Maplirpacept

研究CD47抑制剂的生物制药公司，最近大多过的不太好。吉利德在其CD47靶向抗体Magrolimab上的数十亿美元赌注岌岌可危；艾伯维最近结束了与另一种抗CD47药物生产商天境生物的合作，并在去年8月终止了该候选药物的两项早期临床研究。CD47这个曾经看起来竞争激烈的领域，如今正是四面楚歌。一些业内人士推测，CD47抗体药物可能存在致命的缺陷。被认为是下一个PD-1CD47是一种广泛表达的跨膜糖蛋白，广泛表达于体细胞表面，可与信号调节蛋白 α (SIRP α)、血小板反应蛋白 (TSP1) 以及整合素相互作用，介导凋亡、增殖、免疫等一系列反应。其作用机制是与巨噬细胞表面的SIRPα结合，形成CD47-SIRPα信号复合物，进而促进“别吃我”信号的释放，这些信号抑制巨噬细胞介导的吞噬作用，保护正常细胞免受免疫系统的损害。癌细胞利用这个“被吃我”信号机制，在肿瘤细胞表面表达高水平的CD47,实现免疫逃逸。研究者认为抑制癌细胞中 CD47 信号可能促进巨噬细胞对肿瘤细胞的吞噬，从而限制肿瘤生长，这为抗肿瘤治疗提供了新的可行的免疫靶点。由于CD47的作用机制与PD-1类似，又能广泛表达在不同的癌细胞，所以CD47被看成是下一个PD-1。全球药企都希望再现PD-1的传奇，从CD47赛道中挖出下一个“全球药王”。据统计，目前全球已有超百款针对CD47靶点的药物处于临床研究阶段，涉及单抗、双抗和融合蛋白等药物类型。其中，仅国内就有36款产品进入临床阶段，涉及天境生物、康方生物和信达生物等超30家药企。不过，由于CD47容易出现安全性问题，研发失败率高，至今没有一款CD47靶向药物能获批上市。难以解决的安全性难题CD47药物研发遇到的第一个问题就是对红细胞的误伤，这是因为CD47不仅表达于肿瘤细胞，还表达于正常的红细胞表面，在正常生理条件下主导红细胞在体内的清除和平衡。在杀伤肿瘤时会波及到红细胞，引发贫血、血小板减少症等血液毒性问题。第一代CD47单抗如Arch Oncdogy公司的Ti-061、新基公司的CC-90002以及Surface Oncology公司的SFR231均由于严重的血液不良反应而被迫终止开发。自此，行业内对CD47药物的成药价值产生了严重质疑。直到2019年，Forty Seven公司展示了其自行研发的IgG4 CD47单抗Hu5F9-G4（Magrolimab）的临床数据，优秀的疗效重新燃起了行业内对CD47的希望。为了解决细胞毒素问题，各大药企采用了不同的研发策略。其中抗体亚型的选择是一大关键，一般而言，针对免疫细胞上靶点，多选IgG4抗体，如K药、O药；针对肿瘤细胞表面靶点，多选择IgG1抗体，如美罗华、赫赛汀等。由于CD47在肿瘤细胞表面表达，理论上应选择Fc效应器功能最强的IgG1型抗体，但由于CD47在正常细胞中的广泛表达，IgG1抗体血液毒性问题可能难以解决。IgG1单药可以展现出一定的抗肿瘤活性，但可能存在安全性问题。而临床上，Fc效应器功能较弱的IgG4、IgG2亚型单抗单药基本无效，多以联合用药为主。Magrolimab就是选择在Fc端采用IgG4亚型而非IgG1亚型，通过削弱抗体的杀伤力来实现减毒目标，并选择联合化疗药物阿扎胞苷，但是结果也是差强人意。一些药企开始将注意力落在了针对CD47亲和力的改造策略和双抗的尝试上。所谓针对CD47亲和力的改造策略，其实就是只结合肿瘤细胞的CD47，不结合红细胞等正常组织的CD47，实现方式有两种：要么利用特殊的SIRPα结合CD47的结构域，要么筛选只针对肿瘤CD47的特殊偏向性抗体。例如，辉瑞斥资22.6亿美元收购的Trillium Therapeutics，以及国内药企宜明昂科、天境生物和康方生物，都是采取这种策略来研发CD47药物。但是不管是哪种策略都会面临新的问题。药企相继折戟对于CD47来说，最严峻的一个问题是，一些生物科技巨头付出了很多努力，都无法将其转化为有效的治疗方法。鉴于Magrolimab让行业看到了新希望，2020年3月，吉利德发布公告称，将支付49亿美元现金来收购Forty Seven，获得该公司旗下的Magrolimab。随后更多的热钱涌入其中，艾伯维与天境生物达成了协议，辉瑞以22.2亿美元收购了两种抗CD47蛋白的生产商Trillium Therapeutics。但是大厂们的入局，以及相继的碰壁，又给CD47的药物研发泼上了冷水。去年1月份，由于研究人员报告的可疑意外严重不良反应（SUSARs）在各研究组间存在明显的不平衡，FDA部分暂停了吉利德Magrolimab+阿扎胞苷的联合研究。虽然3个月后，FDA解除了临床搁置，但是几个月后的八月份，Magrolimab再次因为临床疗法问题碰壁，一项Ib期研究发现，在接受Magrolimab+阿扎胞苷治疗的AML患者中，28.7%发生了与抗CD47药物相关的贫血。今年7月份，吉利德因疗效问题，终止CD47单抗Magrolimab联合阿扎胞苷治疗高风险MDS的III期ENHANCE研究；8月份，FDA暂停了Magrolimab在AML患者中的部门临床试验；9月底，吉利德宣布停止Magrolimab用于TP53突变急性髓系白血病（AML）的ENHANCE-2研究，原因是与现有标准治疗相比，Magrolimab在TP53突变的AML患者中显示出生存获益的可能性并不大。今年9月，艾伯维全面终止与天境生物就CD47单抗在研药物——来佐利单抗等产品的合作协议。但其实在去年艾伯维就有想要终止合作的迹象，2022年8月，艾伯维就决定停止来佐利单抗联合阿扎胞苷和维奈托克治疗MDS和AML的全球1b期临床试验。一些好消息今年10月份，ALX Oncology公布了其CD47单抗Evorpacept治疗Her2阳性胃癌的Ⅱ期临床试验的中期数据，并宣布将在2024年下半年进入III期试验，扭转了该领域近期的颓势。ALX首席执行官Jason Lettmann表示这一积极的结果证明了抗CD47疗法的故事仍在继续。与吉利德的Magrolimab选择在Fc端采用不同亚型的策略不同的是，ALX Oncology采取让“Fc域”灭活的策略。由于失活突变的Fc域无法募集巨噬细胞，因而不会对红细胞造成伤害。放弃CD47抗体引发的杀伤作用，仅利用其将肿瘤细胞充分暴露，联合其他疗法杀死肿瘤。10月3日，ALX宣布其CD47抑制剂Evorpacept（ALX-148）联合曲妥珠单抗、雷莫西尤单抗和紫杉醇治疗HER2阳性胃或为食管交界处（GEJ）癌患者的国际多中心ASPEN-06试验在预先指定的2期部分中期分析中获得积极结果。接受Evorpacept +曲妥珠单抗、雷莫西尤单抗+紫杉醇联合治疗的ORR为52%，而仅接受后三种药物治疗的对照组为22%。ALX计划明年报告该试验的最终分析结果。ALX也并非一帆风顺，该公司最近取消了Evorpacept用于治疗骨髓增生异常综合征（MDS）和急性髓系白血病（AML）的CD47项目。ALX解释说，Evorpacept在这两种血液癌症中的作用机制不同于在实体瘤中的作用机制。在针对CD47亲和力的改造策略方面，也有一些好消息传出。辉瑞收购的Trillium改造策略是利用特殊的SIRPα结合CD47的结构域，通过天然变体V2的Domain1（一种特殊的SIRPα亚型）来结合肿瘤细胞表面的CD47，研发了针对IgG1的TTI-621和针对IgG4的TTI-622两种均没有红细胞毒性的融合蛋白管线。近日，辉瑞的发言人对外表示其抗CD47候选药物Maplirpacept已经显示出与红细胞结合最少的情况，并且很少有贫血的报告病例。该发言人说，Maplirpacept对癌细胞和巨噬细胞都有作用，在超过75例患者的研究中，Maplirpacept作为单药疗法显示出“令人鼓舞的活性”。目前，辉瑞正在进行卵巢癌、多发性骨髓瘤和弥漫性大b细胞淋巴瘤的I期和II期试验。国内的药企也在各自的策略下顺利推进中。宜明昂科也是采用特殊的SIRPα结合CD47的结构域策略，目前，公司布局了7款CD47药物，其中进度最快的IMM01正在推进多项联合疗法；天境生物和康方生物选择筛选只针对肿瘤CD47的特殊偏向性抗体的改造策略，天境生物的来佐利单抗已于2023年4月在中国启动了治疗MDS的Ⅲ期临床研究。康方生物莱法利单抗是目前国内唯一针对三阴乳腺癌适应症的CD47靶向药物，联合阿扎胞苷治疗MDS的随机、双盲、全球多中心II期临床研究已于9月26日获FDA批准。还有一些企业在尝试双抗的研发，包括CD47/PD-L1双抗（如迈威生物的6MW3211、百奥泰的BAT7104）和CD47/CLDN18.2双抗（如康方的AK132、宝船生物的BC007）。虽然艰难坎坷一直都在，但是各个药企都在自己的创新之路上奔跑。参考来源：1.https://www.biospace.com/article/embattled-researchers-see-path-forward-for-anti-cd47-cancer-drugs/2.https://baijiahao.baidu.com/s?id=1779146583620953723&wfr=spider&for=pc3.https://mp.weixin.qq.com/s?__biz=MzA4MzgzMDM5Mg==&mid=2651739174&idx=3&sn=056c6cc0bfbf749fbf5b42bdd97f4b40&chksm=840a8731b37d0e275dc824bb6ea94925ca05d4164f5a5da489151cda3be59feb08fddd65aacc&scene=274.https://baijiahao.baidu.com/s?id=1779171563869776831&wfr=spider&for=pc5.https://it.sohu.com/a/713979727_1211245436.https://weixin.sogou.com/weixin?query=CD47&_sug_type_=&sut=1519&lkt=5%2C1698737045086%2C1698737046345&s_from=input&_sug_=y&type=2&sst0=1698737046455&page=2&ie=utf8&w=01019900&dr=1

Pictured: Pacman, representing the “don’t eat me” signal broadcasted by CD47/iStock, artisteer Companies researching CD47 inhibitors can’t seem to catch a break. Gilead’s multibillion-dollar bet on the CD47-targeting antibody therapy magrolimab appears in jeopardy, and AbbVie recently ended its collaboration with I-Mab, the maker of another anti-CD47 drug, after terminating two early-phase studies of the candidate last August. What once seemed like a competitive field has thinned out considerably, leading some insiders to speculate that CD47 antibodies may be fatally flawed as a therapeutic class. But there is a glimmer of hope. Earlier this month, Bay Area–based ALX Oncology announced positive interim data from a Phase II trial of evorpacept in HER2-positive gastric cancer, bucking the recent downturns across the field. This positive readout, coupled with ALX’s concurrent announcement that it will move into a Phase III trial in the second half of 2024, underscores that the story of anti-CD47 therapies is still being written, said ALX CEO Jason Lettmann. Jason Lettmann “Like most areas of biotech, there's all sorts of ups and downs, but this one has more than its fair share of incredible highs and moments of a lot of doubt,” Lettmann told BioSpace. Still, a fundamental question remains: Why haven’t efforts by some of biotech’s biggest names translated into effective therapeutics? Experts told BioSpace that the apparent setbacks can be attributed to known safety concerns for anti-CD47 antibodies combined with an under-diversified field with too many drugs going after the same target. Even so, they remain hopeful that a CD47-targeting drug can make it to market. Toxic Contradictions CD47 is a transmembrane protein expressed in many human cells, including red blood cells, platelets and immune cells, as well as in a wide variety of cancer cells. The reason cancer cells express this protein is clear: when it binds to its receptor, CD47 inhibits the innate immune system by broadcasting a “don’t eat me” signal. In the past decade, researchers have engineered antibodies to decrease this signal in cancer cells and, in some cases, provide an unambiguous “eat me” signal to macrophages. But these antibody drug candidates often have off-target effects, said Laurence Blumberg, a biotech executive who was formerly the CEO of Arch Oncology, which shuttered earlier this year despite receiving the FDA’s Orphan Drug Designation for its anti-CD47 antibody. Laurence Blumberg “The problem is that CD47 is broadly expressed in normal cells and particularly broadly expressed in components of blood—platelets, white blood cells, red blood cells—and the big issue has been the safety and toxicity of all the different molecules,” Blumberg told BioSpace. “We haven’t gotten to the point where the efficacy has been compelling enough to justify arguably life-threatening toxicities.” Blumberg said these toxicities vary depending on the type of anti-CD47 drug. Monoclonal antibodies, for example, are often associated with conditions such as anemia and thrombocytopenia. This is because the antibodies bind to CD47 on healthy blood cells as well as cancer cells and induce macrophages to engulf and digest both the healthy and diseased cells. Indeed, safety concerns have plagued Gilead’s magrolimab. In January 2022, the FDA placed a hold on trials of the candidate, which was being tested in multiple studies in combination with azacitidine, due to “an apparent imbalance” in suspected unexpected serious adverse reactions. The hold was lifted several months later, but the FDA issued a second partial clinical hold on magrolimab in acute myeloid leukemia (AML) in August. Additionally, a Phase Ib study found that 28.7% of AML patients treated with magrolimab plus azacitidine developed anemia related to the anti-CD47 drug. Gilead has also paused or discontinued multiple clinical trials of magrolimab in recent months. “The efficacy data has been tantalizing,” Blumberg said, “but not really robust enough in light of the fact that you’re dealing with a drug class that is fraught with toxicity risks, and all the molecules have a nuanced toxicity. I don’t think it’s over for the class, but I do think that there’s headwind.” A Field in Flux Prior to the spate of disappointing results, the funding landscape for anti-CD47 immunotherapies looked rosy, buoyed by two multibillion-dollar acquisitions. In March 2020, Gilead acquired magrolimab’s manufacturer, Forty Seven, for $4.9 billion. Soon after, AbbVie entered into its agreement with I-Mab, and Pfizer purchased Trillium Therapeutics, the maker of two anti-CD47 proteins, for $2.22 billion. The acquisitions that occurred alongside promising preclinical and clinical results resulted in the field being flooded with “a lot of money to chase maybe too many drugs going after the same target,” Blumberg said. “But there was nothing wrong with the pursuit.” Some, like Lettmann, believe that many drugmakers unknowingly kneecapped their anti-CD47 antibody therapies by coupling the inhibition of the “don’t eat me” signal with the promotion of the “eat me” signal. “If you try to accomplish both as part of the same molecule, it will be very difficult to effectively target cancer over healthy [cells],” Lettmann said. Magrolimab’s makers tried to skirt the issue by switching from one subclass of immunoglobulin G to another, he continued. Pfizer has similarly stuck to this subclass. In a statement, a Pfizer spokesperson told BioSpace that its anti-CD47 candidate maplirpacept has demonstrated minimal red blood cell binding and few reported cases of anemia. Maplirpacept acts on both cancer cells and macrophages, the spokesperson said, and has demonstrated “encouraging activity” when used as a monotherapy in studies with more than 75 patients. Currently, the company is conducting Phase I and II trials in ovarian cancer, multiple myeloma and diffuse large B-cell lymphoma. ALX has approached drug development with safety in mind, Lettmann said. Evorpacept decouples anti-CD47 monoclonal antibodies’ two mechanisms of action, blocking the cancer cells’ “don’t eat me” signal without turning macrophages into indiscriminate killers—an approach that, when combined with other cancer therapies, has shown preclinical and clinical promise. This month, ALX reported that 52% of patients with gastric/gastroesophageal junction (GEJ) cancer enrolled in a Phase II trial responded to a combination of evorpacept and trastuzumab, ramucirumab and paclitaxel, compared to 22% of patients who received only the three latter drugs. ALX plans to report a final analysis from the trial next year, along with a half-dozen readouts from trials of evorpacept in combination with chemotherapy, a checkpoint inhibitor and an antibody-drug conjugate. Even so, ALX’s journey has not been without its bumps as the company recently axed CD47 programs where evorpacept attempted to treat myelodysplastic syndrome and acute myeloid leukemia—though Lettmann clarified that the mechanism tested in the two blood cancers differs from evorpacept’s mechanism of action in solid tumors. For Lettmann, winning FDA approval for evorpacept would be the culmination of a nine-year journey for ALX and its leadership. Contingent on positive final results from the Phase II trial and the commencement next year of a Phase III trial for gastric/GEJ cancer, Lettmann said he believes the company has “a very logical path to an approval” in this indication. Maddie Bender is a freelance science journalist based in Honolulu, HI. You can contact her through her website, maddiebender.com.