Inhibition of bispecific monoclonal antibody (bsAb)‐targeted cytolysis by human anti‐mouse antibodies in ovarian carcinoma patients treated with bsAb‐targeted activated T‐lymphocytes

Abstract

T lymphocytes of 8 patients with ovarian cancer were targeted to the tumor cells using F(ab')₂ fragments of a bispecific monoclonal antibody (bsAb), specific for CD3 (a component of the T lymphocyte receptor for antigen) and for the folate receptor MOv 18 (overexpressed by ovarian carcinoma cells) as part of a phase l/II study. Phase I (days 0 to 3) consisted of increasing intraperitoneal (i.p.) numbers (10⁶−10⁹) of bsAbtargeted T lymphocytes plus lowdose interleukin‐2 (IL‐2). Phase II (days 6 to 13, and 27 to 33) consisted of daily i.p. infusions of 10⁹ targeted T lymphocytes, 2 mg soluble bsAb, and lowdose IL‐2. Using enzymelinked immunosorbent assays (ELISA), human antimouse antibodies (HAMA) were detected in all patients: in the serum from day 13 onwards and in the peritoneal fluid from day 20 onwards. A significant proportion of the HAMA appeared to be directed against the idiotypes of the bsAb specific for CD3 and MOv18, as suggested by (I) the clearly higher ELISA titers against OC/TR bsAb as compared to those against a monoclonal antibody (MAb) with unrelated specificity, and (2) failure to abrogate the capacity of peritoneal fluid containing HAMA to block the binding of OC/TR bsAb to MOv18⁺ or CD3⁺ cells by absorption of human antimouse IgG‐framework antibodies in peritoneal fluid to immobilized mouse IgG. The OC/TR‐targeted cytolysis of the MOv18⁺ ovarian carcinoma cell line lgrov‐1 by autologous T lymphocytes was inhibited by peritoneal fluid samples containing relatively high HAMA titers. Such inhibitory activity was never detected at the start of phase II, but coincided with the last series of i.p. infusions of targeted T lymphocytes in 2 patients.