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Cbl-independent degradation of Met: ways to avoid agonism of bivalent Met-targeting antibody
1BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT)/Samsung Electronics Co. Ltd, Yongin-si, Republic of Korea.
Abstract:
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.
Insights
A new anti-Met antibody, SAIT301, targets cancer by degrading Met receptor tyrosine kinase via LRIG1, independent of Cbl. This approach avoids agonism and shows therapeutic potential in various tumors.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Met receptor tyrosine kinase is a key target in cancer therapy due to its constitutive activation in many tumors.
- Dysregulation of Met downregulation is linked to aggressive tumor progression.
- Cbl E3 ligase-mediated degradation is a primary negative regulator of Met signaling, but its activation-dependent nature can limit therapeutic antibody efficacy.
Purpose of the Study:
- To develop and characterize a novel anti-Met antibody, SAIT301, that overcomes limitations of previous therapies.
- To investigate the mechanism of Met degradation induced by SAIT301, focusing on its independence from Cbl.
- To evaluate the therapeutic potential of SAIT301 in preclinical models, including those with Cbl deficiencies or Met exon 14 deletions.
Main Methods:
- Development of a potent and selective bivalent anti-Met antibody, SAIT301.
- Demonstration of SAIT301-mediated Met degradation via the LRIG1 pathway.
- Assessment of Met degradation independent of Met activation.
- Evaluation of SAIT301 efficacy in inhibiting tumor growth in models with varying Cbl expression and Met exon 14 deletion status.
Main Results:
- SAIT301 effectively mediates Met receptor degradation through LRIG1, a process not requiring Met activation.
- SAIT301 demonstrates efficacy in downregulating Met and inhibiting tumor growth in models with low or absent Cbl expression.
- The antibody is also effective in tumors with Met exon 14 deletion, which impairs Cbl binding.
- SAIT301 avoids the agonistic activity associated with previously reported Met-targeting antibodies.
Conclusions:
- SAIT301 represents a novel anti-Met antibody with enhanced therapeutic potential.
- The Cbl-independent, LRIG1-mediated degradation pathway utilized by SAIT301 circumvents limitations of existing therapies.
- SAIT301 offers a promising strategy for treating Met-overexpressing tumors, including those resistant to other anti-Met approaches.
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