Highly potent and specific bivalent T cell engager (TCE) targeting PRAME on HLA-A*02:01

BackgroundPreferentially Expressed Antigen in Melanoma (PRAME) is a tumor-specific therapeutic target. This antigen is expressed across a wide range of tumor types such as lung, ovarian, melanoma and endometrial cancers, while exhibiting minimal expression in only few healthy tissues. Targeting PRAME peptides presented on tumor cells by the human leukocyte antigens (HLA) has been clinically validated using TCEs and T cell receptor therapies currently in clinical trials. Here we describe CDR813 an antibody fragment-based T cell engager which bivalently binds to an HLA-A2-restricted PRAME peptide on tumors.MethodsCDR813 was preclinically characterized for selective killing of PRAME/HLA-A*02 positive human cancer cells versus a panel of different PRAME-negative/HLA-A*02-positive human cell lines in co-cultures with PBMCs. Recognition of alternative but similar peptides complexed HLA-A*02 was measured using surface plasmon resonance. Early safety assessment was performed on a panel of primary normal human cell types covering different organs and cell types.ResultsThe bispecific molecule consists of two identical high affinity (KD 80 pM) scFv fragments targeting the PRAME425–433 peptide presented on HLA-A*02:01, and a Fab fragment that binds to the CD3 receptor of T cells. CDR813 demonstrated potent anti-tumor activity against PRAME+/HLA-A*02:01+ cancer cell lines, minimal binding to similar peptides presented in healthy human tissues, and negligible activity on HLA-A*02:01+ normal human primary cells from essential organs. The biophysical properties of the molecule were optimized for an ideal developability profile. Stability and solubility measurements predict good shelf-life and in vivo stability, and it can be manufactured in a standard CHO-based platform process.ConclusionsConsidering the in vitro potency, specificity profile, and drug-like biophysical properties, this clinical candidate holds the potential to exhibit best-in-class characteristics in a clinical setting.Legal entity responsible for the studyCDR-Life AG.FundingCDR-Life AG.DisclosureA. Dasargyri, S. Jungmichel, N. Alijaj, F. Scheifele, P. Knobel, P. Richle, H. Merten, R. Doerig, A. Evangelopoulou, M. Priola, B. Pavlovic, L. Bickel, T. Schleier, G. Acuña, S. Biswas: Financial Interests, Personal, Full or part-time Employment: CDR-Life. A. Vilarrasa: Financial Interests, Personal and Institutional, Full or part-time Employment: CDR-Life. T. Fugmann: Financial Interests, Personal, Leadership Role: Alithea. C. Leisner: Financial Interests, Personal, Member of Board of Directors: CDR-Life. L. Borras: Financial Interests, Personal, Leadership Role: CDR-Life. All other authors have declared no conflicts of interest.