GSK Submits New Clinical Application in China for GSK3359609, the Fastest-Advancing Global ICOS Agonist Antibody

Author | Xiao Yaowan

On August 4, the official website of the Center for Drug Evaluation (CDE) showed that GSK’s investigational Class 1 therapeutic biologic, the ICOS receptor agonist GSK3359609 injection, had submitted a new clinical trial application in China and was accepted for review. To date, no drug targeting the same mechanism has been approved globally. GSK3359609 is currently in Phase III clinical trials worldwide, making it the most advanced investigational new drug in its class.

Source: CDE

Potential Therapies to Enhance the Efficacy of Cancer Immunotherapy

Inducible T-cell COStimulator (ICOS) was first discovered by scientists in 1999 and, along with CTLA-4 and PD-1, belongs to the CD28 family. As a costimulatory molecule, ICOS is primarily expressed on activated T cells in vivo, where it induces cell proliferation, survival, and differentiation, and modulates various T cell functions, including the activation of CD8+ effector T cells, interactions with B cells, and the infiltration of regulatory T cells.

Animal models of various diseases have demonstrated that immunomodulation targeting the ICOS pathway holds significant clinical implications for autoimmune diseases and the establishment of long-term tolerance in transplantation immunity.

The primary role of costimulatory receptors is to enhance the antitumor activity of T cells. Costimulatory receptor agonists targeting ICOS, whether used as monotherapy or in combination with other types of inhibitors, hold promise for improving response rates to antitumor immunotherapies. Meanwhile, the ICOS signaling pathway also demonstrates potential as a biomarker for immunotherapy.

Based on this understanding, ICOS co-stimulatory receptor agonists are expected to overcome the limitations of existing immunotherapies in clinical applications, such as PD-1 antibodies and CTLA-4 antibodies, becoming a potential therapy that can enhance the efficacy of tumor immunotherapy.

GSK's Investigational ICOS Receptor Agonist Monoclonal Antibody GSK3359609

GSK3359609, an investigational IgG4 ICOS agonist monoclonal antibody under development by GSK, is designed to activate the ICOS receptor without inducing T-cell exhaustion in vivo, thereby potentially enhancing T-cell immune responses and improving the efficacy of immune checkpoint inhibitors.

In October 2019, at the European Society for Medical Oncology (ESMO) Annual Meeting, GSK presented results from the INDUCE-1 study, demonstrating highly promising antitumor activity of GSK3359609 in combination with the PD-1 monoclonal antibody pembrolizumab in patients with head and neck squamous cell carcinoma (HNSCC) who had not previously received PD-1/L1 immune checkpoint inhibitor therapy. Among the 34 evaluable patients receiving the combination therapy, the overall response rate (ORR) was 24%; all responding patients maintained a duration of response ≥6 months; and the median progression-free survival (PFS) was 5.6 months. Among the 21 patients with PD-L1 expression, the majority of responders and patients with stable disease had a PD-L1 score <20.

Multiple Clinical Trials Conducted Globally

To date, GSK has conducted multiple clinical trials globally on the monoclonal antibody GSK3359609 for the treatment of various cancer types, with indications including head and neck cancer and malignant solid tumors.

In the Chinese market, GSK3359609 has been approved for two clinical trials: one evaluating its combination with the PD-1 immune checkpoint inhibitor pembrolizumab for the treatment of head and neck squamous cell carcinoma, and the other for the treatment of recurrent and/or refractory malignant solid tumors.

Global Pipeline of Investigational ICOS Agonist Antibody Drugs in the Same Class

In recent years, a substantial body of preclinical studies has thoroughly validated the activity of agonistic antibodies targeting ICOS. Research into modulating specific immune responses via co-stimulatory pathways is increasingly prevalent, with the antitumor efficacy of such agents in combination with PD-1/L1 immune checkpoint inhibitors showing particular promise.

Since 2016, multiple ICOS agonist antibodies have entered clinical development worldwide. In addition to the monoclonal antibody GSK3359609, other investigational new drugs in this class currently in clinical stages include Jounce Therapeutics’ JTX-2011 monoclonal antibody, Bristol Myers Squibb’s BMS-986226 monoclonal antibody, AstraZeneca’s MEDI-570 monoclonal antibody, and Xencor’s XmAb23104 bispecific antibody. Among these, GSK’s GSK3359609 is the most advanced in development and is poised to become the first approved ICOS agonist globally.

Source: Compiled from public information