The bispecific
monoclonal antibody (bsmAb) 2B1, targeting the extracellular domain of c-erbB-2, the
protein product of the HER-2/neu proto-ocogene, and
Fc gamma RIII (CD16), expressed by human natural killer cells, neutrophils and differentiated monocytes, mediates the specific cytotoxic activity of these effector cells to
tumor cells. A group of 24 patients with c-erbB-2-overexpressing
tumors were treated with intravenously administered 2B1 in a phase I clinical trial and followed
after treatment to evaluate the diversity and extent of the 2B1-induced humoral immune responses. As expected, 17 of 24 patients developed human anti-(murine Ig)
antibodies (HAMA) to whole 2B1
IgG in a range from 100 ng/ml to more than 50000 ng/ml; 10 of these patients (42%) had strong (at least 1000 ng/ml) HAMA responses, some of which were still detectable at day 191. These responses were usually associated with similar reactivity to the F(ab')2 fragments of the parental
antibodies 520C9 (anti-c-erbB-2) and 3G8 (anti-CD16). We sought evidence of an idiotypic cascade induction, indicating a prolonged specific treatment-induced effect on at least one selected target of 2B1. Using competition-based
enzyme-linked
immunosorbent assays, specific
anti-idiotypic antibodies (Ab2) were detectable against 520C9 in 11 patients and against 3G8 in 13 patients. Peak
anti-idiotypic antibodies generally occurred 3-5 weeks from treatment initiation, with a downward trend thereafter. There was a statistically significant correlation among the induction of significant HAMA responses, anti-idiotypic antibody production and the development of
antibodies to c-erbB-2. The anti-c-erbB-2 responses, which were distinct from anti-anti-idiotypic (Ab3)
antibodies, were detected in the post-treatment sera of 6/16 patients examined. No obvious correlation could be made between the development of humoral immune responses, the dose received, and the clinical response. Future investigation involving 2B1
therapy will concentrate on investigating an association of these humoral responses to any c-erbB-2-specific cellular responses. Manipulations of 2B1
therapy effects that augment immunity to c-erbB-2 could provide additional avenues for
immunotherapy with this and other
bispecific antibodies.