TCX-201, a novel ADC targeting a specific tumor-associated carbohydrate antigen (TACA) with excellent preclinical efficacy, PK and safety profile in solid tumor models

Tumor-associated carbohydrate antigens (TACAs) are defined oligosaccharide structures that are expressed on the surface of cancer cells. They are derived from changes in glycosylation pathways associated with malignancy, which lead to overproduced or aberrant structures, and represent a still unexplored target class for cancer therapy. We have generated specific antibodies against several of these difficult to target antigens and obtained a high affinity, fully humanized monoclonal antibody (mAb), TCX-201, against one of these TACAs, highly expressed across a broad range of cancer indications, including various gastrointestinal cancer types as well as NSCLC. This mAb shows superior internalization, affinity, and specificity for the target compared to the available benchmark, as assessed by glycan array, flow cytometry, and immunohistochemistry or immunofluorescence. Three ADC-variants were created by conjugation with MMAE (DAR 4), Exatecan (DAR 8), and Deruxtecan (Dxd, DAR 8) via a cleavable linker and were subsequently analyzed regarding their potency. In vitro studies showed effective killing of various pancreatic and colon cancer cell lines expressing different levels of the TACA (e.g. HuP-T4 (high expressing, IC50 of 0.3 nM), Capan-2 (heterogeneous expression, IC50 of 1.03 nM), Colo-205 (high expressing, IC50 of 0.013 nM), LS180 (medium expressing, IC50 of 4.7 nM). Moreover, high efficacy was observed for the tested payloads in different xenograft models with weekly iv administration: Capan-2 pancreatic cancer (reaching T/C of 16% and 6% at 3 and 7 mg/kg MMAE, respectively and T/C of 27% with 7 mg/kg Dxd) and Colo-205 colorectal cancer reaching T/C of 3% with 7 mg/kg MMAE. In addition to CDX models, PDX in vitro screening on PDAC and CRC models showed highly effective killing in 5/8 PDAC PDX and 2/5 CRC PDX with TCX-201 MMAE. These results, coupled with a favorable PK and safety profile make this ADC a first-in-class molecule for the treatment of various solid tumors that express different levels of the target structure.In conclusion, our antibody represents a new promising treatment option for different cancer indications and can be effectively employed as an ADC using different payloads.