A Phase 2 Randomized Study of BMS-986207 in Combination With Nivolumab and Ipilimumab as First-line Treatment for Participants With Stage IV Non-Small Cell Lung Cancer

The purpose of this study is to determine the safety and efficacy of BMS-986207 in combination with nivolumab and ipilimumab as first-line treatment for participants with stage IV non-small cell lung cancer (NSCLC).

开始日期2022-10-03

申办/合作机构

Bristol Myers Squibb Co.

NCT04570839

/ Completed临床1/2期

A Phase 1/2 Study Evaluating the Safety, Tolerability and Preliminary Antitumor Activity of COM701 in Combination With BMS-986207 (Anti-TIGIT Antibody) and Nivolumab in Subjects With Advanced Solid Tumors.

This is a phase 1/2 open label sequential dose escalation and cohort expansion study evaluating the safety, tolerability and preliminary antitumor activity of COM701 in combination with BMS-986207 and nivolumab in patients with advanced solid tumors.

开始日期2020-08-31

申办/合作机构

Compugen Ltd.

[+1]

NCT04150965

/ Terminated临床1/2期IIT

A Phase I/II Assessment of Combination Immuno-Oncology Drugs Elotuzumab, Anti-LAG-3 (BMS-986016) and Anti-TIGIT (BMS-986207)

This a Phase I/II randomized trial for patients with relapsed refractory Multiple Myeloma who have relapsed after treatment with prior therapies. The protocol is designed to evaluate two agents, Anti-LAG-3 and Anti-TIGIT, in order to understand their immunologic effects and safety both as single agents and in combination with pomalidomide and dexamethasone. In these arms, patients will be treated with either Anti-LAG-3 or Anti-TIGIT respectively for one cycle as single agent followed by the addition of pomalidomide and dexamethasone in combination for subsequent cycles.
A third arm allows patients to be treated with the FDA approved combination of elotuzumab plus pomalidomide and dexamethsone as a control. This arm will thus allow a concurrent standard of care comparator for the experimental arms.

开始日期2020-07-10

申办/合作机构

Multiple Myeloma Research Consortium

[+10]

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2025-08-01·Journal for ImmunoTherapy of Cancer

Pharmacological and structural characterization of vibostolimab, a novel anti-TIGIT blocking antibody for cancer immunotherapy

Article

作者: Blumenschein, Wendy ; Keenan, Tanya ; Chien, Ellen ; Chakravorty, Srishti ; Fayadat-Dilman, Laurence ; Seghezzi, Wolfgang ; Ban, David ; Pradhan, Komal ; McCoy, Mark A ; Bahmanjah, Soheila ; Wilson, Douglas ; Yuan, Jing ; Williams, Sybil M G ; Baker, Jeanne ; Wong, Janica C ; Beaumont, Maribel ; Grein, Jeffery ; Malashock, Daniel ; Hsieh, Mark ; Fischmann, Thierry O ; Mayhood, Todd ; Han, Jin-Hwan ; Ahn, Eunseon ; Wang, Hongmei ; Cai, Mingmei

Background:

Vibostolimab is a humanized anti-T cell immunoreceptor with immunoglobulin (Ig) and ITIM domains (TIGIT) antibody was recently investigated in late-stage clinical trials. Vibostolimab was developed based on its specific binding property to the human and cynomolgus monkey TIGIT protein and its functional blocking activity of the TIGIT:CD155 interaction.

Methods:

The biochemical properties of vibostolimab, in a comparison with tiragolumab, were assessed with Biacore, nuclear magnetic resonance (NMR), and X-ray crystallography, while the T-cell activation was examined using engineered Jurkat cells in an in vitro co-culture system by measuring interleukin (IL)-2 production as a readout of T-cell activation. The mouse surrogate anti-TIGIT antibodies were identified and used to extensively investigate the mechanism of action of anti-TIGIT antibodies as monotherapy or in combination with anti-programmed cell death protein-1 (PD-1) antibody in vivo by gene expression profiling and flow cytometry analyses with a mouse syngeneic tumor model.

Results:

Structural analyses with solution NMR and X-ray crystallography revealed that vibostolimab binds the CC’C’’FG loop interface of TIGIT, completely competing for the binding site of CD155 with a larger coverage area than another anti-TIGIT antibody tiragolumab, consistent with surface plasmon resonance analysis, though mouse models with similar antibodies revealed no functional difference in antitumor efficacy. Biacore-based binding data indicate that both vibostolimab and tiragolumab bind on TIGIT with comparable binding affinity (KD), but different binding kinetics characterized by faster on and off rates, which may contribute to enhanced T-cell activation with vibostolimab, as evidenced by greater IL-2 production in an in vitro cell-based assay. Functional experiments in mouse models demonstrated additional detailed biological mechanisms of the mouse equivalent of vibostolimab, including the differentiating role of myeloid cell activation in addition to improved T cell cytolytic activity, both of which are further enhanced by anti-PD-1 combination therapy.

Conclusions:

Vibostolimab is a novel anti-TIGIT antibody that completely blocks CD155 binding and induces T-cell activation. From experiments using a mouse tumor model and mouse surrogate anti-TIGIT antibody, we demonstrate direct evidence where it not only activates cytotoxic T cells but also induces the activation of antigen-presenting cells. The clinical relevance of vibostolimab, based on these mechanisms, in combination with pembrolizumab was recently tested in registrational trials.

2024-06-14·Cancer research

Fc-Silent Anti-TIGIT Antibodies Potentiate Antitumor Immunity without Depleting Regulatory T Cells

Article

作者: de Groot, Amber E. ; Zhu, Wandi S. ; Walker, Nigel P. ; Foster, Paul G. ; Piovesan, Dana ; Zhao, Xiaoning ; Singh, Hema ; Anderson, Amy E. ; Cho, Soonweng ; Lopez Espinoza, Alejandra Y. ; Walters, Matthew J. ; Seitz, Lisa ; Stagnaro, Carlo E. ; Ray, Rebecca D. ; Mitchell, Casey G. ; Sivick, Kelsey E. ; Patnaik, Amita

Abstract:

T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) is an inhibitory receptor on immune cells that outcompetes an activating receptor, CD226, for shared ligands. Tumor-infiltrating lymphocytes express TIGIT and CD226 on regulatory T cells (Treg) and on CD8+ T cells with tumor-reactive or exhausted phenotypes, supporting the potential of therapeutically targeting TIGIT to enhance antitumor immunity. To optimize the efficacy of therapeutic antibodies against TIGIT, it is necessary to understand IgG Fc (Fcγ) receptor binding for therapeutic benefit. In this study, we showed that combining Fc-enabled (Fce) or Fc-silent (Fcs) anti-TIGIT with antiprogrammed cell death protein 1 in mice resulted in enhanced control of tumors by differential mechanisms: Fce anti-TIGIT promoted the depletion of intratumoral Treg, whereas Fcs anti-TIGIT did not. Despite leaving Treg numbers intact, Fcs anti-TIGIT potentiated the activation of tumor-specific exhausted CD8+ populations in a lymph node–dependent manner. Fce anti-TIGIT induced antibody-dependent cell-mediated cytotoxicity against human Treg in vitro, and significant decreases in Treg were measured in the peripheral blood of patients with phase I solid tumor cancer treated with Fce anti-TIGIT. In contrast, Fcs anti-TIGIT did not deplete human Treg in vitro and was associated with anecdotal objective clinical responses in two patients with phase I solid tumor cancer whose peripheral Treg frequencies remained stable on treatment. Collectively, these data provide evidence for pharmacologic activity and antitumor efficacy of anti-TIGIT antibodies lacking the ability to engage Fcγ receptor.

Significance::

Fcs-silent anti-TIGIT antibodies enhance the activation of tumor-specific pre-exhausted T cells and promote antitumor efficacy without depleting T regulatory cells.

2024-05-01·Structure (London, England : 1993)

Structural insights into the unique pH-responsive characteristics of the anti-TIGIT therapeutic antibody Ociperlimab

Article

作者: Chen, Xin ; Li, Kang ; Zhang, Xiangxiang ; Xue, Liu ; Huang, Chichi ; Song, Jing ; Cheng, Liang ; Shen, Zhirong ; Sun, Jian ; Wang, Lai ; Zhang, Jing

TIGIT is mainly expressed on T cells and is an inhibitory checkpoint receptor that binds to its ligand PVR in the tumor microenvironment. Anti-TIGIT monoclonal antibodies (mAbs) such as Ociperlimab and Tiragolumab block the TIGIT-PVR interaction and are in clinical development. However, the molecular blockade mechanism of these mAbs remains elusive. Here, we report the crystal structures of TIGIT in complex with Ociperlimab_Fab and Tiragolumab_Fab revealing that both mAbs bind TIGIT with a large steric clash with PVR. Furthermore, several critical epitopic residues are identified. Interestingly, the binding affinity of Ociperlimab toward TIGIT increases approximately 17-fold when lowering the pH from 7.4 to 6.0. Our structure shows a strong electrostatic interaction between ASP103_HCDR3 and HIS76_TIGIT explaining the pH-responsive mechanism of Ociperlimab. In contrast, Tiragolumab does not show an acidic pH-dependent binding enhancement. Our results provide valuable information that could help to improve the efficacy of therapeutic antibodies for cancer treatment.

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2025-06-13

·FierceBiotech

The trouble with TIGITs: How \'overenthusiasm\' led to Big Pharma\'s risky $6B gamble

“People went for Fc-competent [TIGITs] because it worked best in mice,” said Leerink Partners analyst Daina Graybosch, Ph.D. “They couldn\'t help themselves.\"\n Once hailed as the future of immuno-oncology, it’s been a tough few months for any remaining fans of anti-TIGIT antibodies.In April, BeOne Medicines, formerly known as BeiGene, announced it was scrapping ociperlimab over a disappointing phase 3 outlook two years after Novartis handed back the asset. Specifically, the study’s independent data monitoring committee deemed the trial unlikely to show that a combination of ociperlimab and BeOne’s own PD-1 inhibitor Tevimbra would beat Keytruda in patients with PD-L1-high non-small cell lung cancer (NSCLC).The following month brought more tough times for TIGITs, as GSK halted development of its own candidate belrestotug after deciding the iTeos Therapeutics-partnered drug in combination with anti-PD-1 inhibitor Jemperli wouldn’t score a phase 2 win in a similar NSCLC population.Even executives at Roche, whose tiragolumab appeared to buck the trend with a caveated phase 3 win in esophageal cancer in 2024, reaffirmed to Fierce Biotech earlier this year that “we stopped all of the tiragolumab trials that we could stop, and those that couldn\'t be stopped are just running out.”With Big Pharma having pumped $6 billion into this modality, what went so wrong for TIGITs?Daina Graybosch, Ph.D., a senior research analyst at Leerink Partners who covers immuno-oncology, traces the problems back to the exuberant reaction to Roche’s impressive phase 2 tiragolumab data that read out across 2020 and 2021. The Cityscape trial demonstrated that the TIGIT drug in combination with Roche’s own PD-L1 blocker Tecentriq shrank tumors in 31% of patients with metastatic lung cancer—twice as many patients as Tecentriq alone.“That\'s probably the biggest point where the field went wrong, in that they looked at this massive benefit in the small phase 2, and everybody ran after it in a parallel and broad way,” Graybosch told Fierce in an interview.“We had randomized phase 2 data from Roche, from Arcus-Gilead, from iTeos-GSK, and they all consistently showed benefit in response rate and in [progression-free survival],” she added.“I think the challenge ultimately was: How much benefit is there really? Is it enough benefit to be clinically meaningful? And are we developing the drugs in the right way, in the right format, to optimize and bring that benefit to patients?”The industry’s “overenthusiasm” for the potential of TIGITs led to a “simplistic approach” to how other companies planned to develop their own candidates, according to Graybosch.If pharmas had anticipated a “more realistic demonstration of benefit,” as seen in the failed Skyscraper-01 phase 3 study in NSCLC, “I think everybody would have developed [TIGITs] differently,” she suggested.Companies swimming in the TIGIT space have broadly fallen into two camps. Roche’s tiragolumab, along with Merck & Co.’s vibostolimab, GSK and iTeos’ EOS-448, and BeOne’s ociperlimab, are all Fc-enabled. These antibodies retain a fully functional Fc region, meaning they can bind to Fc receptors found on the cell surface and contribute to the protective antitumor functions of the immune system.The theory behind Fc-enabled anti-TIGIT antibodies is that they have enhanced tumor-killing effects. However, the risk is that they could possibly also eliminate certain regulatory T cells and therefore lead to unwanted immune responses.In fact, side effects did cast a shadow over some of the Fc-enabled TIGIT trials, with Merck halting a phase 3 trial of vibostolimab due to a higher than expected rate of discontinuations blamed on “immune-mediated adverse experiences.”“Toxicity that may lead patients to discontinue I think ended up being a contributing factor across the Fc-enabled TIGITs that are all now dead,” Graybosch said.The last TIGITs still standing—Arcus Biosciences and Gilead’s domvanalimab, as well as AstraZeneca’s TIGIT/PD-1 bispecific antibody rilvegostomig—have mutated out the Fc function. This should mean they are less toxic for patients.“People went for Fc-competent because it worked best in mice,” Graybosch explained. “They couldn\'t help themselves, even though they knew there was some risk of depleting T effector cells that are actually what you need to fight your tumor.” Focusing on \'modest benefit\'So, what would a more measured approach to the TIGIT gold rush have meant in practice?“I think you ultimately do what Astra is doing,” said Graybosch, referring to AstraZeneca’s ongoing phase 3 trials of its bispecific rilvegostomig in a range of phase 3 studies for NSCLC or stomach cancer, including in combination with its Daiichi Sankyo-partnered antibody-drug conjugates Enhertu or Datroway.“Astra is recognizing the modest benefit,” she explained. “Their bispecific is very safe because it\'s Fc silent. And in some ways, Astra can\'t lose because [rilvegostomig] doesn\'t need to work that much for a lot of their trials to be successful.”AstraZeneca’s Puja Sapra, Ph.D., senior vice president for biologics engineering and oncology target discovery, was also upbeat about rilvegostomig’s prospects when she spoke to Fierce back in April. She pointed to the fact that engineering the bispecific to reduce Fc effector functionality should reduce unwanted side effects, while blocking both PD-1 and TIGIT at the same time “should hopefully help us increase the response rate and durability.”“At least in preclinical studies, we see that a bispecific molecule has better responses than a combination of both agents alone,” Sapra said at the time. “The molecule is doing very well in the clinic so far, so we continue to believe in this molecule.”Gilead is also staying loyal to its TIGIT candidate, which is being evaluated in phase 3 trials for first-line NSCLC as well as for locally advanced unresectable or metastatic gastric, gastroesophageal junction and esophageal adenocarcinoma.The pharma’s chief medical officer Dietmar Berger, M.D., Ph.D., told Fierce earlier this month that the Arcus-partnered domvanalimab still has a chance, pointing to its Fc-silent character.“We believe there is differentiation but, of course, we need to see how those studies read out,” Berger said. “Any additional activities around that will be based on what we see in those studies.”With AstraZeneca and Gilead still holding a candle for their Fc-silent candidates, Leerink’s Graybosch doesn’t think “it\'s fair to completely write off TIGIT.”“But if you ask 99% of average investors, generalists or specialists and [key opinion leaders], I think they’ll tell you it\'s dead,” she added.Angus Liu contributed to this reporting.

$The trouble with TIGITs: How \'overenthusiasm\' led to Big Pharma\'s risky $6B gamble$

临床3期临床结果临床2期

2025-06-09

·FierceBiotech

\'We are in a good spot\': Gilead\'s new chief medical officer is committed to pipeline diversification

“We have a pipeline that can deliver at this point, but we will absolutely further optimize it,” Gilead Sciences\' Dietmar Berger, M.D., Ph.D., told Fierce.\n Dietmar Berger, M.D., Ph.D., joined Gilead Sciences as chief medical officer at the start of this year after the company’s oncology department suffered some prominent setbacks. The run of bad luck included two back-to-back phase 3 flops of Trodelvy in non-small cell lung cancer and bladder cancer as well as the demise of the anti-CD47 drug magrolimab from a $4.9 billion acquisition.But Berger, who boasts a deep background in cancer drug development, still believes the virology giant made the right move to branch out into oncology and immunology.“I am a strong believer that diversification for Gilead is the right decision,” Berger told Fierce in an interview on the sidelines of the 2025 American Society of Clinical Oncology (ASCO) annual meeting.“I also think that oncology and immunology are the right areas for Gilead, because of the emerging science … and because we can apply a lot of the strength that Gilead has—for example in chemistry, in protein design and deep understanding of biology—very strongly to oncology and immunology.”As a new head of development joining a biopharma company, it’s natural to think about ways to improve the portfolio, he said. “We have a pipeline that can deliver at this point, but we will absolutely further optimize it,” Berger added.The CMO said he’s trying to build a “balanced” and “partially derisked portfolio” by combining direct cytotoxic mechanisms with immuno-oncology. Again, diversification is key here. At ASCO, Gilead’s cell therapy unit Kite Pharma reported some early positive data for its anti-CD19/CD20 bicistronic CAR-T therapy in advanced B-cell lymphoma. Another bivalent CAR-T candidate partnered with the University of Pennsylvania targeting EGFR and interleukin-13 receptor alpha 2 recorded notable tumor shrinkage in eight (62%) of 13 patients with recurrent glioblastoma, a notoriously aggressive and hard-to-treat brain cancer.Trodelvy also had a positive story to tell at this year’s ASCO, courtesy of two positive phase 3 readouts in first-line triple-negative breast cancer (TNBC). In a potentially practice-changing data set, Trodelvy and Merck & Co.’s Keytruda significantly reduced the risk of progression or death by 35% versus Keytruda and chemotherapy in first-line PD-L1-positive TNBC.In immuno-oncology, Berger highlighted GS-1811, an anti-CCR8 antibody Gilead obtained from Jounce Therapeutics. The drug, designed to remove immunosuppressive tumor-infiltrating T regulatory cells, is still in early-stage development.All told, Gilead has 58 projects across virology, oncology and immunology in its portfolio, the largest and most diverse pipeline in the biopharma\'s history. Challenges in ADC and immuno-oncologyFor Trodelvy, new TROP2 competition has arrived in the form of AstraZeneca and Daiichi Sankyo’s Datroway and Merck and Kelun-Biotech’s sac-TMT.In Trodelvy’s home base of second-line TNBC, the Gilead drug is the only one that has demonstrated an overall survival benefit. Parallel data that could help experts compare these drugs side by side in a cross-trial fashion have not yet read out, Berger explained.Besides first-line TNBC, Trodelvy is also being tested in earlier-line HR-positive, HER2-negative breast cancer, which could represent a bigger patient population than TNBC. Following the Evoke-01 flop, the Evoke-03 study for Trodelvy and Keytruda in first-line PD-L1-high NSCLC remains ongoing.Since Gilead’s $21 billion acquisition of Immunomedics in 2020, the company still has only one antibody-drug conjugate asset, whereas other players in the space such as AstraZeneca and Pfizer have developed multiple products.The Immunomedics deal was a strategic acquisition designed to give Gilead an anchor in its diversification into solid tumors, and the company then built R&D capabilities around that, Berger noted.“That bit of a time lag is largely based on: How do you build an oncology organization?” Berger said.New oncology molecules are now coming out of Gilead’s internal research capabilities, and the company will also “focus strongly” on external opportunities, he said. Berger wouldn’t name specific ADC projects outside of Gilead that he’s interested in. Toward the end of 2024, before Berger officially moved across from Sanofi, Gilead penned a deal with Tubulis to develop a topoisomerase I inhibitor-based ADC.“There’s usually the question, do you combine different mechanisms, or do you double down on a specific pathway,” Berger said of target selection for ADCs.Choosing the linker is dependent on whether a bystander effect—in which the cytotoxic payload from the ADC kills cells surrounding the target cell—is desired, and the toxin needs to be carefully evaluated because these payloads hit different tumor types differently, Berger noted.Meanwhile, things don’t look too promising for Gilead’s late-stage immuno-oncology program, the Arcus Biosciences-partnered domvanalimab. The drug is one of the few remaining anti-TIGIT antibodies still in development after companies such as Merck, Bristol Myers Squibb, GSK and BeOne (formerly BeiGene) walked away from the field. Roche’s Genentech, where Berger used to lead oncology clinical development, has all but abandoned tiragolumab after several disappointing studies, and the pharma is now only waiting for two fully enrolled phase 3 trials to read out.Berger argued that domvanalimab may still stand a chance. The TIGIT molecules that have failed so far are mostly Fc-competent antibodies, whereas domvanalimab is Fc-silent.Fc-enabled anti-TIGIT antibodies theoretically have enhanced tumor-killing effects because they can bind to FcγRs and activate immune cells. But they could possibly also eliminate certain regulatory T cells and therefore lead to unwanted immune responses. Before nixing its TIGIT candidate vibostolimab, Merck had noted a higher rate of immune-related adverse events in at least two failed phase 3 trials. Only data will tell whether Fc-competence is the key. Gilead and Arcus are running two phase 3 trials that combine domvanalimab with Arcus’ PD-1 drug zimberelimab and chemotherapy in first-line NSCLC and gastric, gastroesophageal junction and esophageal adenocarcinoma.Gilead has a stated goal to have 30% of its revenue from oncology products by 2030. Berger acknowledged that the huge clinical success—and potential imminent approval—of twice-yearly lenacapavir for HIV prevention could make achieving that goal harder but said the company remains committed to a target of 30% of revenue from outside virology.“It does place a stronger focus on oncology,” Berger said. “But don’t get me wrong, I think we are in a good spot now.”

$\'We are in a good spot\': Gilead\'s new chief medical officer is committed to pipeline diversification$

临床3期免疫疗法临床结果ASCO会议并购

2025-04-21

·药事纵横

免疫治疗的下一个“黄金靶点”为何集体哑火？盘点那些年我们追过的TIGIT

TIGIT作为癌症免疫治疗领域的热门靶点，一度被视为“下一个PD-1”，吸引了罗氏、默沙东、阿斯利康、百济神州等多家药企的重金投入。但现实却给了它们重重一击，近几年关于TIGIT靶点的研究接连折戟，2025年4月3日，中国创新药企百济神州宣布终止其TIGIT抗体药物欧司珀利单抗（Ociperlimab）的肺癌适应症临床开发。此前，默沙东、罗氏、百时美施贵宝等跨国药企已相继终止同类项目，曾被寄予厚望的TIGIT靶点，如今深陷临床失败潮......TIGIT靶点为何被寄予厚望？2009年，罗氏基因泰克团队首次解析了TIGIT（T cell immunoreceptor with Ig and ITIM domains）的分子机制，其这个拥有免疫球蛋白样结构域和ITIM抑制性基序的靶点，被证实能够通过与CD155等配体结合，调控T细胞和NK细胞的活性。这种“双重免疫激活”的理论模型，让TIGIT迅速成为肿瘤免疫领域的焦点。在PD-1/L1抑制剂大获成功的背景下，TIGIT迅速被捧为“下一个百亿赛道”。2016年罗氏启动Tiragolumab临床试验时，行业预测TIGIT药物市场规模将在2030年突破50亿美元。默沙东押注Vibostolimab，BMS豪掷2亿美元引进AGEN1777，百济神州更是不惜投入20亿人民币推进欧司珀利单抗。到2024年，全球已有超过80个TIGIT相关临床项目，覆盖肺癌、肝癌、黑色素瘤等主要癌种。那些年我们追过的TIGIT药物罗氏的TiragolumabTiragolumab的临床研发之路充满波折。2022年3月，III期研究SHYSCRAPER-02在广泛期小细胞肺癌（ES-SCLC）一线治疗中，Tiragolumab联合阿替利珠单抗及化疗方案未能显著改善无进展生存期（PFS）和总生存期（OS），首战告负。随后在同年5月，针对PD-L1高表达非小细胞肺癌（NSCLC）的III期SKYSCRAPER-01研究初步分析显示，虽然联合治疗组的中位PFS（15.2月 vs 14.0月）与对照组（阿替利珠单抗单药）相比未达统计学差异，但基于OS数据尚未成熟，研发方罗氏决定继续推进研究。2023年8月的中期分析：联合治疗组展现出22.9个月的中位OS（对照组16.7个月），风险比（HR）降至0.81，但这一差异仍未跨越统计学显著性阈值，使得市场对TIGIT靶点的预期开始动摇。2024年7月公布的SKYSCRAPER-06研究结果显示，在非鳞状NSCLC一线治疗中，Tiragolumab联合方案不仅未能改善疗效（PFS HR=1.27，OS HR=1.33），其生存数据甚至显著劣于阿替利珠单抗联合化疗的对照组。最终在2024年11月，SKYSCRAPER-01研究的最终分析确认OS未达主要终点，正式宣告Tiragolumab在肺癌一线治疗领域的全线失利，这一系列挫折也为TIGIT抑制剂的研发前景蒙上浓重阴影。默沙东的Vibostolimab默沙东在TIGIT靶点药物Vibostolimab与王牌PD-1抑制剂K药（Keytruda）的联用探索上遭遇了连环挫折。这个项目最初在2023年3月就显出颓势，当时公布的II期KeyVibe-002临床试验结果显示，针对非小细胞肺癌二线治疗，联合疗法组的中位无进展生存期（2.7个月）甚至不如传统化疗药物多西他赛（3.2个月），首战告负。进入2024年后，噩耗接踵而至：5月因严重免疫相关不良反应紧急叫停黑色素瘤辅助治疗的III期KeyVibe-010研究；8月针对小细胞肺癌一线治疗的III期KeyVibe-008试验又因总生存期未达预期且存在安全隐患宣告终止；最终在12月，默沙东宣布全面停止Vibostolimab的临床开发计划，所有肺癌适应症研发线集体搁浅，标志着其TIGIT管线彻底崩塌。虽然期间默沙东尝试通过收购抗体偶联药物（ADC）和T细胞衔接器技术来补充小细胞肺癌产品线，但TIGIT+PD-1的联合疗法策略已完全退出历史舞台。至此，这家制药巨头成为全球首个全面撤离TIGIT赛道的大型药企，转而将重心投向双特异性抗体等新型免疫治疗方向。百时美施贵宝（BMS）的AGEN17772021年5月，BMS宣布以2亿美元首付款加13.6亿美元潜在里程金，收购Agenus公司临床前阶段的TIGIT/CD96双抗药物AGEN1777。这个时期TIGIT靶点正因罗氏早期临床数据引发行业热潮，BMS希望通过差异化布局抢占先机。2023年2月，BMS宣布终止其自主研发的TIGIT单抗BMS-986207的II期临床试验。该试验探索了BMS-986207与PD-1抑制剂Opdivo（O药）、CTLA-4抑制剂Yervoy（Y药）的三联疗法，但因观察到联合用药的毒性问题（具体细节未披露），出于安全性考虑决定终止开发，这一失败让BMS在TIGIT领域的自研管线受挫。2024年5月，BMS进一步收缩TIGIT布局，将此前重金引入的AGEN1777双抗退回给Agenus。退回原因可能与临床数据不及预期、市场竞争风险及公司战略调整有关。至此，BMS完全退出了TIGIT领域的研发竞争。百济神州的欧司珀利单抗2020年，百济神州开始推进其TIGIT抗体药物欧司珀利单抗（Ociperlimab，代号BGB-A1217）的研发。临床前数据显示，该药物效力比罗氏的同类产品Tiragolumab高出4倍，并与自家PD-1药物替雷利珠单抗联用进入Ⅰ期临床试验。2021年12月，百济与诺华达成重磅合作，以29亿美元的交易金额（含预付款、里程碑付款及销售分成）授权诺华负责欧司珀利单抗在欧美等多国的商业化，成为当时国产创新药海外授权的标杆案例。没想到这段跨国合作仅维持了20个月就宣告破裂。2023年7月，双方宣布终止协议，诺华退出开发，百济不得不收回权益单干。就在协议终止前一个月，百济神州悄悄暂停了该药联合疗法在肝癌领域的Ⅱ期试验。业内人士普遍认为，这波操作与罗氏TIGIT药物在肺癌Ⅲ期临床试验折戟有关系当时整个TIGIT靶点研发赛道都遭遇了信任危机。苦撑两年后，坏消息还是来了。2025年4月，独立数据监查委员会经过评估，认为试验数据难以达到预设的总生存期目标。至此，这个累计烧掉20.9亿人民币的重磅项目被迫画上句号。为何TIGIT走不出实验室？面对TIGIT靶点的集体溃败，大家开始重新审视这个曾被过度美化的机制。TIGIT并非孤立存在的靶点，它与CD226、PVR等配体构成动态平衡网络。当药物阻断TIGIT通路时，CD226的激活可能引发代偿性免疫抑制，这种“按下葫芦浮起瓢”的效应让单抗药物难以精准调控免疫反应。另一个致命问题在于患者筛选。现有临床试验大多沿用PD-L1表达水平作为入组标准，但TIGIT的疗效可能与完全不同的生物标志物相关，或许是由于缺乏成熟的检测手段和统一标准，药企至今无法在III期试验中精准锁定受益人群。联合疗法的增效神话也在现实中破碎。早期研究认为，TIGIT抑制剂与PD-1药物的联用能产生“1+1>2”的效果，但大规模临床试验揭示的却是另一番图景。默沙东的Vibostolimab与帕博利珠单抗联用时，3级以上免疫相关不良反应发生率高达38%，是PD-1单药治疗的两倍。讽刺的是在百济神州的试验中，联合治疗组部分患者的肿瘤进展速度反而加快。TIGIT靶点的溃败也给中国创新药行业上了沉重一课。百济神州在TIGIT项目上累计投入的20.9亿元，相当于其2024年研发总支出的31%。尽管代价惨痛，但全球化临床团队的建设、与FDA沟通的经验、以及应对研发危机的管理体系，都成为企业转型的隐形资产。今天对TIGIT靶点的及时撤退，是为了明天更聪明的进攻。信息来源：[1]Chauvin, J. M., & Zarour, H. M. (2020). TIGIT in cancer immunotherapy. Journal for ImmunoTherapy of Cancer, 8(2), e000957. https://doi-org.libproxy1.nus.edu.sg/10.1136/jitc-2020-000957[2]Roche. (2024, November 15). Final analysis of SKYSCRAPER-01 study in PD-L1-high metastatic non-small cell lung cancer [Press release]. https://www.roche.com/investors/updates/inv-update-2024-11-15[3]Merck & Co. (2024, December 10).Merck provides update on vibostolimab clinical development program [Press release].https://www-merck-com.libproxy1.nus.edu.sg/news/merck-provides-update-on-vibostolimab[4]Agenus Inc. (2024, May 3). Agenus regains global rights to AGEN1777 from Bristol Myers Squibb [Press release].https://investagenus.mediaroom.com/2024-05-03[5]BeiGene. (2025, April 3). BeiGene discontinues ociperlimab development in lung cancer [Press release]. https://www.beigene.com/news-media/press-releases/detail/435药事纵横投稿须知：稿费已上调，欢迎投稿

免疫疗法临床3期细胞疗法临床结果

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适应症	最高研发状态	国家/地区	公司	日期
转移性非小细胞肺癌	临床2期	美国	Bristol Myers Squibb Co.	2022-10-03
转移性非小细胞肺癌	临床2期	阿根廷	Bristol Myers Squibb Co.	2022-10-03
转移性非小细胞肺癌	临床2期	澳大利亚	Bristol Myers Squibb Co.	2022-10-03
转移性非小细胞肺癌	临床2期	比利时	Bristol Myers Squibb Co.	2022-10-03
转移性非小细胞肺癌	临床2期	智利	Bristol Myers Squibb Co.	2022-10-03
转移性非小细胞肺癌	临床2期	法国	Bristol Myers Squibb Co.	2022-10-03
转移性非小细胞肺癌	临床2期	德国	Bristol Myers Squibb Co.	2022-10-03
转移性非小细胞肺癌	临床2期	以色列	Bristol Myers Squibb Co.	2022-10-03
转移性非小细胞肺癌	临床2期	意大利	Bristol Myers Squibb Co.	2022-10-03
转移性非小细胞肺癌	临床2期	波兰	Bristol Myers Squibb Co.	2022-10-03

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT05005273 (CTgov)	临床2期	转移性非小细胞肺癌	1	BMS-986207+Ipilimumab+nivolumab (Treatment 1)	鬱鹹夢鏇淵遞憲遞構衊(夢齋憲壓鹽衊繭廠糧衊) = 獵醖衊觸顧構鹽鏇繭築鏇顧願蓋鬱夢襯製觸夢 (顧齋鹹鬱廠簾艱淵襯簾, 繭築淵積憲積繭淵襯鏇 ~ 鹽製廠構鏇獵鹽糧鹹鏇) 更多	-	2024-02-28
				Placebo+Ipilimumab+nivolumab (Treatment 2)	觸淵鑰選願網襯築鏇艱 = 願製遞鑰夢構鬱淵夢網鹽鏇鑰齋淵夢願襯築遞 (齋觸齋積壓餘壓願網廠, 餘衊夢廠積衊齋鏇窪糧 ~ 淵憲鏇構鹹餘獵鹹憲夢) 更多
NCT04570839 (ASCO2023) 人工标引	临床1/2期	子宫内膜癌 Microsatellite Stable (MSS)	9	COM701 20 mg/kg+BMS-986207 480 mg+nivolumab 480 mg	構觸製簾廠廠選膚膚醖(衊糧製衊顧選齋餘簾鬱) = 艱繭襯鑰壓壓鹹夢齋襯糧鹽夢糧艱顧蓋構遞觸 (選獵窪簾獵襯廠構積壓 ) 更多	积极	2023-05-31
NCT04150965 (AACR2023) 人工标引	临床1/2期	多发性骨髓瘤末线	14	BMS-980616+Pomalidomide+Dexamethasone (anti-LAG-3 arm)	憲蓋簾範顧範鹽鑰鹹餘(獵窪繭觸衊鬱淵憲糧鬱) = in the anti-LAG-3 arm were dyspnea and neutropenia; those in anti-TIGIT arm were neutropenia, thrombocytopenia, and anemia 衊夢餘遞繭網構壓鹹衊 (顧獵壓築觸積築鹹顧積 ) 更多	积极	2023-04-14
				BMS-986207+Pomalidomide+Dexamethasone (anti-TIGIT arm)
NCT04570839 (ESMO_IO2022) 人工标引	临床1/2期	铂耐药性卵巢癌	20	nivolumab+BMS 986207+COM701	獵齋簾衊廠襯網襯淵鏇(網遞蓋簾繭餘範鏇鹽鹹) = 膚顧遞淵膚餘範願鏇鏇憲遞顧製鏇範廠簾鑰選 (衊蓋壓鏇襯積衊遞簾遞 ) 更多	积极	2022-12-08