Fc Gamma Receptors Facilitate Antigenic Modulation of LILRB4 and Function as Predictive Biomarkers in Acute Monocytic Leukemia

Joshua Morse (Advisors: Zhiqiang An, PhD and Jeffrey Molldrem, MD)

                 Acute monocytic leukemia (monocytic AML) is a subtype of AML marked by a proliferation of abnormal monoblasts. This subtype represents approximately 10% of AML cases. The prognosis of monocytic AML is poor, with 5-year survival of ~30%. Most patients are diagnosed at an age when they are unlikely to survive first line non-targeted cytotoxic chemotherapy as a bridge to hematopoietic stem cell transplant (HSCT). Even patients who achieve remission commonly relapse. This population of patients would greatly benefit from precision-targeted therapies but currently there are none approved for monocytic AML.

                Leukocyte immunoglobulin-like receptor B4 (LILRB4) is an immune checkpoint expressed specifically on the cell surface of monocytic AML with limited expression on other cell types, making it an excellent target for antibody-based precision therapy. We have developed an antibody targeting this receptor which makes use of a Fc gamma receptor scaffolding mechanism to interact with its target. This mechanism is specific to antibodies targeting cells of the hematopoietic lineage which possess Fc gamma receptors. It has been described in the literature as antigenic modulation or antibody bipolar bridging and has been shown to reduce the effector function of anti-CD20 antibodies targeting B cell malignancies.

                Through this Fc-mediated mechanism, the anti-LILRB4 mAb and others bind their target receptor, inducing internalization of the antigen complex. In the case of anti-LILRB4, this antigenic modulation mechanism leads to improved disinhibition of T cell cytotoxicity and reduced Fc-mediated effector function, as observed with anti-CD20 antibodies. Fc gamma receptors thus represent clinically useful predictive biomarkers for the efficacy of antibodies targeting receptors found on monocytic AML and other hematologic malignancies. Appropriate use of these biomarkers will help clinicians better identify patients who will respond to these precision-targeted antibody therapies in the future, leading to superior outcomes in clinical trials and much-needed approvals of novel therapeutic antibodies.

Advisory Committee:

• Zhiqiang An, PhD, Chair
• Jeffrey Molldrem, MD, Co-Chair
• Xiaodong Cheng, PhD
• Michael Davies, MD, PhD
• Naval Daver, MD
• Chengcheng Zhang, PhD

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