Tiragolumab

iStock/ Afry Harvy TIGIT-targeting therapies have largely disappointed in recent months, with failed studies, terminated partnerships and shuttered businesses. Here are five biopharma players staying alive with differentiated candidates against the once promising immuno-oncology target. When GSK turned its back on development partner iTeos Therapeutics in May, a terminal countdown began for the Massachusetts-based biotech. Weeks later, time ran out and iTeos was forced to shutter operations. The biotech is only the latest casualty in a therapeutic space that is turning into a drug development wasteland. The asset that led to iTeos’ ultimate demise was belrestotug, an anti-TIGIT therapy that was being assessed for multiple solid tumors, including non-small cell lung and head and neck cancer. Though the partners did not reveal specific data, iTeos noted in May that even when used with GSK’s PD-1 blocker Jemperli, belrestotug was unable to improve progression-free survival in patients with NSCLC versus Jemperli alone. Findings in patients with head and neck cancer were likewise disappointing. Belrestotug is just one therapy in the long line of TIGIT assets that have run into insurmountable clinical roadblocks. Found in certain cells of the immune system, TIGIT —which stands for T cell immunoreceptor with immunoglobulin and tyrosine-based inhibitory motif domain—is a receptor with immunosuppressive effects. Under healthy circumstances, TIGIT helps regulate the release of cytokines, in turn suppressing the activity of T cells. TIGIT is overexpressed in many cancers , allowing tumor cells to inhibit the immune system’s anti-cancer response. Many biopharma players have seized on this mode of action, identifying molecules that can block TIGIT in cancers in hopes of boosting the body’s antitumor activity. But none have been successful so far, and the experience of GSK and iTeos has become the unfortunate standard. In July 2024, Roche’s tiragolumab failed to improve survival in patients with NSCLC in the closely watched SKYSCRAPER-06 trial . A few months later, another study of tiragolumab, SKYSCRAPER-01, flopped . Merck has also been stymied by TIGIT. In May 2024, the pharma scrapped a late-stage study for its anti-TIGIT antibody vibostolimab due to treatment toxicity that led to a high rate of study dropouts. Safety concerns also led to the demise of another Phase III study later that same year, this time in extensive-stage small-cell lung cancer. A key reason behind these failures, according to Padmanee Sharma, a professor in the department of Genitourinary Medical Oncology at MD Anderson Cancer Center, is that much remains unknown about how this pathway specifically works. Other proteins may also be involved in the overall TIGIT mechanism, she told BioSpace in an email, or TIGIT itself may have a role to play in other cellular functions. “TIGIT is a complex biologic target,” Sharma said. “The exact mechanism is not clear.” Still, many persist in developing a TIGIT therapy, largely because its signals of efficacy are encouraging. “Pre-clinical data indicate that TIGIT is a relevant pathway to pursue,” Sharma said, particularly for antibodies, which in lab studies have shown “anti-tumor responses.” But a more complete picture of the TIGIT pathway, including the biological pathways that regulate TIGIT, are required to set the field up for success. Here, BioSpace looks at four companies that claim differentiated approaches. Will they succeed where their peers have failed? AstraZeneca’s Sprawling Development Program for Rilvegostomig AstraZeneca’s TIGIT rilvegostomig is enrolled in an extensive late-stage development program, with 10 Phase III studies underway in NSCLC, gastric cancer, biliary tract cancer and other solid tumors, Shubh Goel, the company’s global franchise head of oncology, told BioSpace in an email. AstraZeneca is also leveraging its partnership with Daiichi Sankyo to test combinations of the TIGIT with the antibody-drug conjugate Datroway for specific subtypes of NSCLC. The goal of such a broad development push, Goel explained, is to establish rilvegostomig as a “best-in-class [immuno-oncology therapy] and the preferred IO backbone for combination therapies.” Aside from these late-stage programs, AstraZeneca is also running multiple early studies of rilvegostomig “across different tumor settings and in combination with a range of standard of care and novel agents,” Goel said. AstraZeneca’s steep investment into rilvegostomig is underpinned by what Goel called a “differentiated” mechanism of action. The molecule’s bispecific structure “optimizes dual PD1/TIGIT check point control.” Rilvegostomig first anchors itself to TIGIT before targeting PD-1, in turn “leading to enhanced immune activation and improving anti-tumor responses,” Goel explained, as compared with dosing patients with separate PD-1 and TIGIT agents. Simultaneously, rilvegostomig minimizes the unwanted depletion of effector immune cells that also express TIGIT, which results in a cleaner safety profile. Aside from a differentiated molecule, AstraZeneca is also being deliberate with its trials, focusing on patients most likely to respond to PD-1/TIGIT co-inhibition, Goel said. So far, AstraZeneca’s strategy seems to be working, at least in NSCLC. At the American Society of Clinical Oncology meeting in May, the pharma presented Phase Ib data showing that rilvegostomig plus Datroway could elicit a 57.5% confirmed overall response rate (ORR) and a 95% disease control rate as a first-line treatment for patients with advanced or metastatic NSCLC. Gilead, Arcus Forge New TIGIT Path With ‘Silent’ Killer Joining AstraZeneca in the late-stage TIGIT field are Gilead and Arcus Biosciences, which are co-developing the monoclonal antibody domvanalimab for solid tumors. Unlike rilvegostomig, domvanalimab only targets TIGIT. To address a second immune checkpoint, the partners are co-administering it with Arcus’ zimberelimab, an investigational PD-1 inhibitor, plus chemotherapy. The companies are proposing this regimen as a first-line therapy for NSCLC and upper gastrointestinal cancer—both programs are in late-stage development —and for head and neck carcinoma, currently in mid-stage studies. What sets domvanalimab apart from the rest of the TIGIT field, according to Ashish Jhingan, program strategy leader of oncology at Gilead, is its Fc-silent properties. That is, the antibody tail—the part that isn’t involved in binding to its targets—has been rendered inert. Such an approach, which goes against the current trend in the TIGIT space, minimizes the likelihood of inadvertently killing cells other than the malignant target, according to Arcus’ website . “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 the peripheral regulatory T cells important in avoiding immune-related toxicity,” Jhingan told BioSpace in an email. This silent approach has so far worked well for the partners. In November 2023, they released data from the Phase II EDGE-Gastric trial, demonstrating a 59% ORR in patients after treatment with the domvanalimab-based regimen. This effect was stronger in those with high PD-L1 expression level, hitting 80% ORR. Six-month progression-free survival (PFS) at the time was 77%. Follow-up results in June 2024 showed that the domvanalimab combo could maintain its efficacy through a median of 49.4 weeks on treatment. ORR dipped only slightly to 58.5% while 12-month progression-free survival (PFS) reached 57.6% in the overall study population. Gilead and Arcus have moved domvanalimab into late-stage development. The partners are running the STAR-221 study, which will test the same regimen of domvanalimab plus zimberelimab and chemotherapy in locally advanced unresectable or metastatic HER2-negative gastric, gastroesophageal junction or esophageal adenocarcinoma. Enrollment began in June 2024 , with initial findings expected in 2026, according to Jhingan. Agenus Pushes Ahead After Losing Powerhouse Partner In May 2021, when the TIGIT space was still young, Bristol Myers Squibb sought to get ahead of its cancer competitors with a $200 million spot payment to Agenus , licensing the biotech’s anti-TIGIT therapy AGEN1777. The deal included up to $1.36 billion in development, regulatory and commercial milestone payments. But ultimately, BMS found the partnership to be more burdensome than beneficial. In August 2024, the company walked away from the pact and returned AGEN1777 to Agenus, a move that was attributed to the “broader strategic realignment of [BMS’] development pipeline,” according to an Aug. 2, 2024 SEC document from Agenus. The contract termination formally took effect on Jan. 26. According to the regulatory filing, under the partnership, Agenus and BMS were able to generate “significant safety data” in early studies, with “indications of clinical activity.” With these in hand, Agenus in August said it intends “to explore further development and/or relicensing” of AGEN1777, but has yet to provide concrete plans for the molecule. Among these development prospects is the possibility of combining the asset with Agenus’ other immuno-oncology therapies. It might take some time, however, before Agenus provides next steps for its TIGIT program, since the biotech is currently in the midst of a strategic realignment initiative aimed at lowering its cash burn to $100 million during the 2025 fiscal year. Mereo Seeks Strategic Sponsors for Etigilimab Rounding out this list is Mereo BioPharma and its troubled program etigilimab , an IgG1 monoclonal antibody designed to target TIGIT, in turn, potentially “improving the activation and effectiveness of T-cell and NK [natural killer] cell anti-tumor activity,” as per its website. Unlike Gilead and Arcus, Mereo has decided against silencing the Fc domain of etigilimab, instead deliberately giving the TIGIT therapy the added functionality of reducing regulatory T cells while also maintaining the levels of CD8-positive cytotoxic T cells. In turn, etigilimab retains the immune system’s cancer-killing action while also delivering a clean safety profile, the biotech claims . Early testing of the mechanism suggests promise in the clinic so far. Phase Ib/II data published in October 2023 demonstrated an ORR of 25% in 40 treated patients, including three who achieved a complete response and seven who saw a partial response. Eleven patients had stable disease beyond 120 days, while seven maintained clinical benefit for more than a year. Despite a promising mechanism and clinical profile, however, Mereo has struggled to rally the support it needs to take etigilimab forward. In June 2019—just months before it would be swallowed by BMS in a $74 billion acquisition—Celgene decided not to exercise an option to license etigilimab. This was despite Mereo advancing the antibody as part of a two-therapy combo with BMS’ PD-1 blocker nivolumab. Since then, and even through a mid-stage readout in 2023, the industry has continued to overlook etigilimab. In a 2024 year-end report, Mereo revealed that it has put TIGIT on the backburner . “We intend to out-license or sell etigilimab . . . to third parties for the further development, recognizing the need for greater resources to take [this asset] to market,” the company wrote.

一、从明星靶点到滑铁卢：TIGIT 的兴衰启示曾几何时，TIGIT 作为肿瘤免疫治疗的 “明日之星”，吸引了全球制药巨头竞相布局。然而短短数年间，随着临床数据接连折戟，BMS、GSK、诺华等行业领军者纷纷撤离，留下超 14 亿美元前期投资付诸东流的残酷现实。这场资本与科学的双重挫败，不仅让药企血本无归，更暴露出创新药研发领域 “热门靶点扎堆” 的系统性风险。BMS、吉利德、GSK 和诺华四大药企为切入 TIGIT 赛道，合计支付 14 亿美元 upfront 费用，加上默克、罗氏等玩家，整个领域的前期投入规模惊人。其中吉利德为获得 Arcus Biosciences 的 domvanalimab，不仅支付 2.75 亿美元期权费，更斥资 7.4 亿美元增持股权，如今 Arcus 股价较投资时暴跌超 60%，这笔投资几乎沦为 “沉没成本”。二、临床失败全景：从 III 期折戟到项目关停罗氏的 tiragolumab 曾被寄予厚望，其开展的 10 项 III 期试验累计招募近 4600 名患者，覆盖非小细胞肺癌等多个癌种，但 2023 年公布的 KEYNOTE-966 试验显示，与 Keytruda 单药相比，联合治疗未显著改善总生存期。默克的 vibostolimab 同样在 III 期试验中碰壁，五大研究项目因疗效不足陆续终止。GSK 与 iTeos 合作的 TIGIT 抗体开发计划更显悲壮 —— 双方原计划投入 9 亿美元用于全球开发，却在 II 期试验失败后黯然收场。iTeos 因核心资产折戟直接宣布关停，其累计融资 11 亿美元中超 5 亿美元化为研发损耗，成为 TIGIT 靶点崩塌的标志性事件。三、研发烧钱黑洞：隐藏在预算里的巨额损耗尽管药企财报未单独披露 TIGIT 研发支出，但通过合作项目可窥见冰山一角。Arcus 在 2022-2024 年间从合作方获得 1.61-1.65 亿美元研发补偿，而吉利德主导的试验投入尚未完全统计。罗氏 2024 年 150 亿美元研发预算中，tiragolumab 相关项目占比可观，其多癌种布局的 III 期试验单项成本或超 2 亿美元。更值得警惕的是，TIGIT 失败并非孤例。2018 年 BMS 斥资 18.5 亿美元与 Nektar 合作 IL-2 项目，最终因毒性问题折戟；2020 年吉利德 49 亿美元收购 Forty Seven 的 CD47 抗体，同样因临床失败告终。这些案例共同构成肿瘤免疫治疗的 “失败图谱”，揭示出靶点机制验证不足便盲目投入的行业乱象。四、行业转向与风险警示：从单靶点到双抗竞赛当 TIGIT 热潮退去，PD-1/L1xVEGF-A 双抗成为新风口。过去九个月内，BioNTech、BMS 等企业已豪掷 40 亿美元争抢该类资产，潜在里程碑付款更可达 200 亿美元。Akeso 的 ivonescimab 在肺癌试验中击败 Keytruda，虽全球试验仍存争议，却点燃了药企的押注热情。“TIGIT 的溃败暴露了靶点同质化的致命伤。” 一位资深行业分析师指出，“当数十亿美元涌向同一机制，临床失败的多米诺骨牌效应难以避免。” 如今双抗赛道的疯狂投入，正重演 TIGIT 当年的剧本 —— 若疗效未达预期，新一轮资本浩劫或将上演。五、反思与启示：创新药研发的理性回归TIGIT 的折戟为行业敲响警钟：在免疫治疗领域，仅凭临床前数据便大规模投入的时代已然过去。专家呼吁建立更严格的靶点筛选机制，例如结合单细胞测序等技术深入解析靶点生物学功能，避免 “跟风式研发”。对于投资者而言，TIGIT 危机揭示了生物医药投资的高风险属性 —— 即便是巨头押注的热门靶点，也可能因机制缺陷或临床设计失误而全盘皆输。随着双抗等新赛道的资金涌入，如何在创新与风险间寻找平衡，成为整个行业亟待解答的命题。当罗氏、默克们陆续注销 TIGIT 相关资产，这场耗资数十亿美元的科学实验最终以失败告终。但对肿瘤患者而言，更沉重的代价在于：无数潜在的治疗希望，已随着靶点的陨落而消逝在研发管线的废墟之中。参考来源：https://www.biospace.com/business/tigit-turmoil-how-pharma-burned-billions-on-failed-immuno-oncology-projects识别微信二维码，添加抗体圈小编，符合条件者即可加入抗体圈微信群！请注明：姓名+研究方向！本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。