutical composition comprising specific isolated antibodies or antibody fragments directed to a defined epitope in CFH, as well as their use in kits.
Pharmaceutical composition comprising epitope-specific CFH antibody
A pharmaceutical composition that includes an isolated antibody or antibody fragment which immunospecifically binds to Complement Factor H (CFH) protein, specifically to the PIDNGDIT (SEQ ID NO: 3) epitope within SCR19 of CFH. The antibody comprises defined variable heavy and light domain sequences, including combinations such as: - Heavy chain SEQ ID NO: 73 with light chain SEQ ID NO: 84 - Heavy chain SEQ ID NO: 74 with light chain SEQ ID NO: 83 - Heavy chain SEQ ID NO: 75 with light chain SEQ ID NO: 85 - Heavy chain SEQ ID NO: 78 with light chain SEQ ID NO: 88 - Heavy chain SEQ ID NO: 79 with light chain SEQ ID NO: 89 - Heavy chain SEQ ID NO: 76 with light chain SEQ ID NO: 86 - Heavy chain SEQ ID NO: 77 with light chain SEQ ID NO: 87
Kit for assaying CFH comprising the antibody composition
A kit for assaying a test sample for Complement Factor H (CFH), wherein the kit comprises the pharmaceutical composition containing the specific epitope-binding CFH antibody or antibody fragment referenced above.
The claims define inventive features centered on pharmaceutical compositions and diagnostic kits involving isolated antibodies or fragments with precise sequence specificity for a functional epitope within CFH SCR19, offering both therapeutic and diagnostic utility.
Stated Advantages
The antibodies recognize a cryptic epitope in CFH that is only exposed in the tumor microenvironment, enabling targeted therapy against cancer cells while sparing normal tissues.
The CFH inhibitors can increase complement-dependent lysis and C3b deposition specifically on tumor cells, enhancing direct cytotoxic effects against cancer.
The use of human-derived or humanized antibodies minimizes risks of reactivity against self-antigens.
The antibodies do not cross-react with a panel of known autoantigens, suggesting minimal unwanted immune responses.
The combination of these antibodies with known cancer therapeutics provides additive effects in tumor cell killing.
Documented Applications
Treatment of cancer, including lung cancer and breast cancer, by administering the isolated antibody or antibody fragment, nucleic acid, cell, or pharmaceutical composition.
Increasing complement-dependent lysis of tumor cells, including A549 lung carcinoma, MCF7 breast cancer, SKBR3 breast cancer, and MDA-MB-231 breast cancer cells.
Inhibiting Complement Factor H (CFH) binding to C3b in a subject or cell.
Increasing C3b deposition on cancer cells through administration of the antibody or composition.
Inhibiting tumor growth in a subject, including lung tumor growth, by administering the antibody, nucleic acid, cell, or pharmaceutical composition.
Detecting or measuring Complement Factor H (CFH) or its reduced form in a sample using the isolated antibody or antibody fragment.
Use of the antibody or related composition in diagnostic kits, including kits for assaying test samples for CFH or reduced CFH.
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