Abstract 3493: A novel T cell engager antibody for the treatment of HLA-A*01/KK-LC-1-positive tumors

Abstract Kita-Kyushu lung cancer antigen-1 (KK-LC-1) is a cancer-testis antigen prevalently expressed in multiple tumors including lung and gastric cancers but not in normal tissues. Here, we describe CDR505, a novel antibody-based T cell engager (TCE) for the treatment of KK-LC-1-expressing solid tumors. Since most HLA-restricted TCEs currently in clinical development are targeted against peptides presented on HLA-A*02, there is a high unmet need to develop TCEs for other HLA-A patient subpopulations. CDR505 is the only TCE to date, which is being developed against an intracellular target presented on HLA-A*01+ tumors. CDR505 is a humanized, affinity-matured, and stability-engineered TCE that binds with one Fab arm to CD3 on T cells and with two scFv arms to the HLA-A*01-restricted KK-LC-1 peptide NTDNNLAVY on cancer cells. With a molecular weight of 100 kDa, this format is predicted to achieve a favorable PK likely allowing Q2W or Q3W dosing. CDR505 shows very efficient cancer cell killing as demonstrated with KK-LC-1+/HLA-A*01+ cancer cell lines NCI-H1703 and EKVX in co-cultures with human PBMCs. Upon CDR505-mediated cancer cell killing, increased expression of activation (CD69, CD25) and proliferation (Ki67) markers were observed on CD3+ cells. T cell activation was further confirmed by the presence of cytokines detected in culture supernatants, including IFNγ, IL2, TNFα, IL6, and granzyme B. KK-LC-1 is a highly challenging target due to high levels of similar off-target peptides presented in healthy tissues. Extensive assessments for binding specificity and cross-reactivity in normal human cells were performed with CDR505. The binding profile of CDR505 was determined using surface plasmon resonance (SPR). This binding profile was used to identify potential off-target peptides in mass-spectrometry databases containing peptides presented in healthy tissues. None of the peptides identified caused relevant T cell activation in presence of CDR505 when presented on TAP-deficient, (empty) HLA-A*01-expressing T2 cells. Furthermore, CDR505 did not induce relevant T cell reactivity towards a panel of HLA-A*01 positive normal human cells from different organs and tissues. These results support a low risk for CDR505 off-target reactivity and a favorable safety profile. Collectively, CDR505 potently activates T cells and induces efficient cytotoxicity against KK-LC-1+/HLA-A*01+ cancer cells. It shows high specificity for KK-LC-1/HLA-A*01 and shows an overall safe profile in the presence of normal human cells. Future studies will include in vivo efficacy testing and a broader range of cellular assays using tissues and cultured cells as part of the preclinical studies that will be included in the IND application. Citation Format: Athanasia Dasargyri, Melissa Vrohlings, Stephanie Jungmichel, Blaz Pavlovic, Martina Priola, Zoi Barou, Hannes Merten, Philip Knobel, Luca Scheu, Fabian Scheifele, Gonzalo Acuna, Matteo Morotti, Christian Leisner, Swethajit Biswas, Leonardo Borras. A novel T cell engager antibody for the treatment of HLA-A*01/KK-LC-1-positive tumors [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 3493.