Abstract 3494: Durable and potent in vitro T cell activity with repeated exposure to CDR404, a potential best-in-class T cell engager targeting MAGE-A4

Abstract T cell engagers (TCEs) targeting the melanoma antigen gene A4 (MAGE-A4) have entered first-in-human trials for HLA-A*02:01+ patients with MAGE-A4 expressing solid tumors. CDR404 is a bispecific antibody-based TCE that binds bivalently to the MAGE-A4230-239 peptide on HLA-A*02:01 and monovalently to CD3. The safety, tolerability and preliminary therapeutic efficacy of CDR404 are currently being evaluated in a dose-finding Phase 1 trial in multiple solid cancers including NSCLC (NCT06402201). The only other MAGE-A4 targeting TCE currently in clinical trial is a TCR-based TCE with a low affinity T cell recruiter, bearing an Fc region (TCR-TCE-Fc). Therefore, there are fundamental differences in format, functionality and pharmacology between these two TCE molecules. This preclinical study provides novel mechanistic insights into the persistence of cancer cell killing with repeated dosing of CDR404, comparing it to the TCR-TCE-Fc molecule. Since upregulation of PD-1 is an obligate immunosuppressive brake to T cell activation, we additionally investigated the in vitro killing activity of a CDR404 and Pembrolizumab combination compared to CDR404 alone. In co-culture assays of MAGE-A4+/HLA-A*02:01+ NSCLC cells (NCI-H1755) and human PBMCs, CDR404 induced higher levels of T cell activation, reflected by activation (CD69, CD25) and proliferation (Ki67) markers, and more potent tumor cell killing compared to the TCR-TCE-Fc. Higher potency of CDR404 was confirmed on different MAGE-A4+ cell lines from various cancer types. CDR404 also showed more efficient cancer cell killing than the TCR-TCE-Fc at low E:T ratios (down to 1:1), indicating that it has the potential to achieve higher efficacy in tumors with low T cell infiltration (“cold tumors”). Strikingly, potency of CDR404 was efficiently maintained over multiple rounds of serial killing of NSCLC cells (NCI-H1755), in contrast to the TCR-TCE-Fc molecule. In this experiment, CDR404 induced significantly less upregulation of T cell exhaustion markers than the TCR-TCE-Fc. These results highlight the potential of CDR404 to achieve more durable responses in solid tumors. Since T cell engagers treatment is accompanied by upregulation of PD-1/PD-L1 axis, we evaluated CDR404 in combination with the anti-PD-1 therapy pembrolizumab, showing enhanced potency of in vitro exhausted T cells on a PD-L1 overexpressing NSCLC cell line compared to CDR404 alone. In conclusion, these results demonstrate the potential of CDR404 to achieve improved efficacy and more durable responses for HLA-A*02:01+ patients with MAGE-A4+ tumors. The combination with an anti-PD-1 therapy may have additive anti-tumor activity in patients, and could potentially allow a transition into earlier, anti-PD-1/PD-L1 containing lines of treatment for multiple solid cancers including NSCLC, thus benefiting a larger patient population. Citation Format: Alessio Vantellini, Nora Wettstein, Melissa Vrohlings, Stephanie Jungmichel, André Luis Fonseca da Silva, Alice Langer, Anna Howald, Zoi Barou, Daniel Lenherr-Frey, Matteo Morotti, Christian Leisner, Swethajit Biswas, Leonardo Borras. Durable and potent in vitro T cell activity with repeated exposure to CDR404, a potential best-in-class T cell engager targeting MAGE-A4 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3494.