Résumé
Background: NRG1 fusions or rearrangements are oncogenic drivers that have been observed in various tumor types including lung, breast and pancreatic cancers. The oncoprotein binds HER3 and activates a downstream signal involved in resistance to anti-HER2 therapy. Some anti-HER3 antibodies have shown activity against tumor bearing NRG1 fusion but this activity remained limited by the competition with ligand NRG1 (neuregulin also named heuregulin) for binding to HER3. Tumor responses have been observed with tyrosine kinase inhibitors afatinib and tarloxotinib, but durable responses are rare and emergence of toxicity and resistance to these drugs could not be avoided. Consequently, a potent agent against tumors bearing NRG1 fusion or highly expressing NRG1 is still awaited.
Results: In vitro, 9F7-F11 antibody was characterized as a non-competing anti-HER3 antibody with increased binding in the presence of ligand NRG1. This allosteric stimulation confers to 9F7-F11 signal inhibition and antiproliferative activity superior to other anti-HER3 antibodies. In vivo activity of 9F7-F11 was evaluated in comparison to MM121 using xenograft models with MDA-MB-175 breast cancer cell line or CTG-0943 patient-derived pancreatic tumor bearing respectively DOC4-NRG1 and APP-NRG1 fusion. Nude mice bearing MDA-MB-175 tumors implanted subcutaneously and treated biweekly for 4 weeks with vehicle or with 15mg/kg of 9F7-F11 or MM121. In these conditions, 100% of cure were obtained with 9F7-F11 whilst only tumor growth stabilization and regrowth after treatment were observed with MM121. These results were confirmed on CTG-0943 patient-derived model after only 3 weeks of bi-weekly injection at 20mg/kg of 9F7-F11 or MM121. Moreover, after 2-weeks of post-treatment tumor regrowth in mice initially treated by MM121, injection of 9F7-F11 led a complete tumor shrinkage. In vivo superiority of 9F7-F11 was also observed with tumors secreting NRG1, suggesting a larger application than tumors with NRG1 fusion.
Conclusions: 9F7-F11 antibody displays a unique potential for targeted treatment of NRG1-positive cancers. 9F7-F11 binding to HER3 is promoted by the ligand NRG1. This binding property was translated in vivo by an outstanding activity against xenograft models bearing NRG1 fusion, characterized by 100% of eradicated tumors. Clinical development of 9F7-F11 for treating NRG1-altered cancers presents a highly attractive perspective.
Citation Format: Thierry Chardès, Olivier Dubreuil, André Pèlegrin, Jean-François Prost, Jean-Marc Barret. 9F7-F11, a non-competing anti-HER3 antibody with allosteric potentiation by NRG1, eradicates in vivo tumors with NRG1 fusion and offers new perspectives for treating NRG1-dependent tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3362.