Humanized Antibodies Targeting Ectodomains of IL ‐ 6R and GP130 Suppress Satyajit Dey Pereira, Guruprasad Baipadithaya, Keshava Prasad, Ritam Naha, Lavanya Prakash Acharya, Ganesh Prasad Uppenda Gopalakishna, Ramyaa Periasamy, Arun Chandrashekar, Shama Bhat, Manjunath B. Joshi, Kapaettu Satyamoorthy

ABSTRACT

Interleukin‐6 (IL‐6) signalling is a key driver of breast cancer progression, activating pro‐survival, pro‐inflammatory and metastatic programs through its receptors, IL‐6R and GP130. Elevated IL‐6 levels correlate with poor prognosis in breast cancer patients and persistent IL‐6/STAT3 activation promotes tumour proliferation, metastasis, angiogenesis and therapy resistance. Although therapeutics targeting this pathway have shown promise, most have focused on individual signalling nodes and yielded limited efficacy in breast tumours. In this study, we generated murine monoclonal antibodies targeting ectodomains of IL‐6R and GP130 receptors involved in IL‐6/IL‐6R/GP130 complex formation and humanized the lead candidates E17 (anti–IL‐6R) and NA7 (anti–GP130). The resulting humanized antibodies, huE17 and huNA7, exhibited target specificity and effectively inhibited IL‐6 induced STAT3 activation and tumour promoting phenotypes in vitro. In vivo evaluation using orthotopic breast cancer xenografts and agarose plug angiogenesis assays showed both individual and combined antibody treatments significantly suppressing tumour growth. Structural modelling suggested that huE17 and huNA7 engage receptor surfaces spanning multiple ectodomains of IL‐6R and GP130, consistent with disruption of IL‐6/IL‐6R/GP130 complex receptor assembly. Together, these findings support the preclinical development of huE17 and huNA7 and the potential of dual IL‐6R and GP130 targeting in IL‐6–driven breast cancer.