onartuzumab (RG3638)

Collectively, the new complexation and chemoselective photoconjugation chemistries overcome some of the limitations in traditional labeling approaches. Photoradiosynthesis represents an excellent platform for building future antibody-based radiotracers for applications in diagnostic and therapeutic medicine.

Here, we report the synthesis and characterization of 99mTc- and 188Re-onartuzumab by labeling of the cancer-specific mAb onartuzumab (MetMAb) with the corresponding metal-tricarbonyl complexes derived from a novel photoactivatable ligand...Overall, the experiments demonstrated that photoradiosynthesis can be employed to develop a variety of rhenium based radioimmunoconjugates for future applications in tumor targeted radioimmunotherapy. Furthermore, these results underline the high potential of rhenium and technetium radioconjugates as theranostic platforms.

In summary, [99mTc]Tc-HYNIC-cycOn shows substantial promise as a candidate for clinical applications. We show that [99mTc]Tc-HYNIC-cycOn can effectively target and visualize c-Met-expressing tumors in vivo, providing a promising approach for enhancing diagnostic accuracy when detecting c-Met in CRC.

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.