An immunoconjugate of Lys3-bombesin and monoclonal antibody 22 can specifically induce FcgammaRI (CD64)-dependent monocyte- and neutrophil-mediated lysis of small cell carcinoma of the lung cells
Small cell carcinoma of the lung (SCCL) accounts for 25% of all lung cancers and has a very poor prognosis. It is known that SCCL cells produce gastrin-releasing peptide, a peptide which has similar biological actions to that of bombesin, an amphibian counterpart of gastrin-releasing peptide, and express high affinity cell surface bombesin/gastrin-releasing peptide receptors. These receptors can serve as targets for specific immunotherapy. Cell surface receptors for the Fc portion of IgG (FcgammaR) are a family of molecules that can mediate a variety of immune reactions, including tumor cell cytotoxicity. We hypothesized that an immunoconjugate of bombesin and a mAb directed to the high-affinity FcgammaRI (mAb 22) should be able to trigger specific cytotoxicity against SCCL cells. In this article, we report the construction of this immunoconjugate and demonstrate its capacity to redirect immune effector cells toward SCCL cells and elicit lysis of these target cells. The immunoconjugate stained the majority of cells from four SCCL cell lines and reacted with FcgammaRI on activated monocytes and neutrophils. After preincubating monocytes and neutrophils with recombinant gamma interferon to enhance the expression of FcgammaRI on the cell surface, we demonstrated that 60-98% of SCCL cells could be lysed in the presence of the immunoconjugate in a chromium release assay. Tumor cell lysis was observed over a wide range of immunoconjugate concentrations, was dependent on the ratio of E:T cells, and could be blocked by the addition of either parental molecule of the immunoconjugate. Bispecific molecules redirecting immune effector cells to target SCCL cells may have clinical application in the therapy of SCCL.
Chen
J
Division of Hematology/Bone Marrow Transplantation, University of Pittsburgh Medical Center and Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213, USA.
Mokotoff
M
Zhou
JH
Fanger
MW
Ball
ED