Bloodstream samples were collected throughout the study for pharmacokinetic analysis and clinical pathology assessments. after dosing. Taken together, our data indicate that targeting CLDN18.2 with an ADC or bispecific modality could be a valid therapeutic approach for the treatment of gastric and pancreatic cancer. Subject terms: Cancer, Gastrointestinal cancer Introduction Gastric and pancreatic adenocarcinomas are diseases of malignant glandular cells. Approximately one million new cases of gastric cancer are diagnosed worldwide each year. Despite recent advances in treatment options, relapse is inevitable and patients become LDN-214117 refractory to treatment. The five-year survival is about 5C20% and the median overall survival is about 10 months for patients with advanced gastric cancer1C3. For pancreatic cancer, the overall five-year survival rate is about 6~8%3C5. The poor prognosis of these two cancer types highlights the need for additional treatment approaches. One such approach is that of targeted therapies, an ever evolving field with promising modalities including antibody drug conjugates (ADCs) and CD3 bispecific antibodies now being tested in multiple indications6C15. LDN-214117 Covalently linking a cytotoxic payload to an antibody to form an ADC provides a mechanism for selective delivery of the cytotoxic agent to cancer cells via the specific binding of the antibody to cancer-selective cell surface molecules. Various payloads and linkers such as DNA damaging agents, microtubule inhibitors and cleavable or non-cleavable LDN-214117 linkers can be combined to afford ADCs different characteristics9,10. FDA approvals of ado-trastuzumab emtansine (Kadcyla?; T-DM1) and inotuzumab ozogamicin (BESPONSA?) have validated this modality in the treatment of solid and hematological malignancies16,17. Despite these approvals, ADCs have limitations including undesired release of the toxic payload in circulation and off-target payload-related adverse events, such as lymphopenia/thrombocytopenia, which limit the maximum tolerated dose18,19. In addition, ADCs require a relatively high number of cell-surface tumor associated antigens (TAAs) per cell to achieve maximum efficacy8,18. Cytotoxic T cells are considered to be the most potent effector cells of the immune system. In general, antigen-induced cytotoxic T-cell immunity is dependent on target cell antigen presentation and recognition of the presented peptide/MHC by the T-cell receptor (TCR), which includes the CD3 molecule. Bispecific antibodies can bind two different antigens simultaneously. By binding both a tumor target antigen and CD3, modalities such as CD3 bispecific antibodies can redirect T cells towards the recognition of tumor target antigen and induce T cell-mediated cell killing20. The idea of using bispecific antibodies to redirect circulating T cells to tumor sites and engaging them with cancer cells emerged in the 1980s21,22. The recent FDA approval of blinatumomab (the first-in-class LDN-214117 bispecific T cell engager (BiTE) antibody against CD3CCD19) highlights the role of bispecifics as potentially transformative medicines23,24. T cell-redirecting bispecifics vary in format. This manuscript will focus on CD3 bispecific antibodies and diabodies. Identifying a specific TAA for an oncology target that has limited normal tissue expression is critical. CLDN18.2 represents a potentially attractive TAA because it LDN-214117 fulfills this criterion. The claudin multigene family encodes tetraspan membrane proteins that are crucial structural and functional components of tight junctions. In mammals, there are at least 27 claudin members identified and they exhibit complex tissue-specific patterns of expression. CLDN18.2 is highly expressed in the normal stomach and is strictly confined to differentiated epithelial cells of the gastric mucosa. Furthermore hCLDN18.2 is also expressed in a significant proportion of primary Rabbit polyclonal to TGFB2 gastric cancers and their metastases, as well as in.
