A Phase 1, Open-label, Dose Finding Study of CC-90002, a Monoclonal Antibody Directed Against CD47, in Subjects With Acute Myeloid Leukemia and High-Risk Myelodsplastic Syndrome

Study CC-90002-AML-001 is an open-label, Phase 1 dose escalation (Part A) and expansion (Part B), clinical study of CC-90002, administered by intravenous (IV) infusion, in subjects with relapsed and/or primary refractory AML and high-risk MDS. The study will explore escalating doses of CC-90002 using a 3 + 3 dose escalation design in Part A, followed by dose expansion in Part B.
The primary objective is to determine the safety and tolerability of CC-90002 and also to define the non-tolerated dose (NTD), the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) of CC-90002.

开始日期2016-03-01

申办/合作机构

Celgene Corp.

NCT02367196 / Completed临床1期

A Phase I, Open-Label, Dose Finding Study of CC-90002, a Monoclonal Antibody Directed Against CD47, in Subjects With Advanced Solid and Hematologic Cancers

CC-90002-ST -001 is an open-label, Phase 1, dose escalation clinical study in subjects with advanced, refractory solid and hematologic cancers.

开始日期2015-03-12

申办/合作机构

Celgene Corp.

100 项与 CC-90002 相关的临床结果

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100 项与 CC-90002 相关的转化医学

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100 项与 CC-90002 相关的专利（医药）

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项与 CC-90002 相关的文献（医药）

2022-03-01·Annals of hematology3区 · 医学

Phase 1 study of anti-CD47 monoclonal antibody CC-90002 in patients with relapsed/refractory acute myeloid leukemia and high-risk myelodysplastic syndromes

3区 · 医学

Article

作者: Wei, Xin ; Seet, Christopher S ; Stock, Wendy ; Kopytek, Stephan ; DeAngelo, Daniel J ; Palmer, Jeanne ; Sriraman, Priya ; Hege, Kristen ; Tallman, Martin S ; Bewersdorf, Jan Philipp ; Burgess, Michael R ; Zeidan, Amer M ; Raymon, Heather

CC-90002 is an anti-CD47 antibody that inhibits CD47-SIRPα interaction and enables macrophage-mediated killing of tumor cells in hematological cancer cell lines. In this first clinical, phase 1, dose-escalation and -expansion study (CC-90002-AML-001; NCT02641002), we evaluated CC-90002 in patients with relapsed/refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS). CC-90002 was administered in escalating doses of 0.1-4.0 mg/kg, using a modified 3 + 3 design. Primary endpoints included dose-limiting toxicities (DLTs), non-tolerated dose (NTD), maximum tolerated dose (MTD), and recommended phase 2 dose. Secondary endpoints included preliminary efficacy, pharmacokinetics, and presence/frequency of anti-drug antibodies (ADAs). Between March 2016 and July 2018, 28 patients were enrolled (24 with AML and 4 with MDS) at 6 sites across the USA. As of July 18, 2018, all patients had discontinued, mainly due to death or progressive disease. The most common treatment-emergent adverse events were diarrhea (46.4%), thrombocytopenia (39.3%), febrile neutropenia (35.7%), and aspartate aminotransferase increase (35.7%). Four patients experienced DLTs (1 patient had grade 4 disseminated intravascular coagulation and grade 5 cerebral hemorrhage, 1 had grade 3 purpura, 1 had grade 4 congestive cardiac failure and grade 5 acute respiratory failure, and another had grade 5 sepsis). The NTD and MTD were not reached. No objective responses occurred. CC-90002 serum exposure was dose-dependent. ADAs were present across all doses, and the proportion of ADA-positive patients in cycle 1 increased over time. Despite no unexpected safety findings, the CC-90002-AML-001 study was discontinued in dose escalation for lack of monotherapy activity and evidence of ADAs. However, as other anti-CD47 agents in clinical trials are showing promising early results for AML and MDS, understanding preclinical and clinical differences between individual agents in this class will be of high importance.

2022-02-01·Cancer immunology, immunotherapy : CII2区 · 医学

Modulation of CD47-SIRPα innate immune checkpoint axis with Fc-function detuned anti-CD47 therapeutic antibody

2区 · 医学

Article

作者: Modi, Hardik ; Timmer, John ; Wong, Lilly ; Eckelman, Brendan P ; Escoubet, Laure ; Deveraux, Quinn ; Narla, Rama Krishna ; Hariharan, Kandasamy ; Bauer, Daniel ; Kopytek, Stephan ; Zhu, Dan ; Abbasian, Mahan ; Leisten, Jim ; Piccotti, Joseph R ; Raymon, Heather K

Cluster of differentiation 47 (CD47) is a transmembrane protein ubiquitously expressed on human cells but overexpressed on many different tumor cells. The interaction of CD47 with signal-regulatory protein alpha (SIRPα) triggers a "don't eat me" signal to the macrophage, inhibiting phagocytosis. Thus, overexpression of CD47 enables tumor cells to escape from immune surveillance via the blockade of phagocytic mechanisms. We report here the development and characterization of CC-90002, a humanized anti-CD47 antibody. CC-90002 is unique among previously reported anti-CD47 bivalent antibodies that it does not promote hemagglutination while maintaining high-affinity binding to CD47 and inhibition of the CD47-SIRPα interaction. Studies in a panel of hematological cancer cell lines showed concentration-dependent CC-90002-mediated phagocytosis in acute lymphoblastic leukemia, acute myeloid leukemia (AML), lenalidomide-resistant multiple myeloma (MM) cell lines and AML cells from patients. In vivo studies with MM cell line-derived xenograft models established in immunodeficient mice demonstrated significant dose-dependent antitumor activity of CC-90002. Treatment with CC-90002 significantly prolonged survival in an HL-60-disseminated AML model. Mechanistic studies confirmed the binding of CC-90002 to tumor cells and concomitant recruitment of F4-80 positive macrophages into the tumor and an increase in expression of select chemokines and cytokines of murine origin. Furthermore, the role of macrophages in the CC-90002-mediated antitumor activity was demonstrated by transient depletion of macrophages with liposome-clodronate treatment. In non-human primates, CC-90002 displayed acceptable pharmacokinetic properties and a favorable toxicity profile. These data demonstrate the potential activity of CC-90002 across hematological malignancies and provided basis for clinical studies CC-90002-ST-001 (NCT02367196) and CC-90002-AML-001 (NCT02641002).

2018-11-01·Blood reviews2区 · 医学

Blocking “don't eat me” signal of CD47-SIRPα in hematological malignancies, an in-depth review

2区 · 医学

Review

作者: Montfort, William R ; Anwer, Faiz ; Carew, Jennifer S ; Persky, Daniel ; Hua, Anh B ; Riaz, Irbaz Bin ; Khalid, Muhammad Umar ; Russ, Atlantis ; Rahman, Bushra ; Nawrocki, Steffan T

Hematological malignancies express high levels of CD47 as a mechanism of immune evasion. CD47-SIRPα triggers a cascade of events that inhibit phagocytosis. Preclinical research supports several models of antibody-mediated blockade of CD47-SIRPα resulting in cell death signaling, phagocytosis of cells bearing stress signals, and priming of tumor-specific T cell responses. Four different antibody molecules designed to target the CD47-SIRPα interaction in malignancy are currently being studied in clinical trials: Hu5F9-G4, CC-90002, TTI-621, and ALX-148. Hu5F9-G4, a humanized anti-CD47 blocking antibody is currently being studied in four different Phase I trials. These studies may lay the groundwork for therapeutic bispecific antibodies. Bispecific antibody (CD20-CD47SL) fusion of anti-CD20 (Rituximab) and anti-CD47 also demonstrated a synergistic effect against lymphoma in preclinical models. This review summarizes the large body of preclinical evidence and emerging clinical data supporting the use of antibodies designed to target the CD47-SIRPα interaction in leukemia, lymphoma and multiple myeloma.

项与 CC-90002 相关的新闻（医药）

2024-09-12

·Business Wire

Global CD47 Inhibitor Drug Clinical Trials Insight & Market Opportunity Outlook to 2028 - ResearchAndMarkets.com

DUBLIN--( BUSINESS WIRE )--The "Global CD47 Inhibitor Drug Clinical Trials Insight & Market Opportunity Outlook 2028" report has been added to ResearchAndMarkets.com's offering. Inhibition of the cell surface protein CD47 has emerged as a novel cancer immunotherapy approach that has piqued the interest of both academia and industry in the recent years. Cancer cells often overexpress CD47, which triggers the "don't eat me" signal pathway, thereby helping malignant cells to escape immune surveillance. CD47 inhibitors seek to uncover cancer cells by inhibiting this protein, leaving them open to immune system attack, specifically through increased macrophage phagocytosis. Although no CD47 inhibitor is currently approved for therapeutic usage, the availability of candidates in phase 3 trials suggests that one may be approved in the coming years. With multiple candidates at varying stages of development, the field of CD47 inhibitor research and development is rapidly evolving. Developed by Forty Seven, which is now a part of Gilead, magrolimab is among the most advanced CD47 inhibitors. In early stage clinical trials for hematological tumors, it has demonstrated encouraging outcomes, especially when combined with other cancer treatments. Furthermore, late stage clinical trials evaluating Magrolimab in solid cancer alongside conventional cancer treatments such as docetaxel, Nivolumab, Pembrolizumab, Azacitidine, and Venetoclax are now under progress. Another significant candidate is Evorpacept (ALX148) from ALX Oncology, a high affinity SIRP? fusion protein that inhibits CD47. Currently, evorpacept is being assessed as a monotherapy and in combination with widely used anticancer drugs in a number of early phase clinical trials for a variety of solid and hematological tumors. Furthermore, a late-phase trial evaluating Evorpacept in combination with Trastuzumab, Ramucirumab, and Paclitaxel for the treatment of HER2+ gastric cancer is also under progress. A number of other CD47 inhibitors, including as TQB 2928 (Chia Tai Tianqing Pharmaceutical), MP 0621 (Molecular Partners), IMC-002 (ImmuneOncia Therapeutics), and CC 90002 (Celgene), are in the early phases of clinical research. The emphasis on combination therapies is undoubtedly one of the key trends in clinical development. Combining CD47 inhibitors with other immunotherapies, targeted treatments, and chemotherapy is being studied in an effort to overcome resistance mechanisms and provide synergistic benefits. Anticipated growth in the global market for CD47 inhibitors is attributed to the rising cancer incidence and increased use of immunotherapies in the upcoming years. The potential of CD47 inhibitors has been acknowledged by a number of prominent pharmaceutical companies, which has resulted in notable partnerships and acquisitions. The commercial interest in this field is demonstrated by Gilead Science's US$ 4.9 billion acquisition of Forty Seven in 2020 and Pfizer's US$ 2.26 billion acquisition of Trillium Therapeutics in 2021. Although Chinese and American companies presently dominate the market, there is increasing participation from South Korea, Australia, Canada, and Japan. Through clinical research, companies such as Shaperon, InnobationBio, Bitterroot Bio, and ImmuneOncia Therapeutics are making strides with their CD47 inhibitors. The market is becoming increasingly competitive, with several firms striving for market share. Therefore, for commercial success, differentiation based on safety profile, efficacy, and possible combination strategies will be essential. The market for CD47 inhibitors has both opportunities and challenges. Strong commercial interest and encouraging clinical evidence point to substantial development potential. However, there are challenges to address, such managing toxicity profiles, coming up with the best combination plans, and demonstrating distinct therapeutic advantages over current treatments. As the field develops, biomarker development for response prediction and patient selection will probably become more crucial for clinical development as well as marketing tactics. In conclusion, the market for CD47 inhibitors globally is an active rapidly expanding area of cancer immunotherapy. In the years to come, CD47 inhibitors could have a big impact on cancer therapy paradigms because there are several candidates in clinical development and a lot of commercial interest. Global CD47 Inhibitor Drug Clinical Trials Insight & Market Opportunity Outlook 2028 Report Highlights Global & Regional Market Opportunity Outlook Insight On More Than 100 CD47 Inhibitor Drugs In Clinical Trials Global CD47 Inhibitors Clinical Trials Insight By Company, Country, Indication & Phase Orphan, Fast Track, Breakthrough Therapy Designation Insight Key Drugs Initiation & Completion Year CD47 Clinical Application & Development Outlook By Indication CD47 Inhibitor Drugs Clinical Developments & Trends By Country Global CD47 Inhibitor Drug Market Dynamics Key Topics Covered: 1. CD 47 As Novel Cancer Immunotherapy Target 2. Global CD47 Inhibitors Drug Clinical Pipeline Overview 2.1 By Country 2.2 By Company 2.3 By Indication 2.4 By Patient Segment 2.5 By Phase 2.6 By Priority Status 3. CD47 Inhibitors Clinical Trials Insight By Company, Country, Indication & Phase 3.1 Research 3.2 Preclinical 3.3 Phase I 3.4 Phase I/II 3.5 Phase II 3.6 Phase II/III 3.7 Phase III 4. Global CD47 Inhibitor Drug Market Opportunity Outlook 4.1 Current Market Overview 4.2 Future Outlook & Opportunities 5. CD47 Clinical Application & Development Outlook by Indication 5.1 Solid Cancers 5.1.1 Breast Cancer 5.1.2 Colorectal Cancer 5.1.3 Lung Cancer 5.1.4 Urogenital Cancer 5.1.5 Gastrointestinal Cancer 5.2 Hematological Malignancies 5.2.1 Lymphoma 5.2.2 Leukemia 5.2.3 Multiple Myeloma 5.2.4 Myelodysplastic Syndrome 5.3 Microbial Infections 6. CD47 Inhibitor Drugs Clinical Developments & Trends By Country 6.1 China 6.2 US 6.3 South Korea 6.4 Australia 6.5 Canada 7. Global CD47 Inhibitors Market Dynamics 7.1 Favorable Parameters 7.2 Market Restraints 8. Competitive Landscape Adagene ALX Oncology ImmuneOncia Therapeutics ImmuneOnco Biopharma Light Chain Bioscience Phanes Therapeutics Virtuoso Therapeutics For more information about this report visit https://www.researchandmarkets.com/r/qs8ua0 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.

免疫疗法临床3期快速通道并购临床研究

2024-05-09

·精准药物

创新靶点的崛起与黯淡

PREFACE前言创新药的研发总是伴随着不确定性。一边海水，一边火焰，如履薄冰。一批曾经备受关注的靶点最终悄然沉寂，似卷着过往而远，无不令人唏嘘。这样的靶点很多，不胜枚举，譬如CD47、TIGIT、TIM-3、TGF-β等，"眼看他起朱楼,眼看他宴宾客,眼看他楼塌了。"本文通过盘点曾经盛极一时、又悄然而去的“明星”靶点，为创新药研发提供参考。01CD47血液毒性的难言之隐CD47是一种广泛表达的跨膜糖蛋白，可与巨噬细胞表面信号调节蛋白α（SIRPα）的N末端结合，并发出“别吃我”（Don’t eat me）信号，抑制巨噬细胞的吞噬作用。当细胞老化或病变时，细胞表面的CD47逐渐丧失，衰老或病变的细胞由此被巨噬细胞吞噬。但狡猾的肿瘤细胞也盯上了这一条“保命”通路，通过高表达CD47，肿瘤细胞向巨噬细胞发出“别吃我”信号，抑制巨噬细胞的吞噬作用，进而实现免疫逃逸。由于CD47在许多肿瘤细胞表面均高表达，利用单克隆抗体、融合蛋白或双特异性抗体来阻断CD47-SIRPα间的信号通路，恢复巨噬细胞对肿瘤细胞的吞噬作用是肿瘤免疫治疗的重要发展方向之一。 CD47与SIRP-α通路图示资料来源：SIRPα–CD47 Immune Checkpoint Blockade in Anticancer Therapy尽管CD47和SIRPα通路抗癌原理清晰，但由于CD47同样表达于正常细胞表面（尤其是红细胞），因此，CD47抗体的脱靶毒性（On target，Off tumor）始终是一个隐患。由于红细胞表面也高表达CD47，一旦CD47抗体与红细胞表面的CD47结合，可引起红细胞凝集，进而导致红细胞裂解。2017年，由于患者出现红细胞凝集而死亡的问题，Tioma公司终止了CD47单抗Ti-061的临床研究。2018年，Celgene的CC-90002也因遭遇严重不良事件而中止了药物的临床研究。尽管后续企业持续探索CD47的改进方案，包括改良给药方式（低剂量诱导）、降低药物与红细胞的结合能力、结合独特抗原表位等。但CD47有限的疗效更是成为了压倒骆驼的最后一根稻草，2023年，吉利德就宣布终止CD47单抗Magrolimab联合阿扎胞苷一线治疗高危骨髓增生异常综合征（MDS）的III期临床ENHANCE失败。2023年8月10日，凭借CD47管线纳斯达克上市的ALX Oncology宣布终止核心管线SIRPα融合蛋白Evorpacept治疗MDS、AML的临床研究。2023年9月22日，艾伯维终止与天镜生物就CD47抗体lemzoparlimab的合作协议。2024年2月，吉利德终止magrolimab用于治疗急性髓性白血病（AML）的III期ENHANCE-3研究，在该分析中，magrolimab联合阿扎胞苷和venetoclax无治疗效果，并观察到死亡风险增加，主要由感染和呼吸衰竭引起。但CD47/SIRPα的故事并未结束，2023年10月份传来Evorpacept在治疗HER2阳性胃或胃食管交界处癌的II期研究中取得积极结果的消息，次日ALX Oncology股价大涨56%。或许实体瘤才是CD47的最后救赎？让我们拭目以待。02TIGIT惨遭滑铁卢，一线肝细胞癌赋予新希望 TIGIT是脊髓灰质炎病毒受体（PVR）/Nectin家族的成员，常表达于记忆T细胞、调节T细胞、滤泡辅助细胞及NK细胞。TIGIT由细胞外免疫球蛋白可变区（IgV）结构域，1型跨膜结构域和具有经典免疫受体酪氨酸抑制基序和免疫球蛋白酪氨酸尾基序的细胞内结构域组成。2020年，因tiragolumab出色的Ⅱ期临床数据，TIGIT一度被业内人士称为“下一个PD-1”。但自2022年以来，TIGIT单抗惨遭滑铁卢。2022年3月，罗氏宣布tiragolumab（TIGIT单抗）一线治疗小细胞肺癌的III期临床SKYSCRAPER-02研究未能达到无进展生存期（PFS）共同主要终点，在中期分析中没有达到总生存期（OS）的主要终点。2022年5月，罗氏宣布tiragolumab联合PD-L1一线治疗非小细胞肺癌三期临床SKYSCRAPER-01未达到无进展生存期的主要终点。2023年3月，默沙东宣布 PD-1+TIGIT 复方制剂 MK-7684A 治疗转移性非小细胞肺癌（NSCLC）的 II 期非注册 KeyVibe-002 研究的最新结果未达预期。尽管TIGIT近年来数据不甚靓眼，但一线肝癌赋予了TIGIT新的希望。Tiragolumab联合阿替利珠单抗（atezo）和贝伐珠单抗（bev）一线治疗不可切除、局部晚期或转移性肝细胞癌（uHCC）。58名患者被随机分组（tira + atezo + bev组，n=40；atezo + bev组，n=18）。截至2022年11月28日，ORR分别为42.5% vs. 11.1%；中位无进展生存期（PFS）分别为11.1m vs 4.2m（HR=0.42）。03TIM-3诺华剔除TIM-3单抗，GSK继续推进TIM3全称为T cell immunoglobulin and mucin domain-containing protein 3，于2002年首次被发现，是免疫调节蛋白TIM家族的一员。2016年，在免疫治疗靶点PD-1发展“如日中天”之时，Nature Reviews发表了一篇题为“PD-1 says goodbye, TIM-3 says hello”的文章，让诸多研究者关注到了TIM3这一免疫治疗靶点。然而，TIM-3靶点的研发并不如PD-1般顺利，作为单药，TIM3抗体没有实质性的临床益处，于是研究者将目光投向联用的治疗。然而，2024年1月，诺华在2023年财报中更新了其TIM-3单抗sabatolimab（MBG453）联合治疗中度、高或极高风险骨髓增生异常综合征（MDS）或慢性粒单核细胞白血病-2（CMML-2）的III期STIMULUS MDS2研究未达到总生存期（OS）的主要终点。基于此，诺华已将其从管线中剔除。但GSK仍在推进旗下TIM-3管线cobolimab与PD-1单抗Dostarlimab联用的Ⅱ/Ⅲ期临床，布局的适应症包括末线黑色素瘤和末线非小细胞肺癌等。目前，cobolimab联合Dostarlimab在实体瘤上展现出初步的疗效。04TGF-β默克终止M7824的研发转化生长因子β（TGF-β）是一种有效的多效性细胞因子，在肿瘤发生中具有复杂的、相互矛盾的作用。临床前的研究表明，阻断TGF-β信号是治疗肿瘤的有效方法，它能减轻Treg介导的免疫抑制，增加T细胞毒性，促进T细胞向肿瘤中心的渗透，从而引起强烈的抗肿瘤免疫和肿瘤消退。此外，阻断TGF-β信号增强了肿瘤对免疫检查点抑制剂（ICI）的反应。尽管临床前研究效果良好，但临床的实际疗效却给了研究者当头一棒。2021年，默克旗下的TGF-β/PD-L1双功能融合蛋白bintrafusp alfa（M7824）接连失败，先是在1月宣布终止肺癌的三期临床，紧接着在3月宣布单药二线治疗局部晚期或转移性胆道癌疗效不佳，随后于8月宣布终止M7824一线治疗胆管癌的临床研究，接连的失败为TGF-β蒙上了阴影。最终，于2021年9月，默克与GSK达成协议，终止关于bintrafusp alfa（M7824）的合作。目前，恒瑞仍在积极推动旗下SHR-1701（PD-L1×TGF-βRⅡ双功能融合蛋白）的临床研究，在2023ASCO上，SHR-1701联合SHR2554（EZH2抑制剂）治疗末线cHL展现出良好的临床获益，此外，SHR-1701正在探索诸多实体瘤适应症，包括胃癌、宫颈癌等。SUMMARY小结医药研发可谓如履薄冰，根据Pharmapremia基于近一万项临床试验的统计数据，Ⅰ、Ⅱ、Ⅲ期临床研究的成功率分别是63.8%、33.2%和60.1%。其中Ⅱ期临床失败率最高，成功率仅33.2%；即便通过了Ⅱ期临床试验，Ⅲ期临床试验的成功率也仅为60.1%。因此，对于医药企业而言，一方面要做到靶点差异化，努力实现人无我有，人有我优；另一方面，聚焦成药性高的靶点，加速研发，最终实现弯道超车的目的。声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓

临床3期免疫疗法

2024-02-08

·药时代

49亿美元的失败，CD47单抗之殇仍未消解

2020年，吉利德以49亿美元收购Fourty Seven，以获取其核心产品Magrolimab。这款被吉利德给予厚望的产品却为它带来无尽的失望，最终以“停止所有CD47血液瘤适应症项目”而宣告基本失败。对于CD47成药性的怀疑并非近期才出现的风言风语，这个曾被认为存在“成为下一个PD-1”潜力的靶点就未曾从争议泥潭中拔出。CD47的至暗之年2023年7月21日，吉利德就已宣布终止CD47单抗莫洛利单抗（Magrolimab）联合阿扎胞苷一线治疗高危骨髓增生异常综合征（MDS）的III期临床ENHANCE失败，这项研究曾在2022年1月被FDA以“非平衡安全性问题”暂停，意味着Magrolimab很有可能存在较大的安全性问题，根据报告可见为重度贫血问题，再次印证靶向CD47的抗体药物普遍存在较为严重的血液毒性。尽管临床试验后续恢复进行，但问题并未解决，并最终招致试验失败。并非吉利德个例，2023年期间，有多家先一步进入CD47抗体药物研发阶段的药企传来噩耗。2023年的第一个月，原先专注于CD47靶点开发的明星biotech Arch Oncology宣布终止其在CD47抗体上的研发工作，公司大部分员工离职。Arch Oncology是最早布局CD47靶点的biotech，也是最早在CD47研发之路上碰壁的企业之一，其开发的第一代CD47抗体Ti-061在2017年就因会造成严重的“红细胞凝集”而中道崩殂。2023年8月10日，凭借CD47管线纳斯达克上市的ALX Oncology也宣布终止核心管线SIRPα融合蛋白（CD47-SIRPα信号通路的巨噬细胞一端）Evorpacept治疗MDS、AML的临床研究。整家公司转向PD-1 ADC抗体研发。2023年9月22日，艾伯维已终止与天镜生物就CD47抗体lemzoparlimab的合作协议，该协议在2020年9月3日达成，天镜生物已收到2亿美元预付款和里程碑付款。本次合作终止基于此前艾伯维已经停止相关临床研究的决定作出。CD47是否是难以成药靶点？CD47是最早发现的“别吃我”信号。肿瘤可以通过高表达CD47向巨噬细胞发出“别吃我”信号，阻止先天免疫系统对本该排除的肿瘤发起攻击。如果阻断肿瘤的“别吃我”信号，那么就可以通过人体免疫系统清除肿瘤（如果是阻断巨噬细胞接收“别吃我”信号，就是靶向巨噬细胞上的SIRPα蛋白，也属于阻断CD47-SIRPα信号通路的范畴）。CD47在多种实体瘤、血液瘤上高表达，泛用性极广，一旦成药，则适应症开发拓展潜力巨大，全球大量药企投身于CD47靶向药物的开发之中。但可惜的是，CD47在红细胞上也高度表达，并且参与红细胞的正常更替，这才是CD47在正常人体中的主要功能。“年轻”的红细胞会高表达CD47以防止巨噬细胞吞噬，而衰老的红细胞上的CD47表达水平则会降低或构象改变，“主动求吞噬”。这也导致CD47抗体极易脱靶，促使巨噬细胞攻击功能正常的红细胞，引起贫血、溶血等严重不良反应，血液毒性成为了CD47抗体迈不过去的一道槛。第一代CD47药物：Arch Oncdogy的Ti-061、新基的CC-90002以及Surface Oncology的SFR231等，均由于严重的血液毒性而被迫终止开发。尽管后续包括Magrolimab在内的新一代CD47抗体药物已经想方设法强化了对肿瘤的选择性，甚至不惜牺牲一部分药物效果。Magrolimab曾是其中的教科书级药物。这里需要简单回顾一下抗体药物的作用机制：抗体药物对细胞的杀伤力主要来自抗体依赖性细胞毒作用（ADCC）和抗体依赖性细胞介导的吞噬作用（ADCP）。当抗体与靶细胞结合时，其尾部Fc端的IgG蛋白会召唤免疫细胞的到来，与免疫细胞的Fc受体结合，触发免疫细胞对靶细胞的杀伤行为。如果来的是NK细胞等具有细胞毒作用的免疫细胞，就是ADCC；如果来的是巨噬细胞等具有吞噬作用的免疫细胞，就是ADCP。杀伤效果的强度与抗体Fc端的IgG蛋白亚型有关，最常见的IgG1亚型与免疫细胞Fc受体的结合性最强，而IgG4的结合性就很弱，甚至会抑制过度的免疫反应。因此，选择Fc端为IgG4亚型的抗体，几乎放弃了抗体特有的杀伤力，只依赖“别吃我”信号的调节。Magrolimab寄希望于牺牲药效，用自断一腕的方式减轻毒副作用。但这也使能单药使用，必须与其他药物联用起到辅助作用。药效和毒性本是天平两端，需要寻求一个精妙的平衡，但难以想象已经做出如此退让，依然不足以使CD47抗体药物拥有充分的安全性。Magrolimab的转机尽管吉利德暂时没有放弃Magrolimab在实体瘤方向的后续研发，但至少在现在的理论与实践中，CD47是一个在血液瘤中更有潜力的靶点。与已经大获成功的PD-（L）1类抗体不同，CD47抗体并不以T细胞作为主要的辅助对象。巨噬细胞在人体各组织中广泛分布，平时处理一些入侵的病原体和衰老或异常的细胞，尽管偶然间产生的肿瘤细胞也包括在内，但巨噬细胞消灭肿瘤细胞的手段非常有限。在巨噬细胞不“摇人”，也就是唤醒T细胞的前提下，只能凑到问题细胞上慢慢吞噬（ADCP效应）。这导致了尽管阻断”CD47-SIRPα”信号通路后，能够观测到实体瘤的缓解，但是治疗效果并不如治疗分散在人体中的血液瘤明显，所以即便吉利德当初为magrolimab规划了将近20个癌种的适应症，但进展最快的还是血液瘤领域的几个适应症。并且理论上，由于CD47抗体药物和红细胞具有较强的结合力，在静脉注射的情况下有可能会在进入靶器官前先一步耗竭，导致真正起到药效的剂量变少，也很可能会导致CD47抗体的疗效进一步下降。如果针对实体瘤的效果不佳，安全性又堪忧，还不能单药使用，很难为这样的药物描绘一个乐观的市场前景。CD47成药如此之难，必须要引入一些新的办法打开局面。CD47的下一站另一类最知名的辅助药物莫过于TIGIT单抗了。TIGIT单抗最特别的地方莫过于失败也失败得不明朗，成功也成功得不明朗，无论成败都有着强烈的不确定性，非常微妙。此前默沙东有过一个涉及735例、35个癌种的样本分析，对TIGIT表达程度按癌种排序。结果显示，在肺癌患者里观察到了最高的中值表达。结果无论是默沙东还是罗氏，多家参与TIGIT单抗竞争的药企都把肺癌定为优先开发的适应症，却又纷纷失败，反倒是罗氏的tiragolumab在肝癌方面取得了暂且令人宽慰的数据，不能否认这样的奇迹也会发生在C47抗体药物上。此外为了在保证安全性的同时维持对肿瘤的杀伤效果，CD47抗体也可以采取双抗技术路线，通过另一半抗体片段带来超额的杀伤。目前依然在研全球一百多条CD47开发管线里，联合的靶点涵盖了PD-(L)1、SIRPα、CLDN18.2、CD20、CD33、CD38、CD40、CD19、FLT3、4-1BB……可以说是包罗万象。先行者的陨落即是对后人的危机警醒，也是一种机会激励。吉利德留出来的空窗可以交给后人填补……参考资料：[1]国外「三足鼎立」，国内「遍地开花」，拥挤的CD47赛道，有人坚守，有人退出，风口过后，未来将何去何从?[2]吉利德这CD47的疗效，咋说没就没了呢…[3]“CD47单抗”时代落幕了吗？[4]其他互联网公开资料封面图来源：pixabay礼来2023财报：除了替尔泊肽，收购支出大增是另一看点！165亿美元！2024年至今最大的一笔收购！诺和诺德大股东收购CDMO巨头Catalent背后的逻辑诺华29亿美元收购的B面：裁员、抄底、拯救点击这里，发现药时代的秘密！

引进/卖出并购临床3期临床失败抗体药物偶联物

100 项与 CC-90002 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
实体瘤	临床1期	西班牙	Celgene Corp.	2021-04-04
多发性骨髓瘤	临床1期	西班牙	Celgene Corp.	2021-03-08
Timothy综合征	临床1期	美国	Celgene Corp.	2016-03-01
急性髓性白血病	临床1期	美国	Celgene Corp.	2016-03-01
骨髓增生异常综合征	临床1期	美国	Celgene Corp.	2016-03-01
非霍奇金淋巴瘤	临床1期	-	Inhibrx, Inc.	-

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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


NCT02641002 (CC-90002-AML-001, Pubmed \| Ann Hematol) 人工标引	临床1期	急性髓性白血病 \| 骨髓增生异常综合征	28	CC-90002	製憲築積製繭網製獵廠(夢壓願鹽衊觸獵範壓鹽) = not reached 構鏇顧憲醖襯鏇蓋膚餘 (蓋鏇顧選繭窪襯選鹽願 ) 更多	不佳	2022-01-04
NCT02367196 (ASH2019) 人工标引	临床1期	难治性非霍奇金淋巴瘤 CD20 Positive	28	Rituximab+CC-90002	壓積鹽壓窪製積鹽衊餘(網壓構構網願衊鹽艱糧) = 3 pts ：1 pt developed dyspnea attributed to an infusion-related reaction at 15 mg/kg Q2W CC-90002 and 2 pts had grade 3 thrombocytopenia requiring platelet transfusion occurring at 30 mg/kg Q2W CC-90002 製醖憲鬱襯膚觸鑰築繭 (遞選鑰襯製窪鏇鹽襯餘 ) 更多	积极	2019-11-13