Promotion of an Antitumor Immune Program by a Tumor-specific, Complement-activating Antibody

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Tumor-targeting antibodies are crucial for initiating antitumor immune responses and achieving durable clinical responses in cancer patients.
• An autoantibody against complement factor H (CFH) is associated with early-stage non-small cell lung cancer.
• An mAb, GT103, cloned from patient B cells, recognizes a tumor-specific CFH epitope and exhibits in vitro and in vivo antitumor activity.

Purpose of the Study:

• To elucidate the mechanisms by which an antibody targeting a tumor epitope promotes an effective antitumor immune response.
• To investigate the impact of a murinized version of GT103 (mGT103) on the tumor microenvironment and antitumor immunity in a preclinical model.
• To explore the potential of GT103 as a therapeutic agent in combination with other immunotherapies.

Main Methods:

• Utilized the syngeneic CMT167 lung tumor C57BL/6 mouse model to study mGT103's effects.
• Analyzed the activation of complement and enhancement of antitumor immunity mediated by mGT103.
• Assessed changes in the tumor microenvironment, including regulatory T cells and myeloid-derived suppressor cells.
• Evaluated the additive antitumor effect of mGT103 in combination with anti-PD-L1 mAb.
• Examined the immune landscape of tumors from early-stage patients expressing anti-CFH autoantibodies.

Main Results:

• Murinized GT103 (mGT103) activates complement and enhances antitumor immunity through multiple pathways.
• mGT103 creates a favorable tumor microenvironment by decreasing immunosuppressive regulatory T cells and myeloid-derived suppressor cells.
• mGT103 enhances antigen-specific effector T cells and exhibits an additive antitumor effect when combined with anti-PD-L1 mAb.
• Tumors from early-stage patients with anti-CFH autoantibodies show an immunologically active tumor microenvironment.
• GT103 targets a unique CFH epitope present on tumor cells.

Conclusions:

• GT103, an antibody targeting a tumor-specific CFH epitope, activates complement and generates an immune program to inhibit tumor growth.
• The study provides novel mechanistic insights into how tumor-specific, complement-activating antibodies can elicit an effective antitumor immune response.
• These findings support the therapeutic potential of GT103 in cancer treatment, particularly in combination strategies.