A platform for phenotypic discovery of therapeutic antibodies and targets applied on Chronic Lymphocytic Leukemia

Area of Science:

• Oncology
• Immunology
• Drug Discovery

Background:

• Antibody therapeutics offer significant potential for improving cancer treatment by targeting novel pathways.
• Developing effective antibody-drug combinations requires efficient discovery platforms that utilize patient-relevant biological systems.

Purpose of the Study:

• To describe a phenotypic discovery platform for identifying therapeutic antibody-target combinations.
• To apply this platform to Chronic Lymphocytic Leukemia (CLL) to discover novel antibody therapies.

Main Methods:

• The platform integrates differential phage display cell panning, high-throughput cell-based screening, and phenotypic in vitro and in vivo assays.
• Primary patient cells were used throughout the discovery process, including target deconvolution and xenograft model validation.

Main Results:

• The platform identified antibodies targeting six receptors on CLL cells: CD21, CD23, CD32, CD72, CD200, and HLA-DR.
• Antibodies targeting CD32, CD200, and HLA-DR demonstrated superior in vitro cytotoxicity compared to rituximab (anti-CD20).
• Enhanced antibody efficacy was confirmed in a patient-derived xenograft model.

Conclusions:

• The described phenotypic discovery platform enables efficient identification of potent antibody-target pairs for cancer therapy.
• Novel antibodies targeting CD32, CD200, and HLA-DR show promise as next-generation treatments for Chronic Lymphocytic Leukemia.
• The platform's ability to validate efficacy in vivo highlights its potential for accelerating antibody drug development.