Abstract 2890: The development of an Adaptable Drug Affinity Conjugate (ADAC) targeting CD40 for a flexible therapeutic peptide cargo delivery to dendritic cells

Abstract

Abstract CD40 agonistic antibodies targeting antigen-presenting cells rely on simultaneous antigen presentation for optimal efficacy, as the co-stimulatory signal alone will not lead to T cell activation. Herein we have developed a novel Adaptable Drug Affinity Conjugate (ADAC), a refinement of a traditional Antibody Drug Conjugate (ADC) with a focus on tailored drug design. The cargo for ADAC is synthetic long peptides that can be modified with the profiled genetic data for each patient. The ADAC technology relies on a high-affinity interaction between a short non-immunogenic peptide-tag (pTag) and a single-chain fragment (scFv) and the targeting of CD40 expressing antigen-presenting cells. As a proof-of-concept study, we have generated data supporting a ~20 times improved half-life of peptide therapeutics bound up by the ADAC technology (in vitro), translating to improved peptide half-life in vivo along with a superior expansion of T cells in vitro and in vivo, compared to peptide and antibody mixed but not interacting physically. Through phage-display selection screening of novel CD40 agonistic antibodies, we identified a unique clone (STRIKE-1001). STRIKE-1001 binds a defined structural epitope (HDX-MS) of CD40 in a low nM range and is agonistic in an IgG2 format. Similar to selicrelumab, STRIKE-1001 does not block CD40L binding to Fc-CD40. STRIKE-1001 shows a dose-dependent agonistic activity (EC50 of ~28 nM based on measured induction of HLA-DR expression) on human DCs and can be designed into a bispecific antibody without loss of agonistic activity. STRIKE-1001 is currently incorporated into the ADAC platform to be used as the first-in-class candidate for flexible peptide cargo delivery ensuring T cell priming and expansion in vivo as a means to transform CD40 agonistic antibody to clinically relevant drug candidates. Citation Format: Ida Laurén, Mohamed Eltahir, Aman Mebrahtu, Rosanne Veerman, Juan Astorga, Aljona Saleh, Jimmy Ytterberg, Annika Lindqvist, Leif Dahllund, Anders Olsson, Oskar Andersson, Johan Rockberg, Helena Persson, Sara Mangsbo. The development of an Adaptable Drug Affinity Conjugate (ADAC) targeting CD40 for a flexible therapeutic peptide cargo delivery to dendritic cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2890.