Targeting sialic acid: glycosylation based strategies for the treatment of feline and canine carcinomas

Abstract

The advent of immunotherapies has revolutionized the field of oncology, offering targeted treatments with fewer side effects than conventional approaches. However, many patients fail to respond to these therapies, underscoring the need for innovative targets. Aberrant glycosylation, particularly hypersialylation, is increasingly recognized as a critical driver of tumor progression, immune evasion, and poor prognosis in cancer. Increased expression of sialic acid-capped glycans can activate inhibitory pathways that suppress antitumor immunity and facilitate disease progression. The sialyl-Tn (STn) antigen, a truncated O-glycan found in over 80% of human carcinomas and absent in healthy tissues, represents one of the most well-characterized cancer-associated sialoglycans, making it an attractive diagnostic and therapeutic target. Similarly, the selective desialylation of tumor cells by neuraminidases can disrupt sialoglycan-mediated immune evasion, potentially restoring antitumor immunity. This study explores two glycan-centered strategies for developing novel immunotherapies aimed at canine and feline carcinomas. In the first approach, we investigated the diagnostic and therapeutic potential of a chimeric anti-STn antibody by evaluating its specificity for various carcinoma samples. The antibody demonstrated robust specificity for canine gastric carcinoma tissues, with limited binding observed in feline tumors and other canine cancers. The second strategy focused on the development of a Trop2-targeting antibody conjugated with feline neuraminidase (Neu2-scFv). This construct aimed to induce tumor-specific desialylation of Trop2- expressing feline mammary carcinoma (FMC) cells, enhancing antitumor immune responses. Trop2 binding and cell surface desialylation capabilities were independently assessed revealing that Neu2-scFv can effectively recognize Trop2 and induce desialylation in multiple FMC and human breast cancer cell lines. Future studies will evaluate the conjugate’s capacity to promote Trop2-dependent desialylation and ability to stimulate immune cell-mediated tumor clearance These findings underscore the therapeutic potential of sialic acid-based targeting strategies in veterinary oncology, paving the way for novel diagnostic and therapeutic tools with significant translational value for human cancers.