The
Met receptor tyrosine kinase, found to be constitutively activated in many
tumors, has become a leading target for
cancer therapy. Disruptions in Met downregulation have been associated with aggressive
tumor progression with several therapeutic strategies addressing this aspect of Met biology. Castias B-lineage
lymphoma (Cbl)
E3 ligase-mediated degradation, which attenuates Met signaling via
ligand-dependent Met internalization, is a major negative regulator of Met expression. It is believed that one of the mechanisms by which the therapeutic anti-Met
antibodies induce
cancer cell death in Met overexpressing
tumors is via internalization and subsequent degradation of Met from the cell surface. However, a previously reported Met-targeting antibody demonstrated intrinsic agonistic activity while being capable of inducing Cbl-mediated degradation of Met, suggesting that Cbl-mediated degradation requires receptor activation and impedes therapeutic application. We have developed a potent and selective bivalent Met-targeting antibody (
SAIT301) that invokes Met degradation using an alternative regulator LRIG1. In this report, we demonstrate that LRIG1 mediates degradation of Met by
SAIT301 and this degradation does not require Met activation. Furthermore,
SAIT301 was able to downregulate Met and dramatically inhibit growth of
tumors with low or
no Cbl expression, as well as
tumors with Met exon 14 deletion that prevents Met binding to Cbl. In summary, we demonstrate the enhanced therapeutic potential of a novel
tumor-inhibiting anti-Met antibody,
SAIT301, which utilizes a Cbl-independent, LRIG1-mediated Met degradation pathway and thereby avoids the agonism that limits the effectiveness of previously reported anti-Met
antibodies.