Immunotherapy using T cell-engaging bispecific monoclonal antibodies (BiMAb) is a promising cancer therapy. Such BiMAbs bind simultaneously to immune effector cells and to a cancer-specific antigen on tumor cells, resulting in killing of the latter. Placental alkaline phosphatase (PLAP), a plasma membrane-bound glycoprotein, is one of the four members of alkaline phosphatase isozyme family. PLAP is encoded by the ALPP gene. PLAP is expressed in placenta and has not been detected in other normal tissues. It has been shown that PLAP is released into the serum of patients with PLAP expressing tumours such as testis tumours. When PLAP is expressed ectopically in cancers, such as ovarian or colon carcinomas, it is essentially cancer specific and so an excellent target for immune based antibody therapy .The focus of my work is on colorectal cancer (CRC) and will mainly be based on the use of a well characterised panel of over 100 colorectal cancer derived cell lines about 20% of which express PLAP at the mRNA and protein levels . The cell lines are good representatives of primary tumors to use for in vitro preclinical testing of a new immunotherapeutic PLAP x CD3 BiMAb being developed for treatment of CRC. Worldwide, colorectal cancer has one of the highest cancer incidences and in the United States is the third cause of mortality in cancer patients. This emphasises the need to find novel effective treatments for colon cancer We found that a CD3 x PLAP BiMAb induced specific killing of PLAP-positive colorectal cancer cell lines, using peripheral blood mononuclear cells (PBMCs) as source of T cells, and that the killing depends on PLAP expression. The expression of PLAP in our cells varies and there is heterogeneity of PLAP expression within cell lines. However, we found that the effect of CD3 x PLAP BiMAb treatment was extended to PLAP-negative cells, when co-cultured with PLAP-positive ones, indicating a bystander effect. The bystander effect on PLAP-negative cells is only visible after 48 hours of treatment, suggesting an indirect killing mechanism. The important to study bystander killing to target cancer cells immune killing escape.To investigate further the mechanism of bystander killing, our early findings suggest CD3 x PLAP BiMAb activated T cells induce killing on bystander killing. We are studying the effect of the T cells subtypes and of the soluble factors secreted by the activated T cells.
Disclosure Information N.S. Alrishedan: None. W. Bodmer: F. Consultant/Advisory Board; Modest; ProMab Biotechnologies. V. Liebe lastun: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; Roche Glycart AG , Switzerland. V. Golubovskaya: A. Employment (full or part-time); Modest; ProMab Biotechnologies. J. Wu: A. Employment (full or part-time); Modest; ProMab Biotechnologies. A. Bransi: A. Employment (full or part-time); Modest; Roche Glycart AG, , Switzerland. P. Umana: A. Employment (full or part-time); Modest; Roche Glycart AG, , Switzerland. C. Klein: A. Employment (full or part-time); Modest; Roche Glycart AG, , Switzerland. R. Mateus Seidl: A. Employment (full or part-time); Modest; Roche Glycart AG, , Switzerland.
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