Human neutrophil interactions of a bispecific monoclonal antibody targeting tumor and human Fcγ RIII |
| |
Authors: | L M Weiner R Katherine Alpaugh Anne R Amoroso Gregory P Adams David B Ring Malcolm W Barth |
| |
Institution: | (1) Department of Medical Oncology, Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, PA 19111, USA Fax: (215)728 5338/e-mail: lm_weiner@fccc.edu, US;(2) Chiron Corporation, Emeryville, CA 94608, USA, US |
| |
Abstract: | 2B1 is a bispecific murine monoclonal antibody (bsmAb) targeting the c-erbB-2 and CD16 (FcγRIII) antigens. c-erbB-2 is over-expressed
by a variety of adenocarcinomas, and CD16, the low-affinity Fcγ receptor for aggregated immunoglobulins, is expressed by polymorphonuclear
leukocytes (PMN), natural killer (NK) cells and differentiated mononuclear phagocytes. 2B1 potentiates the in vitro lysis
of c-erbB-2 over-expressing tumors by NK cells and macrophages. In this report, the interactions between 2B1 and PMN were
investigated to assess the impact of these associations on in vitro 2B1-promoted tumor cytotoxicity by human NK cells. The
peak binding of 2B1 to PMN was observed at a concentration of 10 μg/ml 2B1. However, 2B1 rapidly dissociated from PMN in vitro
at 37°C in non-equilibrium conditions. This dissociation was not caused by CD16 shedding. When PMN were labeled with 125I-2B1 and incubated at 37°C and the supernatants examined by HPLC analysis, the Fab regions of dissociated 2B1 were not complexed
with shed CD16 extracellular domain. While most of the binding of 2B1 to PMN was solely attributable to Fab-directed binding
to FcγRIII, PMN-associated 2B1 also bound through Fcγ-domain/FcγRII interactions. 2B1 did not promote in vitro PMN cytotoxicity
against c-erbB-2-expressing SK-OV-3 tumor cells. When PMN were coincubated with peripheral blood lymphocytes, SK-OV-3 tumor
and 2B1, the concentration of 2B1 required for maximal tumor lysis was lowered. Although PMN may serve as a significant competitive
binding pool of systemically administered 2B1 in vivo, the therapeutic potential of the targeted cytotoxicity properties of
this bsmAb should not be compromised.
Received: 3 May 1995 / Accepted: 6 February 1996 |
| |
Keywords: | Human neutrophil interactions Bispecific monoclonal antibodies Targeting |
本文献已被 SpringerLink 等数据库收录! |
|