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iStock/ Marcin Klapczynski After several high-pro including BMS’ $1.5B breakup with Agenus, anti-TIGIT therapies are generating cautious optimism. TIGIT therapeutics have the potential to extend the benefits of checkpoint inhibitors to patients who can’t yet benefit from the anti-PD-1 and anti-PD-L1 therapeutics that have revolutionized cancer treatment. While the modality has seen a spate of high-pro recent mid-stage data from an anti-TIGIT therapy developed by iTeos Therapeutics shines a light on the continued interest and movement in this space. Last month at the 2024 European Society for Medical Oncology (ESMO) Congress, iTeos and GSK revealed Phase II results showing that iTeos’ anti-TIGIT candidate belrestotug plus GSK’s anti-PD-1 therapeutic Jemperli elicited promising response rates in patients with non-small cell lung cancer (NSCLC). The data had been highly anticipated, with the prime ESMO presentation spot alone propelling a rise in iTeos’ shares, according to STAT News . TIGIT, short for T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domains, is an inhibitory receptor that is expressed on the surface of the T cells and natural killer (NK) cells, as well as other immune cells, explained Hua Wang, an assistant professor at the University of Illinois Urbana-Champagne. “Anti-TIGIT therapies . . . aim to reactivate the T and NK cells,” he told BioSpace . But while much excitement has surrounded this class of cancer therapy, companies in the space have suffered numerous setbacks, most recently in August when Bristol Myers Squibb canceled a $1.5 billion TIGIT deal and returned the asset to Agenus. Earlier in the summer, Roche and Merck each announced that recent Phase II/III studies comparing anti-TIGIT therapeutics alone or in combination, against either Keytruda or Keytruda plus chemotherapy, failed to meet the primary endpoints. Despite the challenges, the anti-TIGIT space has remained active. Roche and Merck are both continuing TIGIT studies, for example. “We believe TIGIT is a valid target, based on data and clear activity observed in some tumor types,” a Roche spokesperson told BioSpace in an email. Readouts for Roche’s Phase III trials of tiragolumab are expected this year in NSCLC, and for esophageal cancer and liver cancer in 2025. Meanwhile, Merck is conducting several Phase III studies evaluating a fixed-dose combination of its anti-TIGIT drug vibostolimab and Keytruda in NSCLC, including KeyVibe-003 , KeyVibe-006 and KeyVibe-007 . Other companies in the TIGIT space include BeiGene and AstraZeneca , as well as partners Gilead and Arcus Biosciences. The latter two companies are moving anti-TIGIT therapy domvanalimab and anti-PD-1 antibody zimberelimab plus chemotherapy into Phase III studies for lung and gastrointestinal cancers after positive Phase II data presented in the spring, as GSK and iTeos take their combo into Phase III in first-line NSCLC. Trial Design Matters The recent difficulties in the TIGIT space show how trial design affects outcomes, Michel Detheux, president and CEO of iTeos, told BioSpace by email. “Roche, Merck, and Arcus (with Gilead) each evaluated their TIGIT therapeutics combined with a PD-1 and chemotherapy in first-line NSCLC despite no pattern of care having been established to indicate that chemotherapy enhanced efficacy in that setting.” For example, in 2023, Roche’s SKY-01 Phase III trial “compared its TIGIT+PD-L1 [tiragolumab + atezolizumab] against its own PD-L1 [atezolizumab] instead of the standard of care [Keytruda, a PD-1 inhibitor], which created confusion about the performance of its TIGIT + PD-L1 and PD-L1,” Detheux said. More recently, he continued, Merck’s Keyvive-008 evaluated vibostolimab plus Keytruda in small cell lung cancer (SCLC). “Merck was attempting to beat a newly established standard of care with its TIGIT+PD-1 therapeutic, despite SCLC being an indication where TIGIT had failed previously, and where [Keytruda] also had failed.” Merck discontinued the Keyvive-008 trial. What the failed trials show is that “the immune checkpoint axis is perhaps more complicated than we thought,” Michael Gibson, an associate professor of medicine at Vanderbilt University, told BioSpace by email. “More components are involved in the tumor microenvironment than just the drug-target interaction.” Setbacks should be expected, though, Gibson added. “The nature of clinical investigation teaches us that setbacks are more common than progress. We learn a great deal from so-called negative trials.” The question of whether setbacks related to TIGIT therapeutics may be overcome “is both scientifically interesting and clinically challenging,” Gibson commented. He speculated that in the face of setbacks, this class may add therapeutic benefits as a combination therapy. While checkpoint inhibitors are the current companions of choice, there may be other possibilities. “Some insight may lie, for example, in drug mechanisms such as bispecifics and antibody-drug conjugates, combinations of inhibitors, modulation of the tumor microenvironment and even, perhaps, by affecting the patient’s microbiome,” Gibson said. Notably, “Roche found a correlation between the response to anti-TIGIT therapy and the expression level of CD-155 on the surface of the tumor cell. That’s very positive,” Wang said. “It suggests that patients who are not responding to anti-PD-1 or anti PDL-1 therapies who have a high expression level of CD-155 may respond to anti-TIGIT therapeutics.” Bright Lights Based on recent results from iTeos and GSK, as well as Gilead and Arcus, it appears the tide may be beginning to turn. At ESMO, iTeos and GSK reported that after at least 5.6 months of follow-up, 60% of patients given the belrestotug/Jemperli combo had an objective response, compared to about 30% of those given Jemperli alone. What sets belrestotug apart from most other TIGITs is that it has a mutli-faceted mechanism of action and appears effective at low doses, Detheux noted. TIGIT therapeutics by BeiGene, Roche and Merck required either “very high doses” or were ineffective, he said. Belrestotug is also the only TIGIT program that has had to comply with the FDA’s Project Optimus, with a dose-ranging exercise required to understand the efficacy and safety pro its TIGIT+PD-1 doublet, Detheux said. “We believe this will allow GSK and iTeos to succeed in selecting the optimal dose, whereas others have struggled and launched Phase III trials without conducting a more in-depth review of the dose selection.” Meanwhile, at the 2024 American Society of Clinical Oncology conference, Gilead and Arcus presented Phase II data from a combination of domvanalimab and zimberelimab plus chemotherapy in upper GI cancers. It showed that nearly 60% of patients achieved progression-free survival at 12 months. “By binding to TIGIT with Fc-silent properties, domvanalimab is believed to work by freeing up immune-activating pathways and activate immune cells to attack and kill cancer cells without depleting critical immune cells,” a Gilead spokesperson told BioSpace by email. Currently, fewer than 40% of cancer patients respond to immunotherapy . “Therefore, we need more new technology and immunotherapies and we have to keep testing. Hopefully, patients will respond,” Wang said. But, he added, whether future therapeutic options will include anti-TIGIT therapeutics remains to be seen. “I would be cautious about [speculating] whether anti-TIGIT therapeutics will be successful, but there’s some hope.”

DUBLIN--( BUSINESS WIRE )--The "Anti TIGIT Antibodies Clinical Trials & Market Opportunity Outlook 2028" report has been added to ResearchAndMarkets.com's offering. Anti TIGIT antibodies have emerged a promising approach in cancer immunotherapy, offering new hope for patients with various types of cancers, particularly solid cancers. TIGIT (T cell immunoreceptor with Ig and ITIM domains) is an inhibitory receptor expressed on T cells and natural killer (NK) cells, playing a crucial role in modulating immune responses. By targeting TIGIT, researchers aim to enhance the immune system's ability to recognize and eliminate cancer cells, potentially revolutionizing cancer treatment strategies. The therapeutic potential of TIGIT as a target for cancer immunotherapy lies in its function as an immune checkpoint molecule. When TIGIT interacts with its ligands, such as CD155 and CD112, it suppresses T cell sand NK cell activation, potentially allowing cancer cells to evade immune surveillance. By blocking this interaction with anti-TIGIT therapeutic approaches, researchers hope to reinvigorate the immune response against tumors, leading to improved clinical outcome for cancer patients. Among the various approaches for targeting TIGIT, monoclonal antibodies have emerged as the most widely used and promising agents. These antibodies are designed to specifically bind to TIGIT, preventing its interaction with its ligands and thus releasing the "breaks" on the immune system. Their high specificity and relatively low toxicity of antibodies make them attractive candidates for clinical development. The field of anti-TIGIT antibody development has seen rapid progress, with over 50 candidates currently in clinical development. This robust pipeline underscores the significant interest and potential of this approach in cancer treatment. Among these, more than five anti TIGIT antibodies have advanced to phase 3 clinical trials, representing the most advanced stage of clinical development before potential regulatory approval. These include Vibostolimab, Tiragolumab and Ociperlimab, developed by the pharmaceutical marker leaders, Merck Genentech and BeiGene, respectively. These phase 3 clinical trials are assessing the safety and efficacy of these anti-TIGIT antibodies in various cancer types, with a particular focus on non-small cell lung cancer (NSCLC). The emphasis on NSCLC is not surprising, given its high prevalence and the need for more effective treatment options. NSCLC represents a significant portion of lung cancer cases and has shown promising responses to immunotherapy approaches in the past. Several key factors are driving the market potential of anti-TIGIT antibodies. Firstly, there remains a substantial unmet medical need in cancer treatment, especially for patients who do not respond to or develop resistance to existing immunotherapies. Anti-TIGIT antibodies offer a novel mechanism of action that could address these challenges. Moreover, these antibodies show promising results in combination with established therapies like PD-1/L1 inhibitors, potentially expanding the market for both drug classes and improving treatment outcomes. This becomes visible in Merck's vision of developing a coformulation of its anti-TIGIT antibody Vibostolimab with its blockbuster anti-PD-1 antibody pembrolizumab for the treatment of various solid tumors. The broad applicability of anti-TIGIT antibodies across various cancer forms presents another significant market opportunity. While a majority of clinical trials currently focus on NSCLC, many other ongoing clinical trials are exploring their efficacy in other solid cancers tumors and hematological malignancies, which could lead to multiple approved indications, consequently increasing the anti-TIGIT antibody market size. As evident from the examples above, the competitive landscape for the anti-TIGIT antibody market is dynamic, with major pharmaceutical companies and biotechnology firms vying for market share. While Vibostolimab leverages the company's strong position in the immuno-oncology market, another, Domvanalimab, being developed by Gilead Sciences and Arcus Biosciences, benefits from a partnership between a major pharmaceutical company and a competent biopharmaceutical company. In conclusion, anti-TIGIT antibodies not only represent a significant advancement in cancer immunotherapy, but also present many opportunities for drug development and market expansion. With its potential to address unmet medical needs, broad applicability and alignment with personalized medicine, this emerging class of drugs is poised to capture a substantial portion of cancer immunotherapy market. Anti TIGIT Antibodies Clinical Trials & Market Opportunity Outlook 2028 Report Highlights: Anti TIGIT Antibodies in Clinical Trials: > 50 Antibodies First Anti TIGIT Antibody to Get Approval Within Next 5 Years Global Anti TIGIT Antibodies Clinical Pipeline Insight by Company, Indication and Phase Insight on More Than 50 Anti TIGIT Antibodies in Clinical Trials Anti TIGIT Antibodies Market Trends by Indication & Country Global Anti TIGIT Antibodies Market Dynamics Key Topics Covered: 1. Introduction to Anti TIGIT Antibody 1.1 Overview 1.2 Mechanism of Anti TIGIT Antibodies 1.3 Clinical Approaches to Target TIGIT 2. Global Anti TIGIT Antibodies Clinical Trials Overview 2.1 By Company 2.2 By Country 2.3 By Indication 2.4 By Patient Segment 2.5 By Phase 3. Global Anti TIGIT Antibodies Clinical Pipeline By Company, Indication and Phase 3.1 Research 3.2 Preclinical 3.3 Phase I 3.4 Phase I/II 3.5 Phase II 3.6 Phase III 4. Global Anti TIGIT Antibodies Market Outlook 4.1 Current Clinical & Market Trends 4.2 Future Market Outlook 5. Anti TIGIT Antibodies Market Trends by Indication 5.1 Cancer 5.2 Autoimmune & Inflammatory Disorders 5.3 Microbial Infections 6. Anti TIGIT Antibodies Market by Country 6.1 US 6.2 China 6.3 South Korea 6.4 Australia 6.5 UK 7. Combinations Approaches for TIGIT Therapy 8. TIGIT Co Inhibition with PD1 or PDL1 9. Global Anti TIGIT Antibodies Market Dynamics 9.1 Market Drivers 9.2 Commercialization Challenges 10. Competitive Landscape Akeso Biopharma BeiGene Bio-Thera Solutions Biotheus Compugen FutureGen Biopharmaceutical Merck Sharp & Dohme Nanjing Sanhome Pharmaceutical OriCell Therapeutics Phio Pharmaceuticals Roche Shanghai Henlius Biotech Shanghai Junshi Biosciences Simcere Pharmaceutical Group Tasrif Pharmaceutical For more information about this report visit https://www.researchandmarkets.com/r/sebifx About ResearchAndMarkets.com ResearchAndMarkets.com is the world's leading source for international market research reports and market data. We provide you with the latest data on international and regional markets, key industries, the top companies, new products and the latest trends.

SHANGHAI, China I August 8, 2024 I Shanghai Henlius Biotech, Inc. (2696.HK) announced that the first patient has been dosed in a phase 2 clinical trial (NCT06349980) of HLX53, an anti-TIGIT Fc fusion protein, in combination with HANSIZHUANG (serplulimab, HLX10) and HANBEITAI (bevacizumab, HLX04) for the first-line treatment of locally advanced or metastatic hepatocellular carcinoma (HCC). Liver cancer is one of the most prevalent malignancy in the world. According to GLOBALCAN 2022, there are about 870,000 new cases diagnosed and 760,000 deaths for the tumour in the globe [1] . Meanwhile, primary liver cancer (PLC) is the fifth most common cause and the second mortality cancer in China, with about 370,000 new cases and 320,000 deaths in 2022. From which, hepatocellular carcinoma (HCC) is the predominant pathological type of PLC, which accounts for between 75% and 85% of liver cancer cases [2] . Due to its insidious onset, lack of symptom in its early stage, and quick progression, PLC usually has been in its locally advanced stage or develops distant metastasis when it is diagnosed. As a result, the management becomes extremely difficult and the prognosis usually is poor. The 5-year survival rate of PLC is only about 18% [3] . For patients with advanced liver cancer, the first-line treatment is based on targeted therapy and immunotherapy. And the standard therapy (combination therapies of immune inhibitor plus anti-angiogenic treatment) have shown significant clinical anti-tumour efficacy and survival benefit [2] . However, some patients failed to benefit from the standard therapy and suffered from recurrence or progression of the disease. Thers is still an urgent clinical need to further expand the benefit population with advanced liver cancer and improve the efficacy of immunotherapy. T-cell immunoglobulin and ITIM domains (TIGIT) has emerged as popular inhibitory checkpoint receptor, which is mainly expressed on natural killer (NK) cells, activated CD8+ T and CD4+ T cells, and T regulatory cells. TIGIT binds to the ligand CD155 (poliovirus receptor, PVR) [4] , mainly expressed on antigen-presenting cells (APC) or the surface of tumour cells, to down-regulate T cell and NK cell functions. As an immune checkpoint protein, TIGIT can inhibit innate and adaptive responses in various mechanisms of action and act as “brakes” like PD-1/PD-L1 does to stop T cells from attacking  tumours. Studies have shown that TIGIT inhibitor are effective against lung cancer, gastric cancer, melanoma, multiple myeloma, etc. Moreover, TIGIT has shown a synergistic effect with the PD-1 pathway in preclinical studies, indicating that simultaneous blocking of TIGIT and PD-1/PD-L1 signaling pathways is superior to blocking either pathway alone, which can enhance anti-tumour activity [5] . HLX53 is an anti-TIGIT Fc fusion protein independently developed by Henlius, consisting of variable domain of heavy chain of heavy-chain antibody (VHH) and wildtype IgG1 Fc. Pre-clinical studies have demonstrated that HLX53 exhibits excellent tumour inhibition with good safety. In addition, Henlius has initiated a phase 1 study to evaluate the safety, tolerability, pharmacokinetics characteristics and preliminary efficacy of HLX53 in patients with advanced/metastatic solid tumors. Considering the good efficacy of immune checkpoint inhibitor such as anti-PD-1/PD-L1 antibody plus anti-angiogenic drug in the first-line treatment of patients with advanced HCC, as well as the synergistic effect of TIGIT and PD-1/PD-L1 signaling pathway, Henlius intends to further combine TIGIT inhibitor based on the standard therapy in order to bring greater clinical benefits to patients with advanced HCC. Underpinned by the patient-centric strategy, Henlius has achieved an overall layout of the immune checkpoint products of PD-1/L1, CTLA-4, LAG-3, etc., proactively exploring immuno-oncology combination therapy. Meanwhile, Henlius actively promotes HANSIZHUANG in conjunction with in-house products of the company such as tumour-specific target, angiogenesis target, immunotherapeutic target, etc. and chemotherapy drugs to conduct immune combination therapies in a wide variety of indications, committing to bringing affordable and high-quality innovative biologics to patients around the world. [1] Globocan 2022 (version 1.1) – 08.02.2024；https://gco.iarc.fr/today/en/dataviz/bars-compare-populations?mode=cancer&group_populations=1&cancers=11&populations=900&sort_by=value1&types=0_1&key=total [2]原发性肝癌诊疗指南（2024年版） [3] Asafo-Agyei KO, Samant H. Hepatocellular Carcinoma. 2023 Jun 12. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–. PMID: 32644603. [4] Chauvin, Joe-Marc, and Hassane M Zarour. “TIGIT in cancer immunotherapy.” Journal for immunotherapy of cancer vol. 8,2 (2020): e000957. doi:10.1136/jitc-2020-000957. [5] Chu, Xianjing et al. “Co-inhibition of TIGIT and PD-1/PD-L1 in Cancer Immunotherapy: Mechanisms and Clinical Trials.” Molecular cancer vol. 22,1 93. 8 Jun. 2023, doi:10.1186/s12943-023-01800-3. About NCT05483530 This randomised, double-blind, multicentre phase 2 clinical study aims to evaluate the efficacy, safety, and tolerability of HLX53 in combination with HANSIZHUANG and HANBEITAI versus placebo in combination with HANSIZHUANG and HANBEITAI in previously untreated patients with locally advanced or metastatic hepatocellular carcinoma. The study consists of two parts. Part A is the safety run-in stage, which follows a “3+3” dose-escalation design. Eligible patients will be given different doses of HLX53 (1000 mg or 2000 mg) in combination with HANSIZHUANG (300 mg) and HANBEITAI (15 mg/kg) intravenously, every three weeks. Part B is the preliminary efficacy exploration stage. Eligible patients will be randomly assigned (1:1:1) to receive intravenous HLX53 (1000 mg), HLX53 (2000 mg), or placebo in combination with HANSIZHUANG (300 mg) and HANBEITAI (15 mg/kg), every three weeks. The primary endpoints of Part A are safety and tolerance， evaluating the proportion of patients with a dose-limiting toxicity (DLT) event in each group. The primary endpoints of Part B are objective response rate and progression-free survival assessed by independent radiological review committee per RECIST v1.1. SOURCE: Shanghai Henlius Biotech