onartuzumab (RG3638)

One-pot photoconjugation reactions to human serum albumin (HSA) as a model protein and the clinically relevant monoclonal antibody formulation MetMAb were performed. [Cu]Cu-7-azepin-HSA and [Cu]Cu-7-azepin-onartuzumab were prepared in less than 15 min by irradiation at 395 nm, with radiochemical purities (RCP) of >95% and radiochemical yields (RCYs) of 42.7 ± 5.3 and 49.6%, respectively. Together, the results obtained here open the way for the development of highly stable Cu-radiopharmaceuticals by using aza-heterocyclic tacn-based chelators, and the method can easily be extended to the development of Cu radiopharmaceuticals for future applications in molecularly targeted radio(immuno)therapy.

Together, these findings indicated a significant correlation between MET overexpression and MET amplification in NSCLC patients but no correlation to prognosis.

A phase 1/2 clinical trial of MCLA-129 in solid tumors is ongoing. These data support the further clinical development of MCLA-129 in patients with NSCLC and other solid tumors.

Head-to-head comparison of the biodistribution and excretion profile of [Zr]ZrFe-2versus two control compounds, alongside characterisation of two potential metabolites, showed that the rotaxane-radiotracer has an improved clearance profile with higher tumour-to-tissue contrast ratios and reduced radiation exposure to critical (dose-limiting) organs including liver, spleen, and kidneys. Collectively, the experimental results suggested that non-covalent mechanical bonds between the radionuclide and mAb can be used to fine-tune the pharmacokinetic profile of supramolecular radiopharmaceuticals in ways that are simply not accessible when using traditional covalent design.

Methods : We developed a HER2-CAR/5D5-T, a T-cell co-expressing a first generation HER2-CAR and a c-MET antibody receptor derived from Onartuzumab (MetMAb; OA-5D5), linked to a 4-1BB co-stimulatory domain...However, the pattern of pro-inflammatory cytokine production (e.g., IL6, TNFα, GMCSF) in conditions with variable densities of target antigen HER2 was moderate, density dependent and distinct from 2 nd generation HER2-CART (Figure 1d-g). Conclusion : Our studies suggest a more favorable functional profile of HER2-CAR/5D5-T and support further testing of strategies to combine c-MET inhibition with CART targeting HER2 or other tumor-associated antigens in sarcoma.

Randomised controlled trials (RCTs) were undertaken assessing whether the addition of anti-HGF/MET agent (rilotumumab or onartuzumab) to chemotherapy improves survival outcomes of advanced GC, but conflict conclusions were reached...It is anticipated that the dissemination of results will take place at conferences and through publication in a peer-review journal, any adjustments from the protocol will be clearly documented and explained in its final report. CRD42020177404.

MET expression was examined immunohistochemically before and after treatment in 122 patients with unresectable or recurrent GC, and was evaluated according to H-score or the scoring criteria used in the MetMAb trial. MET expression is altered post chemotherapy and MET status should be evaluated in real-time. Both MET and pMET expressions might need to be considered for patients suitable for volitinib treatment.

Agents targeting MET and its ligand hepatocyte growth factor (HGF) including small molecules such as crizotinib, tivantinib and cabozantinib or antibodies including rilotumumab and onartuzumab have proven their values in different tumors. Recently, capmatinib was approved for treatment of metastatic lung cancer with MET exon 14 skipping...Preclinical and clinical studies on the combination of HGF/MET-targeted agents with conventional chemotherapeutics or molecularly targeted treatments (EGFR, VEGFR, HER2, RAF/MEK, and PI3K/Akt targeting agents) and also the value of biomarkers are examined. Our deeper understanding of molecular mechanisms underlying successful pharmacological combinations is crucial to find the best personalized treatment regimens for cancer patients.

Blocking experiments gave a statistically significant reduction in tumor uptake (6.34±0.47 %ID g) of ZrDFO-azepin-onartuzumab (n = 4). Experiments demonstrate that photoradiosynthesis is a viable alternative approach for producing Zr-radiolabeled antibodies direct in protein formulation buffer which reduces protein aggregation and liver uptake.

In a relevant renal cell carcinoma (RCC) patient derived xenograft (PDX) model, we use zirconium-89 (89Zr)-labeled anti-RTKs antibodies (immunoPET) onartuzumab, panitumumab, and trastuzumab to monitor MET, EGFR, and HER2 protein levels, respectively, during treatment with agents to which the model was resistant (cetuximab) or sensitive (INC280 and trametinib). Conversely, following dual MET/MEK inhibition, tumor growth was significantly blunted, and corresponded with a decrease in RTK levels. These data show the utility of RTK-targeted immunoPET to annotate RTK changes in protein expression and inform tumor response to targeted therapies.

Various kinase inhibitor and monoclonal antibody (e.g. Emibetuzumab and Onartuzumab) have been developed to block the HGF/c-MET interactions, however, those kinase-inhibiting-based therapeutics have shown limited success in clinical trials...An example of this design strategy is the FDA-approved bispecific antibody blinatumomab...Collectively, the novel c-MET/CD3 bispecific antibody can provide immunotherapy for c-MET-overexpressing tumors which conventional antibody or small molecular inhibitor might not. These findings also support the immunotherapeutic effects on combination of T-cell dependent bispecific antibody and immune checkpoint blockade.

These data uncover the molecular basis of adaptive resistance to MET inhibitors and identifies new FDA-approved multi-drug therapeutic combinations that can overcome resistance.

A Met-directed imaging agent was engineered by labeling Met-specific onartuzumab with zirconium-89 (Zr-89) and its in vivo performance was evaluated in subcutaneous and orthotopic PDAC xenograft models...Crizotinib and cabozantinib, TKIs with known activity against Met and other kinases, decreased PDAC cell line viability in vitro. The TKI with the lowest IC for Met, capmatinib, had no activity in PDAC lines... Our findings demonstrate that while over-expression of Met is not predictive of Met-directed TKI response, immunoPET can detect Met over-expression in vivo and predicts for therapeutic response to Met-selective RLT. This phenomenon can be exploited for other Met-overexpressing tumor types specifically, and to any differentially overexpressed surface molecule more broadly.

P3; N=12; Completed; Sponsor: Hoffmann-La Roche; Active, not recruiting --> Completed