Abstract
Targeting CD40 with agonist antibodies is a promising approach to cancer immunotherapy. CD40 acts as a master regulator of immunity by mobilizing multiple arms of the immune system to initiate highly effective CD8 + T-cell-mediated responses against foreign pathogens and tumors. The clinical development of CD40 agonist antibodies requires careful optimization of the antibody to maximize therapeutic efficacy while minimizing adverse effects. Both epitope specificity and isotype are critical for CD40 agonist antibody mechanism of action and potency. We developed a novel antibody, APX005M, which binds with high affinity to the CD40 ligand-binding site on CD40 and is optimized for selective interaction with Fcγ receptors to enhance agonistic potency while limiting less desirable Fc-effector functions like antibody-dependent cellular cytotoxicity of CD40-expressing immune cells. APX005M is a highly potent inducer of innate and adaptive immune effector responses and represents a promising CD40 agonist antibody for induction of an effective anti-tumor immune response with a favorable safety profile.
Highlights
Targeting of immune checkpoint inhibitor (ICI) proteins including cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and program cell death 1 (PD-1) or its ligand, PD-L1, is able to partially reverse cancer immunosuppression of tumor-specific cytotoxic effector cells by unleashing them to kill tumor cells
One promising alternative to ICIs is the use of CD40 agonist antibodies to prime antigen presenting cells (APCs) and invigorate anti-tumor T cells that have been inhibited by the suppressive TME
Agonistic antibodies tend to have different functionality and potency depending upon the affinity, epitope and FcR binding profile emphasizing the importance of careful selection of the appropriate binding epitope, affinity, and Fc engineering to achieve the desired profile of agonist antibodies for cancer immunotherapy
Summary
Targeting of immune checkpoint inhibitor (ICI) proteins including cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and program cell death 1 (PD-1) or its ligand, PD-L1, is able to partially reverse cancer immunosuppression of tumor-specific cytotoxic effector cells by unleashing them to kill tumor cells.
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