APX005M, a CD40 agonist antibody with unique epitope specificity and Fc receptor binding profile for optimal therapeutic application

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.

Sotigalimab and/or nivolumab with chemotherapy in first-line metastatic pancreatic cancer: clinical and immunologic analyses from the randomized phase 2 PRINCE trial

“…Our exploratory data on pharmacodynamic effects aligned with the expected mechanism of action of either PD-1 blockade or CD40 activation 19 , 20 . Additionally, unique immune pharmacodynamic effects for nivo/chemo and sotiga/chemo were individually identified.…”

Rationale and clinical development of CD40 agonistic antibodies for cancer immunotherapy

“…The differences are likely due to variations in assay set up and availability of FcγR. The similar pharmacodynamic responses of these antibodies in the clinical setting [61,82], also indicate that the in vitro comparison by Filbert et al [88], are of limited translational relevance. The very low MTD of SEA-CD40, 0.06 mg/kg, may be due to its high affinity for FcγR [92], which would allow SEA-CD40 to efficiently outcompete free IgG1 from FcγR in the blood.…”

“…Although mitazalimab is tolerable at higher dose levels compared to APX005M, the pharmacodynamic biomarker response in patients is very similar [61,82]. In vitro studies performed by Filbert et al [88], show large differences in potency between APX005M and mitazalimab. This is however not in accord with previous studies demonstrating strong immune activation with mitazalimab in vitro [23].…”

“…The FcγR-dependent human CD40 agonist antibodies in clinical development are all IgG1 isotype antibodies, but can be subcategorized based on their Fc modifications (Table 1). ABBV-927 and APX005M both have mutations in their Fc region (V273Y for ABBV-927 and S267E for APX005M), which increase their affinity for FcγRIIb and FcγRIIa and decrease their affinity for FcγRIIIa [88,89]. Mitazalimab is a wild type IgG1, with natural affinity to the different FcγR.…”

“…APX005M and mitazalimab both bind to epitopes that completely or partially overlap with the CD40L binding site (Table 1). APX005M binds closer to the cell membrane [88], while mitazalimab binds to the distal domain (D1b) on CD40 [23,114] (Table 1). Selicrelumab binds an epitope located on the outer A-module of the membrane proximal domain (D1a), that is distinct from the epitope of mitazalimab [112].…”