The research findings indicate that these patients' tumors, confirmed through FDA-approved tests, harbor epidermal growth factor receptor (EGFR) exon 20 insertion mutations. Compared to chemotherapy alone, the combination of Rybrevant with chemotherapy reduces the risk of disease progression or death by 61% and also improves patients' objective response rate (ORR) and progression-free survival (PFS).
Rybrevant is a humanized bispecific antibody targeting EGFR + c-Met. It received FDA approval through the priority review process as early as May 21, 2021, and had previously been granted breakthrough therapy designation. It also obtained approval from the European Union on December 10 of the same year. In October 2023, Johnson & Johnson submitted the first marketing application for Rybrevant to the China National Medical Products Administration. According to information from the Chinese Clinical Trial Registry and Information Disclosure Platform for Drugs, the drug is currently undergoing various clinical trials, including a Phase 3 trial for the treatment of EGFR mutant NSCLC, a Phase 2 trial for patients with advanced or metastatic solid tumors (including EGFR mutant NSCLC), and a Phase 1b/2 trial for patients with advanced or metastatic colorectal cancer.
The mechanism of action of this drug is complex. It can simultaneously bind to the extracellular structures of both EGFR and c-Met, blocking the signaling pathways mediated by EGFR and c-Met. Additionally, it can guide immune cells to target tumors carrying activating and resistant EGFR/c-Met mutations and amplifications.
The two targeted receptors of this drug, EGFR and c-Met, are also subjects of significant interest in the field of nanobody drug research.
EGFR, an essential transmembrane receptor with tyrosine kinase activity, is a member of the epidermal growth factor receptor (HER) family. It consists of three distinct domains: extracellular, transmembrane, and intracellular domains. Researchers have observed abnormal expression of EGFR in many human cancer cells, including elevated expression levels and even sequence mutations. The significant differences in EGFR expression make therapies targeting EGFR highly promising in drug development [1,2].
Another target receptor of Rybrevant, c-Met (hepatocyte growth factor receptor), is also a transmembrane tyrosine kinase receptor that can be expressed on the surface of various cells. High expression of c-Met has been observed on the surface of various tumor cells, such as liver cancer, lung cancer, colon cancer, breast cancer, and pancreatic cancer. The high expression of c-Met is directly associated with cancer development. The advantages of antibody drugs, including good targeting and minimal side effects, make c-Met an important target and diagnostic marker in tumor-targeted therapy [3].
In 2016, 68Ga-labeled HER nanobodies were used for evaluating HER2 expression in breast cancer [4]. In 2019, a collaborative study between the Department of Nuclear Medicine at Shanghai First People's Hospital and King's College London used 99mTc-labeled PD-L1 single-domain antibodies to assess PD-L1 expression in non-small cell lung cancer patients, laying the groundwork for immune checkpoint antibody therapy.
With the advancement of life sciences, nanobodies have played a crucial role in the field of oncology. By selectively targeting and locating extracellular targets on tumor cells, such as EGFR1/2, VEGFR2, c-Met, CXCR7, etc. [5], nanobodies have achieved efficient tumor therapy. Their excellent tissue penetration and high specificity enable nanobodies to effectively penetrate tumor tissues and interact with tumor cells. Therefore, nanobodies hold broad prospects for applications in targeted therapy, immunotherapy, and imaging diagnosis of tumors. Moreover, through drug delivery technology, nanobodies can precisely deliver anticancer drugs into tumor cells to enhance therapeutic efficacy and reduce toxic side effects.
Moreover, leveraging the easily modifiable nature of nanobodies, researchers can unleash their creativity and propose more innovative and effective drug research schemes, following the spirit of "bold hypotheses, cautious verification," to benefit a large number of patients.
NBLST is dedicated to the modification and application of nanobodies, also anticipating the emergence of more therapeutic drugs based on nanobodies for the treatment of tumors, neurological, and autoimmune diseases in the future.