Abstract 753P
Background
T cell engaging bispecifics redirecting T cells towards human leukocyte antigen (HLA)-presented peptides are emerging as promising treatment modality for patients with solid tumors. We have developed bispecific T cell engaging receptor (TCER®) molecules, which consist of an affinity maturated TCR, a humanized T cell-recruiting antibody and an Fc-part conferring half-life extension and favorable stability characteristics. Our TCER® candidate IMA402 targets an HLA-A*02-presented peptide derived from PRAME, which is highly prevalent across multiple solid tumors incl. melanoma, gynecological cancers, lung cancer, sarcoma and others.
Methods
After systematic evaluation, a TCR with high avidity and specificity towards the PRAME target peptide was selected for affinity maturation via yeast surface display resulting in more than 1,000-fold increased binding affinity while retaining specificity. The maturated TCR was then incorporated into our TCER® format.
Results
IMA402 showed in vitro anti-tumor activity at picomolar concentrations against tumor cells with naturally occurring PRAME target peptide levels and demonstrated absence of reactivity towards normal tissue cells at relevant concentration, suggesting a broad therapeutic window. In preclinical xenograft mouse models, IMA402 led to consistent tumor regression including complete remissions and showed a serum half-life of several days. In these models, low affinity T cell recruiting domain demonstrated superior tumor control compared to analogous TCER® molecules with widely used higher-affinity T cell recruiters. Distinct affinities of the TCR (high) and T cell recruiter (low) are designed to optimize biodistribution and activation of T cells at the tumor site, aiming to reduce occurrence of immune-related toxicities like cytokine release syndrome, while achieving relevant doses in tumor tissue.
Conclusions
Upon preclinical proof-of-concept for the novel bispecific T cell engager IMA402 GMP manufacturing was initiated and is currently ongoing. IMA402 directed against PRAME will be the second TCER® entering clinical development with start of the phase 1 basket trial in several solid tumor indications planned for 2023.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Immatics Biotechnologies GmbH.
Funding
Immatics Biotechnologies GmbH.
Disclosure
S. Missel: Financial Interests, Full or part-time Employment: Immatics Biotechnologies GmbH. S. Bunk: Financial Interests, Full or part-time Employment: Immatics Biotechnologies GmbH. M. Hofmann: Financial Interests, Full or part-time Employment: Immatics Biotechnologies GmbH. G. Pszolla: Financial Interests, Full or part-time Employment: Bayer AG. M. Hutt: Financial Interests, Full or part-time Employment: Immatics Biotechnologies GmbH. F. Schwoebel: Financial Interests, Full or part-time Employment: Immatics Biotechnologies GmbH. F. Unverdorben: Financial Interests, Full or part-time Employment: Immatics Biotechnologies GmbH. C. Wagner: Financial Interests, Full or part-time Employment: Immatics Biotechnologies GmbH. M. Jaworski: Financial Interests, Full or part-time Employment: Immatics Biotechnologies GmbH. H. Schuster: Financial Interests, Full or part-time Employment: Immatics Biotechnologies GmbH. F. Schwoerer: Financial Interests, Full or part-time Employment: Immatics Biotechnologies GmbH. C. Schraeder: Financial Interests, Full or part-time Employment: Immatics Biotechnologies GmbH. O. Schoor: Financial Interests, Full or part-time Employment: Immatics Biotechnologies GmbH. T. Weinschenk: Financial Interests, Full or part-time Employment: Immatics N.V.. D. Maurer: Financial Interests, Full or part-time Employment: Immatics Biotechnologies GmbH. C. Reinhardt: Financial Interests, Full or part-time Employment: Immatics N.V.; Other, Member of the Board of Directors: Revitope Oncology Inc., Theolytics.