A "Function-First" Approach to Identify Regulatory T cell-Targeting Antibodies for Immunotherapy.

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Cancer immunotherapy effectiveness varies due to the tumor microenvironment, particularly suppressive regulatory T (Treg) cells.
• Targeting Tregs specifically while sparing effector T cells is a promising strategy to improve treatment outcomes.

Purpose of the Study:

• To generate and evaluate antibodies that specifically deplete tumor-associated Tregs.
• To validate a target-agnostic antibody discovery platform for therapeutic antibody development.

Main Methods:

• Lymphocytes from tumor-bearing mice were used with a phage antibody library to generate antibodies.
• The F.I.R.S.T. platform evaluated antibody selectivity, specificity, Treg depletion efficacy, and tumor control in preclinical models.
• Target deconvolution identified the binding epitope of a lead antibody.

Main Results:

• 24 antibodies were identified with varying specificities, from pan-T cell to tumor-Treg specific.
• Tumor Treg selectivity, not relative binding, predicted Treg deletion efficacy and tumor control.
• One antibody demonstrated potent tumor-specific Treg depletion, mediated by Fc:FcγR interactions, leading to antitumor effects.

Conclusions:

• A target-agnostic discovery approach is effective for identifying novel therapeutic antibodies.
• Tumor-specific Treg depletion is a viable strategy for enhancing cancer immunotherapy.
• The identified antibody targeting an ICAM-1 epitope shows potential for cancer treatment.