Roche's TIGIT Monoclonal Antibody Suffers Setbacks; Domestic Biotechs Race to Seize the Opportunity

On May 11, 2022, Genentech, a member of the Roche Group, announced the interim analysis results of its Phase III clinical trial SKYSCRAPER-01, evaluating tiragolumab, a TIGIT antibody, in combination with atezolizumab (Tecentriq®), a PD-L1 antibody, as a first-line treatment for patients with locally advanced or metastatic NSCLC with high PD-L1 expression.

The results showed that the combination therapy did not reach its co-primary endpoint of progression-free survival (PFS). However, the other primary endpoint, overall survival (OS), is not yet mature, and Roche stated that it will continue this clinical study until the next planned data analysis.

Source: Roche Official Website

In fact, as early as March 30, 2022, Roche issued a press release indicating that the Phase III pivotal SKYSCRAPER-02 trial of its immunotherapy drug tiragolumab, in combination with Roche's FDA-approved PD-L1 inhibitor Tecentriq (atezolizumab), carboplatin, and etoposide chemotherapy, did not meet the co-primary endpoints of overall survival (OS) and progression-free survival (PFS) in 490 patients with extensive-stage small cell lung cancer (ES-SCLC).

Nevertheless, Roche will continue to study tiragolumab in the treatment of non-small cell lung cancer (NSCLC) in the phase III pivotal trials SKYSCRAPER-01 and SKYSCRAPER-03.

Potential Target for Tumor Treatment: TIGIT

In the field of oncology, the emergence of immunotherapy represents a significant advancement in cancer treatment in recent years. It has now become an indispensable part of cancer therapy and is even regarded as a wonder drug with broad-spectrum anti-tumor effects. However, the overall response rate for PD-1 treatments currently stands at only 10-30%. As a result, identifying new targets for drugs without corresponding antibodies is becoming a key objective that many pharmaceutical companies both within and outside China are striving to achieve.

Among them, TIGIT is considered one of the most promising and potential targets.

TIGIT (also known as WUCAM, Vstm3, VSIG9) is a receptor of the Ig superfamily and plays a key role in limiting adaptive and innate immunity. TIGIT is expressed in lymphocytes, with high expression particularly in effector and regulatory CD4+ T cells, follicular helper CD4+ T cells, effector CD8+ T cells, and natural killer (NK) cells.

The binding of TIGIT to its homologous ligand PVR directly inhibits lymphocyte activation. TIGIT and PVR are widely expressed in different types of solid tumors, indicating that the TIGIT-PVR signaling pathway may be a major mechanism of tumor immune escape, representing a novel immune checkpoint following PD-1/PD-L1.

Although TIGIT antibody alone has limited efficacy, it can synergize with PD-1 drugs, achieving a 1+1＞2 effect when used in combination.

In 2018, Professors Tian Zhigang and Sun Rui from the University of Science and Technology of China published an article in *Nature Immunology* on the potential anti-tumor value of TIGIT. They found that during tumor development, the presence of TIGIT often leads to immune cell exhaustion. In this state, even if immunotherapy is used to enhance the anti-tumor ability of immune cells, the effect remains limited. Anti-TIGIT monoclonal antibodies can reverse the exhausted state of immune cells, thereby enhancing the anti-tumor capability of patients' immune systems and potentially being effective against various tumors.

Which Biotech in China Will Make a Name for Itself in the TIGIT Space?

Nowadays, the TIGIT target has become a popular target, and many companies in China and abroad are developing TIGIT-targeted drugs, including Roche, Merck, BMS, Arcus Biosciences, and OncoMed. Currently, Roche is in the leading position, with two clinical indications for Tiragolumab having entered Phase III clinical trials.

In China, numerous innovative pharmaceutical companies have also ventured into TIGIT-targeted drugs, including BeiGene, Innovent Biologics, Henlius, Junshi Biosciences, Akeso Biopharma, I-Mab, and Promab Biotechnologies.

BeiGene

Currently, the fastest progress in TIGIT research and development in China is BeiGene's ociperlimab, with seven combination clinical trials currently underway. Last year, BeiGene launched an international multi-center Phase 3 clinical trial of its TIGIT monoclonal antibody combined with the PD-1 tislelizumab for the treatment of locally advanced, unresectable, or metastatic non-small cell lung cancer (NSCLC), going head-to-head with Merck's Keytruda.

On December 20, 2021, BeiGene and Novartis reached a cooperation agreement, under which Novartis will obtain the rights to BeiGene's TIGIT antibody in the United States, Canada, multiple European countries, and Japan. For this, Novartis will pay a $300 million upfront payment, an additional payment of $600 million or $700 million, up to $1.895 billion in milestone payments, as well as a 20-25% sales royalty.

BeiGene's TIGIT monoclonal antibody is currently the second in global development progress. Now that Roche's tiragolumab has failed, ociperlimab has the potential to advance from a fast follow to a global first-in-class product. However, this may also imply that the TIGIT target has limited efficacy in non-small cell lung cancer, and its ultimate success still requires clinical validation.

Innovent Biologics

IBI939, developed by Innovent, is the first TIGIT antibody in China. It can bind to TIGIT and block its interaction with CD155, enhancing immune activation. The drug is currently in Phase I clinical trials.

Innovent Biologics also has a PD-1/TIGIT bispecific antibody drug under research, IBI321, which has entered the clinical research stage.

Henlius

Shanghai Henlius Currently Has Two TIGIT Antibody Drugs Under Development. The first, HLX53, is a nanobody monoclonal antibody targeting TIGIT, with the main indication being solid tumors. The second, HLX-301, is a bispecific nanobody that can simultaneously block both PD-L1 and TIGIT targets, and it is currently in Phase 2 clinical trials.

Conclusion

TIGIT, as a new immunotherapy target, plays an important role in immune regulation of the body and has a crucial regulatory effect on the anti-tumor functions of T cells and NK cells.

Although the interim results of Roche's TIGIT drug tiragolumab in Phase III clinical trials did not meet expectations, the industry still believes that TIGIT antibodies may become the next generation of immunotherapy drugs following PD-1/PD-L1 immunotherapy. It remains to be seen who will be the first to successfully develop a TIGIT antibody.

Editor: Liuli

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