Mebrahtu et al. fused a CD40 agonist mAb with an scFv that binds a universal peptide tag handle (pTag), enabling modular loading of pTag-containing antigen peptides, which promoted antigen-specific T cell responses when bound to vaccine peptides. The final BiAb, containing an IgG2 CD40 agonist mAb fused to the scFv/pTag via the heavy chain, was chosen for its optimal yield and agonist activity. The BiAb elicited significant antigen-specific T cell proliferation in the LNs and spleen, which correlated inversely with pTag length. In the TC1 and MC38 models, the BiAb improved tumor control compared to CD40 agonist + free peptide or agonist + CpG.
Contributed by Morgan Janes
ABSTRACT: Current antibody-based immunotherapy depends on tumor antigen shedding for proper T cell priming. Here we select a novel human CD40 agonistic drug candidate and generate a bispecific antibody, herein named BiA9*2_HF, that allows for rapid antibody-peptide conjugate formation. The format is designed to facilitate peptide antigen delivery to CD40 expressing cells combined with simultaneous CD40 agonistic activity. In vivo, the selected bispecific antibody BiA9*2_HF loaded with peptide cargos induces improved antigen-specific proliferation of CD8+ (10-15 fold) and CD4+ T cells (2-7 fold) over control in draining lymph nodes. In both virus-induced and neoantigen-based mouse tumor models, BiA9*2_HF demonstrates therapeutic efficacy and elevated safety profile, with complete tumor clearance, as well as measured abscopal impact on tumor growth. The BiA9*2_HF drug candidate can thus be utilized to tailor immunotherapeutics for cancer patients.
Author Info: (1) KTH Royal Institute of Technology, Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, Stockholm, Sweden. Strike Pharma AB, Up
Author Info: (1) KTH Royal Institute of Technology, Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, Stockholm, Sweden. Strike Pharma AB, Uppsala, Sweden. (2) Strike Pharma AB, Uppsala, Sweden. Department of Pharmacy, Science for Life Laboratory, Uppsala University, Uppsala, Sweden. (3) Strike Pharma AB, Uppsala, Sweden. (4) Strike Pharma AB, Uppsala, Sweden. (5) Strike Pharma AB, Uppsala, Sweden. Department of Pharmacy, Science for Life Laboratory, Uppsala University, Uppsala, Sweden. (6) Strike Pharma AB, Uppsala, Sweden. Department of Pharmacy, Science for Life Laboratory, Uppsala University, Uppsala, Sweden. (7) Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden. (8) KTH Royal Institute of Technology, Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, Stockholm, Sweden. Science for Life Laboratory, Drug Discovery and Development, Stockholm, Sweden. (9) KTH Royal Institute of Technology, Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, Stockholm, Sweden. Science for Life Laboratory, Drug Discovery and Development, Stockholm, Sweden. (10) KTH Royal Institute of Technology, Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, Stockholm, Sweden. Science for Life Laboratory, Drug Discovery and Development, Stockholm, Sweden. (11) KTH Royal Institute of Technology, Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, Stockholm, Sweden. Science for Life Laboratory, Drug Discovery and Development, Stockholm, Sweden. (12) KTH Royal Institute of Technology, Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, Stockholm, Sweden. Science for Life Laboratory, Drug Discovery and Development, Stockholm, Sweden. (13) Strike Pharma AB, Uppsala, Sweden. SciCross AB, Skvde, Sweden. (14) KTH Royal Institute of Technology, Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, Stockholm, Sweden. johanr@biotech.kth.se. Strike Pharma AB, Uppsala, Sweden. johanr@biotech.kth.se. (15) Strike Pharma AB, Uppsala, Sweden. sara.mangsbo@farmaci.uu.se. Department of Pharmacy, Science for Life Laboratory, Uppsala University, Uppsala, Sweden. sara.mangsbo@farmaci.uu.se.
