Bispecific Antibodies Emerge as Promising Immunotherapy Backbone in Cancer Treatment
核心洞察
Bispecific antibodies are gaining traction as a potential successor to Keytruda in cancer immunotherapy, offering enhanced specificity and efficacy.
These antibodies simultaneously target two different molecules, improving the precision and potency of immune responses in tumors.
Clinical trials show bispecifics, like AstraZeneca's volrustomig and Summit's ivonescimab, demonstrate promising results in NSCLC treatment.
The field of cancer immunotherapy is witnessing a significant shift as bispecific antibodies emerge as a promising alternative to traditional monoclonal antibodies. With Merck's Keytruda set to lose exclusivity in 2028, bispecific antibodies, capable of targeting two separate molecules simultaneously, are poised to take center stage.
Advantages of Bispecific Antibodies
Bispecific antibodies offer several advantages over traditional combination therapies. Ryan Schoenfeld, CEO of The Mark Foundation for Cancer Research, noted that bispecifics provide enhanced specificity, working only when both targets are met, allowing for fine-tuned selectivity. This is particularly beneficial in "cold tumors," which lack T cells and are often unresponsive to immunotherapy. By anchoring to the tumor on one side and attracting immune cells on the other, bispecifics can stimulate a localized immune response, mitigating the systemic side effects associated with broad immune stimulation.
John Heymach, chair of thoracic/head and neck oncology at MD Anderson Cancer Center, highlighted the cooperative binding of bispecifics, which promotes clustering and potent signaling, leading to increased efficacy.
Clinical Advancements and Ongoing Trials
AstraZeneca is at the forefront of bispecific antibody development, aiming to overcome the limitations of co-administered drugs. Sunil Verma, SVP and global head of oncology, medical at AstraZeneca, emphasized the cooperative, coordinated receptor binding of their bispecifics, resulting in greater T cell engagement and activation.
Volrustomig, AstraZeneca's PD-1 (搜索)/CTLA-4 (搜索) bispecific, is being studied in combination with chemotherapy for advanced non-small cell lung cancer (搜索) (NSCLC). Data presented at the 2024 World Conference on Lung Cancer (WCLC) demonstrated its effectiveness even in patients with PD-L-1 expression less than 1%, a population traditionally unresponsive to immunotherapy. In non-squamous disease, the response rate was 43%, while squamous disease achieved a 50% response rate, surpassing the efficacy of chemotherapy alone. A Phase III study is currently underway.
Rilvegostomig, another AstraZeneca candidate targeting PD-1 (搜索) and TIGIT (搜索), showed durable responses and favorable tolerability in metastatic NSCLC patients in a Phase I/II trial. In patients with a PD-L-1 tumor proportion score of 50% or higher, the 750 mg dose yielded an overall response rate of 61.8%.
AstraZeneca is also evaluating rilvegostomig with its antibody-drug conjugate (ADC) Enhertu in a Phase III study for HER2-expressing biliary tract cancer (搜索). The combination aims to enhance the immune response while the ADC attacks and kills cancer cells, potentially establishing a new standard of care.
Summit Therapeutics' ivonescimab, targeting PD-1 (搜索) and VEGF (搜索), demonstrated superior performance compared to Keytruda in a Phase III trial for advanced NSCLC. The HARMONi-2 trial showed a nearly 50% reduction in the risk of disease progression or death. However, analysts noted that the trial was conducted exclusively in China, necessitating U.S. data for FDA approval. A follow-up Phase III trial in a more diverse population is planned.
BioNTech is developing acasunlimab, a bispecific targeting PD-L-1 and 4-1BB, utilizing Genmab’s DuoBody technology. This design aims to mitigate off-target effects by requiring simultaneous binding to both PD-L-1 and 4-1BB for activation.
Market Growth and Future Outlook
The bispecific antibody market is experiencing rapid growth, with a global market size of $8.65 billion in 2023 projected to reach approximately $485 billion in the next decade, according to Precedence Research. This growth is driven by the increasing number of approvals and the broad range of patients who could benefit from these therapies.
With numerous bispecifics in clinical development and promising clinical data emerging, the therapeutic modality has firmly established its presence in the oncology landscape.