MP0250, a VEGF and HGF neutralizing DARPin® molecule shows high anti-tumor efficacy in mouse xenograft and patient-derived tumor models

Abstract

BackgroundThe VEGF/VEGFR and the HGF/cMET pathways are key mediators of the interplay of tumor cells and their microenvironment. However, inhibition of VEGF has been shown to produce only limited clinical benefit and inhibition of the activation of cMET by HGF has not translated into clinical benefit in pivotal trials. MP0250, a DARPin® molecule that specifically inhibits both VEGF and HGF has been developed to explore the clinical potential of dual inhibition of these pathways.ResultsMP0250 binding to VEGF and HGF inhibited downstream signalling through VEGFR2 and cMET resulting in inhibition of proliferation of VEGF- and HGF-dependent cells. Antitumor activity was demonstrated in VEGF- and HGF-dependent xenograft and syngeneic models with activity superior to that of individual VEGF- and HGF-blocking DARPin® molecules. Combination therapy studies showed potentiation of the antitumor activity of chemotherapy and immunotherapy agents, including an anti-PD1 antibody.Materials and MethodsPotency of MP0250 was assessed in cellular models and in a variety of xenograft models as monotherapy or in combination with standard-of-care drugs.ConclusionsDual inhibition of VEGF and HGF by MP0250 produced powerful single agent and combination antitumor activity. This, together with increasing understanding of the role of the HGF/cMET pathway in resistance to VEGF (and other agents), supports testing of MP0250 in the clinic.

Design and characterization of MP0250, a tri-specific anti-HGF/anti-VEGF DARPin® drug candidate

“…Its pharmacokinetic profile and pharmacologic activity make MP0250 a promising candidate for cancer therapy. Fiedler et al 25 have shown efficacy of MP0250 in a number of mouse tumor xenograft models, indicating that the drug candidate indeed has the potential to improve patient benefit beyond single agent anti-VEGF therapy. Based on the results shown here, the preclinical in vivo data, as well as safety and tolerability assessments, clinical testing of MP0250 has been initiated (ClinicalTrials.gov Identifier NCT02194426).…”

Alternative Strategies to Inhibit Tumor Vascularization

“…For example, Abs against anti-angiopoietin-2 (like nesvacumab, AMG780, MEI3617, and vanucizumab), and Abs anti-integrin αvβ3 have been successfully tested in phase I/II study [40,41]. Another example of an antibody targeting alternative angiogenic pathways is MP0250, a genetically engineered designed ankyrin repeat protein (DARPin ® ) that specifically binds to VEGF-A, hepatocyte growth factor (HGF), and human serum albumin (HSA) [42,43]. The antibody is currently being studied in phase I and II clinical trials on multiple myeloma relapses (NIH N. NCT03136653) [44] on EGFR-mutated non-small cell lung cancer (NIH N. NCT03418532) and on other neoplasms (NIH N. NCT02194426).…”

Status of Agents Targeting the HGF/c-Met Axis in Lung Cancer

“…A phase 1 study [ 37 ] showed a good safety profile and some activity in patients with c-Met abnormalities. MP0250 is a dual-specific antibody mimetic (a designed ankyrin repeat protein (DARPin ® ) that functions as a neutralizing protein for both VEGF and HGF [ 75 ]. It contains two human serum albumin antibody mimic sequences that flank an anti-HGF and an anti-VEGF sequence, producing a moiety that binds and neutralizes both VEGF and HGF [ 75 ].…”