IMA402, an Off-the-Shelf, Next-Generation TCR Bispecific (TCER®) for Efficiently Targeting an HLA-Presented Peptide from the Pan-Cancer Antigen PRAME

Preferentially expressed antigen in melanoma (PRAME) is an intracellular protein that has been shown to have attractive target attributes that can be leveraged by T cell receptor (TCR)-based immunotherapy. PRAME is cancer-specific, homogenously expressed and presented at high target density. In contrast to most other cancer germline antigens, PRAME is expressed across a multitude of solid tumors as well as hematological malignancies including acute myeloid leukemia and diffuse large B-cell lymphoma. We have developed IMA402, a bispecific T cell engaging receptor (TCER®) molecule targeting an HLA-A*02-presented peptide derived from PRAME. TCER® molecules are fusion proteins consisting of a high-affinity TCR for peptide-HLA targeting and a humanized T cell-recruiting antibody coupled to an effector function-silenced IgG1 Fc domain that aims to extend half-life together with providing antibody-like stability and manufacturability characteristics. For IMA402, a TCR recognizing the selected PRAME pHLA molecule with high avidity and specificity was affinity maturated via yeast surface display resulting in more than 1,000-fold increased binding affinity. During maturation we applied an off-target toxicity screening against normal tissue peptides selected from the our immunopeptidome database to retain specificity and deselect cross-reactive candidate TCRs. The affinity maturated TCR was engineered into the bispecific TCER® scaffold and produced in Chinese hamster ovary cells. In preclinical assays, IMA402 required only picomolar concentrations to induce lysis of various tumor cells with PRAME target peptide levels in the physiological range as found in patients. In different in vivo xenograft mouse models, IMA402 induced consistent tumor regression including complete remissions. In these models, pharmacokinetic profiling determined a terminal half-life of several days. In vivo analyses of various T cell recruiting domains with different affinities confirmed the superiority of the low affinity T cell recruiting domain used in IMA402 when compared to analogous TCER® molecules with higher-affinity T cell recruiter domains. For the safety assessment, we measured TCER® reactivity against more than 20 different human normal tissue cell types. We could demonstrate that IMA402 did not induce killing of normal tissue cells at concentrations of at least 1,000-fold higher than required for tumor cell lysis, suggesting a broad therapeutic window. In patients, the design of our next-generation TCER® molecule harbouring a high-affinity TCR, a low-affinity T cell recruiter and a Fc domain aims at optimizing biodistribution and activation of T cells at the tumor site instead of the periphery. This might reduce occurrence of immune-related toxicities, such as cytokine release syndrome and allow reaching relevant doses in the tumor tissue. Taken together, our preclinical studies demonstrate that our novel, next-generation bispecific T cell engager IMA402 could be a promising therapeutic option for PRAME-positive patients. The phase 1 clinical trial designed as basket trial will start recruitment in 2023.