Abstract A123: Hallmarks of pharmacodynamic activity of CDR404, a new antibody-derived T cell engager (TCE) targeted against MAGE-A4+ solid tumors in HLA-A*02:01+ patients

Abstract Antibodies have not conventionally been used to target the cancer cell surface proteome presented on HLA molecules. Instead, the druggability of the HLA immunopeptidome has predominantly relied on soluble or autologous TCR T cell formats which pose significant developability challenges. We have created a versatile, functionally modular, proprietary rabbit antibody-derived platform called M-gager®, which exploits avidity for specific cancer target binding and has highly favorable developability properties including subcutaneous formulation. The first M-gager® in the clinic is CDR404, a bivalent MAGE-A4 targeted TCE with a CD3 agonist Fab domain and two scFv domains which can separately bind 10-mer MAGE-A4230-239 peptides presented on HLA-A*02:01+ cancer cells with very high specificity. The mechanism-of-action (MOA) of TCEs consists of 4 pharmacodynamic (PD) hallmarks of activity which are all CD8+ T cell dependent and are essential prerequisites for efficacy: 1. T cell activation 2. T cell polyclonal expansion 3. Shift to an effector memory (EM) phenotype 4. T cell recruitment into tumor from the periphery The Phase 1 CDR404-001 trial (NCT06402201) is recruiting patients (pts) from sites in the US, EU and U.K. and satisfies Project Optimus requirements; all pts are prospectively selected for HLA-A*02:01 and MAGE-A4 positivity. Pts receive intravenous (IV) CDR404, QW, in 21-day cycles. To better reflect the MOA of CDR404 in pt tumors, we used quantitative systems pharmacological (QSP) modeling to select an immunologically active starting dose (100mcg). This enabled rapid characterization of all four PD hallmarks within the first 3 dose levels (DL1: 100mcg; DL2: 200mcg; DL3: 300mcg) including in pts with noninflamed tumors, e.g., ovarian cancer (OC). Most pts in DL1-DL3 (N=13) had multifold increases in serum cytokine levels after the first dose, indicative of T cell activation (Hallmark 1), which led to low-grade cytokine release syndrome (CRS) mostly in OC pts. For pts who received multiple target doses, escalation from DL1 to DL3 was associated with slowing of tumor growth rate (TGR). In DL1, one OC pt had a 17% decrease in CA125 levels after 8 doses which was consistent with increasing T cell proliferation (Hallmark 2) and EM expansion (Hallmark 3) during dosing. In DL2, one OC pt also had PD hallmarks 2 & 3 during the first 8 doses of CDR404; a 2nd OC pt had a rapid reduction in the absolute lymphocyte count (ALC) during the first 90-minute drug infusion, indicative of rapid biodistribution of CDR404 and T cell recruitment from the periphery (Hallmark 4). CDR404 has consistently shown PD hallmarks in OC. Therefore, the trial will be enriched with MAGE-A4+ OC pts once the efficacious dose range is reached. Integrated PK-PD data including changes in ctDNA levels will be presented for OC and other solid tumors at the conference. In conclusion, early patient data from the CDR404-001 trial confirms that the first M-gager® in the clinic shows all 4 canonical PD hallmarks for a TCE and has emerging favorable immunological safety. Citation Format: Melissa Vrohlings, Matteo Morotti, Daniel Lenherr-Frey, Nikolina Vachtsevanou, Clare Price, Leonardo Borras, Rouven Bingel-Erlenmeyer, Paul Swiecicki, Coral Olazagasti, Rom Leidner, Mark Diamond, Kristoffer Rohrberg, Sylvie Rottey, Hans Prenen, Jean-Pascal Machiels, Nuria Kotecki, Alberto Hernando Calvo, Guillermo de Velasco, Guillermo Suay Montagud, Desamparados Roda Perez, Juan Jesús. Martin Liberal, Matteo Simonelli, Giuseppe Curigliano, Christian Leisner, Swethajit Biswas, Emiliano Calvo Aller. Hallmarks of pharmacodynamic activity of CDR404, a new antibody-derived T cell engager (TCE) targeted against MAGE-A4+ solid tumors in HLA-A*02:01+ patients [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A123.