Ifinatamab deruxtecan

点击蓝字关注我们本期看点近年来，B7-H3（CD276）作为一种在多种肿瘤中过度表达的免疫检查点蛋白，其ADC研究迅速升温。据不完全统计，全球约有30余个针对B7-H3的ADC项目在研，其中约14个已进入临床开发阶段。这些项目不仅分布于欧美及日本企业（如第一三共/默沙东的Ifinatamab-DXd、MacroGenics的MGC018、BioNTech/的BNT324等），也有由中国企业主导的（如翰森的HS-20093、宜联的YL201、明慧/齐鲁的MHB088C等）。其中在研产品主要集中在实体瘤适应症，尤以小细胞肺癌（SCLC）占比较高。总体看，B7-H3 ADC管线项目丰富，技术平台以新一代拓扑异构酶I抑制剂（如DXd、喜树碱衍生物等）为主，同时链接子和DAR（偶联药物负载量）等设计也趋于多样化，这为各产品带来不同的药效与安全性特点。本文汇总进入临床III期阶段的四家企业及其B7-H3 ADC。本期内容01第一三共/默沙东丨Ifinatamab-DXd02翰森/GSK、齐鲁/明慧丨B7H3 ADC03宜联生物丨B7H3 ADC04总结与展望 【01 第一三共/默沙东丨Ifinatamab-DXd】目前全球进度最快、已进入III期临床的四款B7-H3 ADC药物为：第一三共/默沙东的Ifinatamab deruxtecan (DS-7300a)、翰森/葛兰素史克的HS-20093 (又称GSK5764227)、宜联生物的YL201，以及明慧医药/齐鲁制药的MHB088C。首先介绍进度最快的第一三共/默沙东的Ifinatamab-DXd。Ifinatamab-DXd来自于维基百科临床试验布局2025年7月1日，第一三共和默沙东在中国药物临床试验登记与信息公示平台登记开展 IDeate-Prostate01（CTR20252497）国际多中心Ⅲ期研究，旨在比较 Ifinatamab Deruxtecan 与多西他赛在前线转移性去势抵抗性前列腺癌受试者中的有效性与安全性，这是首个启动前列腺癌Ⅲ期临床的 B7-H3 ADC。此前已启动针对小细胞肺癌、食管鳞癌的Ⅲ期临床，此次启动前列腺癌Ⅲ期临床后，其成为启动Ⅲ期临床最多的 B7-H3 ADC。Ifinatamab deruxtecan 是一款采用第一三共 DXd ADC 技术设计的靶向 B7-H3 的 ADC 药物，由人源化抗 B7-H3 IgG1 单克隆抗体通过可裂解四肽连接子与拓扑异构酶 I 抑制剂有效载荷连接组成。第一三共与默沙东达成合作2023 年，第一三共和默沙东达成合作，共同开展包括 Ifinatamab deruxtecan 在内的 3 款 ADC 药物的全球（日本除外）开发和商业化，第一三共保留日本独家权利，并将获得 220 亿美金的预付款、持续付款和里程碑付款。该药是全球进度最快的 B7-H3 ADC。02 翰森/GSK、齐鲁/明慧丨B7H3 ADC 翰森/GSK丨HS-20093HS-20093（GSK5764227）由翰森自主研发，采用全人源B7-H3抗体偶联拓扑异构酶I抑制剂载荷。临床方面，翰森在中国同时推进多个研究，其中包括针对复发/难治性ES-SCLC的III期、针对局限期SCLC的III期，以及多个I/II期试验（覆盖肺癌、骨肉瘤、头颈癌等）。2024年11月，HS-20093在中国获批纳入突破性治疗品种，拟适应症为铂类化疗联合免疫治疗后进展的ES-SCLC；同时该药由GSK获得大中华区以外的全球开发权（2023年12月签署独家许可协议）。GSK已启动全球I期研究，并于2024年获FDA突破性疗法认定，用于铂类化疗后进展ES-SCLC。此外，HS-20093还在探索骨肉瘤适应症，并已获FDA和NMPA的突破性疗法资格，用于多线治疗的复发难治性骨肉瘤。差异化优势上，HS-20093凭借翰森自有的ADC平台和高亲和抗体设计，实现了早期中国临床高ORR（艺术会议数据显示一期ES-SCLC队列ORR约50–61%）；与此同步的GSK国际合作则加强了其全球化开发进程。明慧/齐鲁丨MHB088C2025 年 5 月 9 日，明慧医药宣布与齐鲁制药达成独家许可与合作协议，专注于在大中华区（涵盖中国大陆、香港、澳门和台湾）开发、生产和商业化其 B7-H3 ADC（MHB088C）药物，该药物已进入临床三期，成为全球第四款启动临床三期的 B7-H3 ADC 药物。合作细节•  权利授予 ：齐鲁制药将获得 MHB088C 在上述区域的独家权利。•  付款结构 ：明慧医药有望获得总额高达 13.45 亿元人民币的付款，具体包括 2.8 亿元的首付款和近期里程碑付款，以及 10.65 亿元人民币的开发、监管和销售里程碑付款。此外，明慧医药还将获得高达两位数的净产品销售分成。•  权利保留 ：明慧医药将保留大中华区外的 MHB088C 全球权利，并继续推进这些地区的开发工作。行业背景与竞争格局在国内医药市场，ADC 药物成为竞争热点，恒瑞、科伦、信达和石药等企业已有 10 款 ADC 药物进入临床阶段。相比之下，齐鲁制药首款自研 ADC（CLDN6）才刚刚启动临床，此次通过外部 BD 引入 MHB088C 这款三期临床产品，显示出其加速布局 ADC 领域的决心。同时，聚焦尚待验证成功性的 B7H3 ADC，且交易对象是处于临床三期阶段的明慧医药的 MHB088C，足见齐鲁制药的魄力。【03 宜联生物丨B7H3 ADC】宜联作为第三款进入临床三期的 B7-H3 ADC，临床数据出色且已开展两项三期临床。并在《Nature Medicine》杂志发表了一项关于B7H3靶向抗体药物偶联物（ADC）YL201的重磅研究。Study flowchart and patient disposition这项全球多中心、I/II期临床试验共纳入312名晚期实体瘤患者，涵盖广泛期小细胞肺癌（ES-SCLC）、鼻咽癌（NPC）、非小细胞肺癌（NSCLC）、食管鳞癌（ESCC）等多种肿瘤类型。最终确定最大耐受剂量为2.8 mg/kg，推荐扩展剂量为2.0 mg/kg和2.4 mg/kg，均采用每3周给药一次的方式。同肿瘤类型的疗效疗效数据整理如下：总体疗效：287例可评估患者中，ORR为40.8%， DCR为83.6%。mPFS为5.9个月， mDOR为6.3个月。作为宜联生物旗下最为核心的产品之一，YL201的临床表现不仅验证了B7H3作为治疗靶点的巨大潜力，也为ADC药物在实体瘤治疗中的应用开辟了新路径。目前，针对小细胞肺癌和鼻咽癌的III期临床试验已启动（NCT06612151和NCT06629597），有望进一步巩固其在精准治疗领域的地位。04 总结与展望综上所述，B7-H3靶向ADC开发正进入关键阶段，诸多产品进入III期且纷纷显示出临床疗效。未来趋势可能包括：一是向适应症前线化和组合用药拓展，譬如探索与免疫检查点抑制剂或靶向药物联用；二是在载荷选择上进一步创新（如新一代拓扑抑制剂、双特异或双抗体ADC等）；三是优化连接子和DAR等以提升治疗指数、降低毒性风险。预计未来随着上述四款产品乃至更多后续B7-H3 ADC的深入临床验证，及更多中国开发者的加入，B7-H3靶点ADC领域将迎来新的突破，中国创新药企在全球抗癌市场中的影响力将持续上升。 ★

At the forefront of cancer treatment, scientists are continually exploring new targets and therapeutic strategies to address this global health challenge. B7-H3 (CD276), a type I transmembrane glycoprotein, has garnered significant attention due to its overexpression in a wide range of human cancers. Initially believed to function as a T-cell costimulatory molecule, B7-H3 has since been found to possess complex immunomodulatory properties, capable of both promoting and suppressing immune responses. As research has progressed, B7-H3 has been shown to play important roles not only in immune regulation but also in non-immune biological processes such as bone development and tumor progression. This multifunctionality positions B7-H3 as a highly promising novel target in oncology, spurring the development of innovative therapeutic approaches including antibody-drug conjugates (ADCs), CAR-T cell therapies, and bispecific antibodies. B7-H3 (CD276), as a member of the B7 superfamily, plays a multifaceted role in both immune regulation and tumor biology. It was originally identified as a T-cell costimulatory molecule due to its ability to promote the proliferation of CD4+ and CD8+ T cells and enhance the secretion of interferon-gamma (IFN-γ). This finding highlighted the molecule’s potential to amplify T-cell-mediated immune responses, contributing to the clearance of pathogens or tumor cells. Researchers observed that when B7-H3 interacts with receptors on the surface of T cells, it can significantly boost their activity, thereby enhancing the body's defense against infection and cancer. The Coinhibitory Role of B7-H3 and Its Effects on the Immune System While early studies focused on B7-H3’s costimulatory properties, subsequent research revealed its coinhibitory functions, particularly in dampening the activity of T cells and natural killer (NK) cells. Specifically, B7-H3 suppresses T-cell function by reducing the secretion of immune-stimulating cytokines such as interferons and tumor necrosis factor-alpha (TNF-α). It also inhibits NK cell activity, indicating that B7-H3 influences both adaptive and innate immunity. This dual role makes B7-H3 a complex immune regulator, with context-dependent biological effects that vary based on environmental and pathological conditions. Non-Immune Functions: Bone Development and Tumor Progression Beyond its role in the immune system, B7-H3 is also involved in non-immune processes such as regulating bone development. In tumor biology, B7-H3 has been implicated in several critical mechanisms including tumor cell proliferation, migration, angiogenesis, and epigenetic modifications. These findings suggest that B7-H3 is not merely an immune checkpoint molecule but also a key player in maintaining physiological balance and driving disease progression. Notably, high levels of B7-H3 expression in malignant tumors are often associated with increased invasiveness and metastatic potential, underscoring its clinical relevance in oncology. B7-H3 as a Novel Target in Cancer Immunotherapy Given its widespread overexpression in various cancers and its role in facilitating immune evasion, B7-H3 has emerged as a promising target for cancer immunotherapy. Multiple therapeutic strategies are currently under development to target B7-H3, including antibody-drug conjugates (ADCs), CAR-T cell therapies, and bispecific antibodies. These approaches aim to block the immunosuppressive functions of B7-H3 and restore or enhance the immune system's ability to effectively attack tumor cells, offering new hope and treatment options for cancer patients. I. Antibody-Drug Conjugates (ADCs) Targeting B7-H3 Ifinatamab Deruxtecan (DS-7300, DS-7300a), BGB-C354, and SKB-500 are all antibody-drug conjugates (ADCs) targeting the B7-H3 (CD276) antigen, but they differ in terms of development progress, mechanism of action, and technical characteristics. 1) Ifinatamab Deruxtecan Ifinatamab Deruxtecan (DS-7300, DS-7300a) is an antibody-drug conjugate (ADC) designed to leverage the high specificity of monoclonal antibodies to target antigens expressed on the surface of tumor cells. By selectively binding to B7-H3, Ifinatamab Deruxtecan delivers a cytotoxic payload directly to cancer cells, thereby minimizing damage to healthy tissues. This ADC consists of a humanized anti-B7-H3 IgG1 monoclonal antibody linked to the topoisomerase I inhibitor DXd. Upon binding to B7-H3 on the cancer cell surface, the entire complex is internalized. Inside the cell, the linker is enzymatically cleaved, releasing DXd. As a potent cytotoxic agent, DXd disrupts DNA structure within cancer cells, inducing apoptosis. This approach enhances treatment precision and helps overcome drug resistance. As of the latest data, Ifinatamab Deruxtecan has entered global Phase III clinical trials—a significant milestone in its development. In the earlier Phase II IDeate-Lung01 study, it demonstrated promising results, particularly in patients with extensive-stage small cell lung cancer (ES-SCLC), achieving an objective response rate (ORR) of 54.8%. The drug has also shown potential in other cancer types. Given the widespread overexpression of B7-H3 across various malignancies, Ifinatamab Deruxtecan may benefit a broad range of cancers beyond a single type, including diseases of the digestive and respiratory systems. Further research may expand its indications, positioning it as a key weapon against refractory tumors. While Ifinatamab Deruxtecan has shown significant efficacy, it is also associated with some risks. Common adverse events include nausea, anemia, and fatigue. To ensure optimal safety and efficacy, researchers are closely monitoring side effects and exploring optimized dosing strategies to reduce patient burden. 2) BGB-C354 BGB-C354 operates through a similar mechanism, using a monoclonal antibody specific for B7-H3 conjugated with a topoisomerase I inhibitor (TOP1). When the ADC binds to B7-H3-expressing tumor cells, the complex is internalized, and the linker is cleaved to release the cytotoxic payload, which damages the DNA of the cancer cell, leading to its death. This enhances treatment specificity while reducing harm to surrounding healthy tissue. BGB-C354 is currently undergoing Phase I clinical trials to assess its safety, tolerability, pharmacokinetics, and preliminary antitumor activity. This phase is critical for establishing the optimal dose range and supporting future Phase II and III studies. Notably, BGB-C354 has shown potential applications in patients with advanced solid tumors, including lung and gastric cancers. Compared to Daiichi Sankyo’s DS-7300, BGB-C354 has a higher drug-to-antibody ratio (DAR) of 8, versus 4 for DS-7300. A higher DAR means each antibody molecule carries more cytotoxic payload, which could enhance tumor-killing efficacy. However, this also requires careful design to balance potency with tolerability and avoid unacceptable toxicity. 3) SKB-500 SKB-500 is designed to deliver a cytotoxic drug directly into cancer cells, minimizing harm to healthy tissues. It uses a high-affinity humanized monoclonal antibody to recognize and bind B7-H3 on tumor cells. The other end of the antibody is linked to a potent cytotoxic agent. Upon successful binding, the entire complex is internalized, and the cytotoxic payload is released inside the cell to destroy key structures such as DNA or microtubules, leading to cancer cell death. This strategy improves treatment precision and helps combat drug resistance. SKB-500 is currently in Phase I/II clinical trials to evaluate its safety, tolerability, and preliminary efficacy. These early studies are essential for determining optimal dosing and laying the foundation for broader clinical development. Researchers are also exploring its use across a range of advanced solid tumors, including but not limited to lung cancer and gastric cancer. Because B7-H3 is widely expressed in many human cancers, SKB-500 has broad therapeutic potential. In addition to lung and gastric cancers, it may also prove effective in treating other advanced solid tumors such as breast and prostate cancers. As more clinical data emerges, SKB-500 may offer a new treatment option for patients who do not respond well to conventional therapies. II. CAR T Therapies Targeting B7-H3 1) B7H3 IL-7Ra CAR T Cell Therapy B7H3 IL-7Ra CAR T cell therapy is an innovative autologous CAR T cell approach specifically designed to target B7-H3 (CD276). By reprogramming a patient’s T cells into "smart bombs" that specifically attack B7-H3–positive cancer cells, this therapy offers a more precise and effective treatment option. The core mechanism involves genetically engineering T cells to express a chimeric antigen receptor (CAR) on their surface that can recognize and bind to B7-H3 on tumor cells. To enhance the persistence and anti-tumor activity of these engineered T cells, an IL-7Ra signaling domain is incorporated into the CAR construct. This modification helps counteract immunosuppressive effects within the tumor microenvironment and promotes prolonged in vivo survival and function of the T cells. As a result, B7H3 IL-7Ra CAR T cells not only kill tumor cells directly but also help recruit other immune cells to support the anti-cancer response. This therapy is currently in Phase I clinical trials, marking its transition from preclinical research to human testing. The primary goals of this phase are to evaluate safety, tolerability, and to gather preliminary efficacy data. While early results have not yet been published, the therapy has shown potential in small patient populations, especially in cases of relapsed solid tumors and diffuse intrinsic pontine glioma (DIPG), which typically respond poorly to conventional therapies. DIPG is located deep within the brain and is difficult to surgically remove, making standard radiation and chemotherapy largely ineffective. B7H3 IL-7Ra CAR T therapy may offer new hope for such patients. Given the widespread expression of B7-H3 across multiple cancer types, this technology could potentially be expanded to treat a broader range of malignancies. Despite its promise, CAR T therapy carries inherent risks and challenges. Common adverse events include cytokine release syndrome (CRS) and neurotoxicity. Therefore, close patient monitoring and prompt adjustments to the treatment plan are critical during early-phase trials. Researchers are also working to optimize CAR constructs and manufacturing processes to further enhance safety and efficacy. 2) GD2/B7H3 CAR T Cell Therapy GD2/B7H3 CAR T cell therapy is a novel immunotherapy that targets two antigens—disialoganglioside (GD2) and B7-H3 (CD276)—to enhance tumor cell recognition and killing. Both antigens are highly expressed in various cancers, particularly in pediatric neuroblastoma. This dual-targeting strategy improves the specificity of CAR T therapy and may help overcome resistance and relapse often seen with single-antigen targeting. In this design, CAR T cells are engineered to recognize and bind both GD2 and B7H3, enabling more effective detection and destruction of cancer cells. Notably, researchers have implemented a SynNotch system, which acts as a logic gate: CAR T cells are first primed by GD2 recognition, and only upon encountering sufficient B7-H3 in the tumor microenvironment is their CAR function activated. This gatekeeping mechanism enhances treatment precision, reduces potential off-target effects, and improves T cell persistence and activity in vivo. According to recent data, GD2/B7H3 CAR T therapy has demonstrated significant efficacy in preclinical models. For example, in a mouse model of metastatic neuroblastoma, this dual-target CAR T cell therapy not only effectively controlled tumor growth but also showed favorable metabolic adaptation and reduced T cell exhaustion. These findings lay a solid foundation for future clinical trials and support continued development. Although initially focused on neuroblastoma, GD2/B7H3 CAR T therapy may be applicable to a wide range of solid tumors due to the broad expression of both GD2 and B7-H3. This approach may be especially beneficial for patients who have not responded well to traditional therapies or who have developed drug resistance. As more clinical data become available, the therapy could be expanded to include adult patients and a wider range of cancers. 3) TX-103 TX-103 is another autologous CAR T cell therapy. It involves engineering a patient’s T cells to express a chimeric antigen receptor that specifically recognizes the B7-H3 molecule. Once re-infused into the patient, these engineered T cells can precisely locate and attack B7-H3–expressing tumor cells. This approach enhances treatment specificity and may reduce damage to healthy tissue, thereby minimizing side effects. Because B7-H3 is expressed in many cancer types, TX-103 has a wide range of potential applications—from brain tumors to other advanced solid tumors. TX-103 is currently undergoing Phase I clinical trials, primarily to assess its safety and feasibility in patients with relapsed malignant gliomas and other B7-H3–positive solid tumors. In addition to monitoring the incidence and severity of adverse events, researchers aim to determine the maximum tolerated dose and establish appropriate dosing regimens for subsequent Phase II studies. Secondary endpoints include evaluating treatment response rates, monitoring cytokine level fluctuations, and analyzing changes in immune cell phenotypes. These data are essential for understanding TX-103's mechanism of action and long-term efficacy. III. Bispecific T Cell Engagers Targeting B7-H3 CC-3 is a bispecific antibody (bsAb) developed by the German Cancer Consortium (DKTK), engineered with dual specificity for CD276 (B7-H3) and CD3. It is being developed to treat patients with metastatic colorectal cancer (CRC) who have failed at least three prior lines of therapy. What sets CC-3 apart is its dual-targeting mechanism—simultaneously binding to CD276 on tumor cells and tumor-associated vasculature—enabling a two-pronged attack on both cancer cells and their blood supply. By engaging CD3, CC-3 directs T cells to target and destroy CD276-expressing tumor cells and enhances immune cell infiltration into the tumor microenvironment. CC-3 exerts its antitumor effect through a bispecific antibody design. One arm binds specifically to CD3 on T cells, activating them even in the absence of conventional T cell receptor (TCR)-mediated antigen recognition. Once activated, T cells release cytotoxic molecules such as perforin and granzyme to kill target cells. The other arm of CC-3 binds to CD276 on the surface of tumor cells, guiding T cells to CD276-positive cells and mediating their destruction. In addition to direct tumor cell targeting, CC-3 interacts with tumor vasculature in CRC, helping to disrupt the tumor’s blood supply and "starve" it, while also facilitating immune cell access to the tumor. CC-3 was specifically engineered to minimize off-target effects by promoting T cell activation primarily within the tumor microenvironment rather than systemically, thereby reducing the risk of adverse effects. To enhance in vivo stability, CC-3 incorporates YTE modifications—engineered mutations that extend the antibody’s half-life in human serum. This prolongs drug activity, simplifies dosing regimens, and improves patient convenience and compliance. The first-in-human clinical trial for CC-3 includes two phases: an initial dose-escalation phase to determine the maximum tolerated dose (MTD), followed by a dose-expansion phase aimed at identifying the recommended Phase II dose. These studies will also evaluate CC-3’s pharmacokinetics, including its half-life and immunogenicity, and assess immune responses induced by the therapy. Given the differences between animal models and humans—particularly in pharmacokinetics and immunogenicity—conducting these evaluations in humans is critical. As a novel treatment strategy, CC-3 holds promise for patients with metastatic CRC who are unresponsive to or have relapsed after standard therapies. More importantly, since CD276 is expressed on both tumor cells and vasculature, the application of CC-3 could extend beyond CRC to other types of solid tumors. Thus, CC-3 not only offers a potential breakthrough for treatment-resistant cancers but also opens new avenues for broadening B7-H3–targeted therapies. Conclusion In summary, B7-H3 has emerged as a compelling target in cancer therapy due to its high expression across various malignancies. Initially identified as a co-stimulatory molecule, B7-H3 was later found to have co-inhibitory functions and roles in non-immune biological processes, underscoring its complex, multifaceted nature. Innovative therapies targeting B7-H3—including antibody-drug conjugates (ADCs) like Ifinatamab Deruxtecan, BGB-C354, and SKB-500, as well as CAR T cell therapies like B7H3 IL-7Ra CAR T and GD2/B7H3 CAR T cells—have shown promising anticancer potential. These therapies precisely target tumor cells and enhance immune responses, offering new hope for patients with treatment-resistant cancers. Despite ongoing challenges such as managing side effects and optimizing efficacy, advances in research and technology continue to position B7-H3 as a key component of future precision medicine, heralding a new era in cancer treatment. Meanwhile, bispecific antibodies like CC-3 further expand the therapeutic landscape, signaling a shift toward more precise and effective immunotherapies in oncology. Refrence 1.Zhao B, Li H, Xia Y, Wang Y, Wang Y, Shi Y, Xing H, Qu T, Wang Y, Ma W. Immune checkpoint of B7-H3 in cancer: from immunology to clinical immunotherapy. J Hematol Oncol. 2022 Oct 25;15(1):153. doi: 10.1186/s13045-022-01364-7. PMID: 36284349; PMCID: PMC9597993. 2.Getu AA, Tigabu A, Zhou M, Lu J, Fodstad Ø, Tan M. New frontiers in immune checkpoint B7-H3 (CD276) research and drug development. Mol Cancer. 2023 Mar 2;22(1):43. doi: 10.1186/s12943-023-01751-9. PMID: 36859240; PMCID: PMC9979440. 3.Lin YJ, Mashouf LA, Lim M. CAR T Cell Therapy in Primary Brain Tumors: Current Investigations and the Future. Front Immunol. 2022 Feb 21;13:817296. doi: 10.3389/fimmu.2022.817296. PMID: 35265074; PMCID: PMC8899093. 4.Koumprentziotis IA, Theocharopoulos C, Foteinou D, Angeli E, Anastasopoulou A, Gogas H, Ziogas DC. New Emerging Targets in Cancer Immunotherapy: The Role of B7-H3. Vaccines (Basel). 2024 Jan 5;12(1):54. doi: 10.3390/vaccines12010054. PMID: 38250867; PMCID: PMC10820813.