Abstract 3493: A novel T cell engager antibody for the treatment of HLA-A*01/KK-LC-1-positive tumors
Authors: 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
Journal: Cancer Research (2025)

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.