The purpose of this study is to evaluate evorpacept with anti-cancer therapies in advanced/metastatic malignancies. The study is comprised of the following substudies:
* Metastatic HER2+ breast cancer (MBC) - single-arm substudy evaluating the efficacy, safety, and tolerability of evorpacept in combination with trastuzumab and chemotherapy in participants with HER2-positive metastatic breast cancer who have previously received trastuzumab-deruxtecan. This substudy is actively recruiting.
* Metastatic colorectal cancer (CRC) - dose escalation phase to evaluate evorpacept in combination with other drugs. This substudy is not recruiting.
* Recurrent/metastatic head and neck cancer (HNSCC) - dose escalation phase to evaluate evorpacept in combination with other drugs. This substudy is not recruiting.

开始日期2025-04-28

申办/合作机构

ALX Oncology, Inc.

NCT05787639

/ Recruiting临床2期IIT

Neoadjuvant Radiation and Evorpacept (ALX148) in Combination With Pembrolizumab In Patients With Previously Untreated Locally Advanced, Resectable, HPVOPC (Human Papilloma Virus Oropharynx Cancer)

The majority of head and neck cancer patients do not respond to immunotherapies, and clinical responses are often not durable. However, targeting tumors with stereotactic radiation in combination with immunotherapy while sparing draining lymphatics enhances anticancer immunity, resulting in dramatic response in HPV (Human Papilloma Virus) virus related cancers of the throat. This trial will leverage targeted tumor radiation and immunotherapy in advance of standard surgical therapy to improve the response of HPV (Human Papilloma Virus) throat cancer to radiation and immunotherapy.

开始日期2024-02-20

申办/合作机构

University of California San Diego

NCT05467670

/ Recruiting临床2期IIT

Safety and Efficacy of Anti-CD47, ALX148 in Combination with Liposomal Doxorubicin and Pembrolizumab in Patients with Recurrent Platinum-resistant Ovarian Cancer: Phase II Study

Immunotherapy with immune checkpoint inhibitors, including pembrolizumab, have emerged as a promising option in several solid cancers with durable effect and low toxicity profile. However, the benefit is limited to smaller subset of solid tumors. This trial involves the enhancement of current immune checkpoint-based immunotherapy with ALX148, an agent that inhibits CD47 (a trans-membrane protein that is highly expressed on the surface of many solid tumors as compared to normal cells).

开始日期2023-03-30

申办/合作机构

University of Pittsburgh

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100 项与 Evorpacept 相关的临床结果

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100 项与 Evorpacept 相关的转化医学

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100 项与 Evorpacept 相关的专利（医药）

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项与 Evorpacept 相关的文献（医药）

2025-11-01·Cancer research communications

Phase II Clinical Trial and Preclinical Evaluation of a Novel CD47 Blockade Combination in Refractory Microsatellite-Stable Metastatic Colorectal Cancer

Article

作者: Messersmith, Wells A. ; Balmaceda, Nicole ; Hochster, Howard S. ; Van Bokhoven, Adrie ; Spencer, Kristen ; Pitts, Todd M. ; Scott, Aaron J. ; Jordan, Kimberly R. ; Binns, Cameron A. ; Bagby, Stacey M. ; Lentz, Robert W. ; Lieu, Christopher H. ; Kim, Sunnie S. ; Wadlow, Raymond C. ; Hu, Junxiao ; Dominguez, Adrian T.A. ; Davis, S. Lindsey ; Robinson, Hannah R. ; Blatchford, Patrick ; Lang, Julie ; Baiyee, Emily ; Boland, Patrick M. ; Leal, Alexis D.

Abstract:

Purpose::

In this preclinical human immune system patient-derived xenograft (HIS-PDX) model and phase II clinical trial, we assessed evorpacept (anti-CD47 engineered fusion protein with inactive Fc), cetuximab, and pembrolizumab (triple therapy) in microsatellite-stable (MSS) colorectal cancer.

Patients and Methods::

HIS BALB/c-Rag2nullIl2rγnullSirpαNOD mice with PDXs were treated with triple therapy or its components. Patients with refractory MSS colorectal cancer were treated with triple therapy in a safety run-in (stage 1) followed by expansion (stage 2, planned N = 42). The co-primary objectives were to determine the recommended dose of evorpacept and objective response rate (vs. historic control).

Results::

In HIS-PDX mice, triple therapy decreased the growth of MSS colorectal cancer tumors and increased tumor-infiltrating CD8+ T cells. Sixteen patients were treated on the clinical trial across two evorpacept dose levels: N = 12 in stage 1 and N = 4 in stage 2. Trial enrollment was terminated early because of safety concerns (one treatment-related grade 5 event each of hemophagocytic lymphohistiocytosis and cytokine release syndrome). Otherwise, the adverse event profile was as expected. Among all patients, the objective response rate was 6.3%; formal hypothesis testing was not performed. The disease control rate was 12.5%, the median progression-free survival was 2.3 months, and the median overall survival was 10.9 months. Blood- and tumor-based clinical trial correlative analyses identified innate and adaptive immune system activation.

Conclusions::

Whereas triple therapy demonstrated evidence of efficacy in refractory MSS colorectal cancer, safety concerns halted enrollment. Further investigation is necessary to determine the optimal use of CD47-targeted therapies in MSS colorectal cancer.

Significance::

Evorpacept, cetuximab, and pembrolizumab demonstrated antitumor activity in a preclinical HIS-PDX model and clinical trial in refractory MSS colorectal cancer; however, immune-related adverse events prompted early termination of study enrollment. Evidence of innate and adaptive antitumor immune activation was identified. The role of SIRPα/CD47 blockade in the treatment of MSS colorectal cancer needs to be further elucidated in future trials.

2024-07-01·CURRENT OPINION IN ONCOLOGY

State of the art and upcoming trends in HER2-directed therapies in gastrointestinal malignancies

Review

作者: Lee, Jaeyop ; Ku, Geoffrey

Purpose of review:

This review critically evaluates the evolution and current status of human epidermal growth factor receptor 2 (HER2)-directed therapies in upper gastrointestinal (GI) malignancies, a timely and relevant inquiry given the dynamic shifts in therapeutic strategies over the past decade. Initial enthusiasm following the Trastuzumab for Gastric Cancer (ToGA) study's demonstration of trastuzumab's efficacy, however, encountered hurdles due to subsequent trials showing limited progress, underscoring the necessity for a reevaluation of therapeutic approaches and the exploration of novel agents.

Recent findings:

The review highlights significant breakthroughs in the form of immune checkpoint inhibitors and innovative therapeutic technologies, which have redefined treatment paradigms and shown promising efficacy in HER2-positive cases. Emerging treatments such as trastuzumab deruxtecan (T-DXd), zanidatamab and evorpacept further illustrate the ongoing efforts to leverage unique mechanisms of action for improved HER2-positive antitumor activity.

Summary:

The advancements in HER2-directed therapies underscore a pivotal era in the management of upper GI malignancies. These developments not only reflect the profound impact of integrating novel therapeutic combinations but also highlight the critical role of ongoing research in overcoming resistance mechanisms and tailoring treatment to individual disease profiles.

2020-04-01·Seminars in oncology3区 · 医学

Just eat it: A review of CD47 and SIRP-α antagonism

3区 · 医学

Review

作者: Oronsky, Bryan ; Reid, Tony ; Carter, Corey ; Knox, Susan J ; Brinkhaus, Franck

The mammalian immune system consists of two distinct arms, nonspecific innate and more specific adaptive, with the innate immune response as the first line of defense and protection, which primes and amplifies subsequent adaptive responses. On the basis of this binary immune interplay, stimulation of T cells through checkpoint inhibitors (CIs), which bypasses innate involvement, seems likely to engender suboptimal or incomplete anticancer immunity, given that the successful induction of effect or responses depends on two-way innate/adaptive coordination. Indeed, the majority of patients-70%-80%, do not respond to CIs, which is potentially problematic if access to more optimal standard therapies is withheld or delayed in favor of ineffective or only marginally effective anti-PD-1/PD-L1 treatment. Therefore, stimulation of the innate immune response in combination with CIs (or other inducers of T cell cytotoxicity) has the potential to make the immune system "whole" and thereby to enhance and broaden the anti-tumor activity of PD-1/PD-L1 inhibitors for example, in relatively nonimmunogenic or "cold" tumor types. A critical innate macrophage immune checkpoint and druggable target is the antiphagocytic and "marker of self" CD47-SIRPα pathway, which is co-opted by cancer cells to mediate escape from immune-mediated clearance and checkpoint inhibition. This review summarizes the status of key CD47 antagonists in clinical trials, including the biologics, Hu5F9-G4 (5F9), TTI-621, and ALX148, as well as the small molecule, RRx-001, now in a Phase 3 clinical trial, which has not been previously included in CD47-SIRPα reviews focused on biologics. Hu5F9-G4 (5F9), TTI-621, ALX148, and RRx-001 are chosen as compounds with potentially promising data that have advanced the farthest in clinical development.

193

项与 Evorpacept 相关的新闻（医药）

2026-01-15

·药创新

从狂热追捧，到理性回归，CD47靶点的破局新路径

不被动摇的信心。撰文丨拿铁近日，在2026年美国临床肿瘤学会胃肠道肿瘤研讨会（ASCO GI 2026）上，一项针对转移性胰腺导管腺癌（mPDAC）的临床研究数据引发广泛关注。在这项研究中，来自海外药企Phanes Therapeutics的双抗新药spevatamig将“癌王”胰腺癌的总生存期与现有化疗药物相比延长近一半（13.2个月），且spevatamig单药安全性好，未观察到细胞因子释放综合征（CRS）或剂量限制性毒性（DLT）。 Spevatamig是一款靶向CLDN18.2/CD47的双抗创新药，此次临床试验虽是初步验证阶段的临床数据，但其展现出的巨大潜力使胰腺癌迎来新的治疗希望。同时，CD47这一屡屡受挫的“黑洞靶点”，或将迎来破局时刻。一切源于更优的结构设计 Phanes Therapeutics是一家专注于肿瘤领域创新药物发现和开发的临床阶段生物技术公司，拥有专有技术平台PACbody、SPECpair和ATACCbody，分别开发具有更高的稳定性、可生产性、以及可调节免疫活性的新型双特异性抗体。 Spevatamig由Phanes Therapeutics自主研发，是一种靶向CLDN 18.2和CD47的天然IgG结构双特异性抗体，基于SPECpair和PACbody技术平台，Phanes Therapeutics使用抗CD47单臂和抗CLDN18.2抗体的单臂，在IgG1骨架基础上，构建而成。spevatamig只有一个抗CD47单臂，这使其对不表达CLDN18.2的红细胞的结合较弱。因此，spevatamig通过其两个单臂与癌细胞的高结合能力，在发挥潜在疗效作用的同时，限制了非肿瘤靶向（胃肠道）毒性。在ASCO GI 2026会议上公布的TWINPEAK研究，是一项针对消化道肿瘤患者的多队列I期临床研究，结果显示，在107例接受了spevatamig单药或联合治疗的mPDAC患者中，在2mg/kg spevatamig+GnP（标准化疗方案：吉西他滨+白蛋白紫杉醇）一线治疗mPDAC方案中（n=15），疾病控制率（DCR）为93%，客观缓解率（ORR）为40%，中位无进展生存期（mPFS）为7.3个月，中位总生存期（mOS）为13.2个月且仍在成熟中。更重要的是，spevatamig展现出了良好的安全性特征，未观察到CRS或DLT。研究期间未观察到≥3级贫血、中性粒细胞减少症或血小板减少症治疗期间不良事件（TEAE）。另外，在CLDN18.2评分≥10%的患者中均观察到了治疗反应。总之，与既往发表的GnP方案一线治疗mPDAC数据相比，spevatamig 2mg/kg+GnP方案展示出了令人鼓舞的疗效。同时，尽管只是小样本的临床研究，但这些临床概念验证中的出色数据表明，spevatamig的分子设计减轻了血液毒性并改善了胃肠道耐受性。这对于CD47靶点的开发是至关重要的，因为此前曾因严重的血液毒性，使不少CD47明星管线临床研发遭遇滑铁卢。 CD47：“下一个PD-1”？ CD47，又称整合素相关蛋白，是一种广泛表达的跨膜糖蛋白。作为一种免疫检查点，CD47大量存在于肿瘤细胞表面，当与巨噬细胞表面的信号调节蛋白α（SIRPα）结合时，会释放出“别吃我”信号，防止巨噬细胞对肿瘤细胞的吞噬作用。因此阻断CD47的结合能力之后，巨噬细胞就可以恢复对肿瘤细胞的吞噬作用。 CD47/SIRPα的作用机制与PD-1/PD-L1之间的基础机理有一定共通性，因此CD47赛道也被称为“下一个PD-1”。而且理论上CD47药物比PD-1抑制剂具有更强的抗肿瘤活性，因为靶向CD47可以激活先天免疫和适应性免疫双重抗癌机制，而PD-1抑制剂只激活适应性免疫，因此行业对CD47抱有更高期待。 2020年，是CD47成为医药行业热门融资标的的一年。这一年3月，吉利德斥资49亿美元收购了CD47单抗先驱Forty Seven；7月，赛生药业斥资1.2亿美元，引进EpicentRx的靶向CD47/SIRPα的免疫刺激小分子药物RRx-001的大中华区权益；9月，天境生物与艾伯维就CD47单抗lemzoparlimab达成总值29.4亿美元的全球战略合作；9月，CD47明星公司Trillium Therapeutics获辉瑞2500万美元投资；10月，癌症免疫疗法开发公司SurfaceOncology（开发靶点包括CD47）收到GSK收购意向。2021年11月，辉瑞更是斥资22.6亿美元收购Trillium Therapeutics，获得maplirpacept和ontorpacept两款CD47靶向药物。巨头的入局，使得CD47靶点迅速成为资本市场关注的焦点，但资本热情并未获得相应回报，目前为止入局药企在CD47领域的探索算不上顺利。连续遭遇挫折 2022年1月，吉利德发布公告，旗下重金押注的CD47单抗Magrolimab因怀疑存在严重不良事件，被FDA暂停了Magrolimab与阿扎胞苷联用治疗骨髓增生异常综合征（MDS）和急性髓系白血病（AML）的临床研究，后虽经审查后恢复，但接下来这个靶点遭遇了连续的挫败。 2023年，天境生物与艾伯维持续了三年的合作宣告终止，这一结局反映了两家公司在CD47靶点药物开发的失败。2024年初，吉利德在公布财报的同时更新了管线进展，旗下关于magrolimab的6项试验均被踢除，意味着吉利德彻底放弃该药物的开发，49亿美元打了水漂。 2025年4月，ALX Oncology宣布其开发的CD47抑制剂Evorpacept，在与Keytruda联用的两项Ⅱ期临床试验ASPEN-03和ASPEN-04中，均未达到主要终点目标：与Keytruda单药相比，Evorpacept+Keytruda未能提高晚期头颈部鳞状细胞癌患者的客观缓解率（ORR）。此前，该公司已终止了Evorpacept针对MDS和AML的临床试验。 2025年6月，辉瑞宣布收购而来的CD47靶向药物maplirpacept在治疗复发/难治性弥漫性大B细胞淋巴瘤的II期研究因患者招募困难终止，此前ontorpacept也已从研发管线中消失。制药巨头和Biotech的接连折戟，证实CD47的开发难度远超预期。综合分析，CD47药物开发失败在安全性和药效方面都有原因。由于CD47在红细胞、血小板等正常细胞表面广泛表达，若靶向CD47的药物（如抗体或SIRPα-Fc融合蛋白）与红细胞结合，可能会通过抗体的偶联作用使红细胞相互凝集，致使其结构和功能遭到破坏，进而出现贫血等血液毒性症状。另外，如果药物的Fc段能够与巨噬细胞表面的Fcγ受体结合，激活巨噬细胞的吞噬功能，那么可能会引导巨噬细胞对红细胞进行吞噬，造成更严重的血液学毒性。为了避免血液学毒性，有药企试图通过弱化CD47药物与红细胞结合能力，来避免对红细胞的杀伤。如辉瑞的maplirpacept，采用SIRPα-IgG4 FC融合蛋白结构，SIRPα部分负责与CD47结合，而IgG4 FC段经过工程化改造，降低了与红细胞表面CD47的亲和力，减少药物对红细胞的非特异性结合。但过度弱化结合力使得疗效不足，治疗需提高剂量，但剂量增加又会提高血液学毒性发生风险。因此，对于跟随者来说，如何平衡疗效与安全性，成了一个棘手问题。不被动摇的信心 CD47对肿瘤存活重要，但对红细胞存活同样关键。这种靶点的生理功能与治疗目标之间的固有矛盾，使得CD47成药性面临巨大挑战，但困难并未动摇业界继续探索的决心。在2025 ASCO会议上，ImmuneOncia Therapeutics公布了旗下新一代CD47抗体IMC-002联合仑伐替尼治疗晚期肝细胞癌（HCC）的Ib期临床试验中期结果。IMC-002具备独特的结合构象与抗原表位，可最大限度地减少与红细胞的结合。初步临床结果展现了IMC-002具有良好的安全性特征，未报告中性粒细胞减少症或血小板减少症病例，96%的不良事件为1-2级。在10例可评估疗效的患者中，ORR为30%，DCR为70%，中位疾病进展时间（TTP）为8.3个月。国内一部分药企也在CD47靶点领域进行了一系列创新性解决方案的探索，并在2025年迎来资本的理性回归。 2025年6月，复宏汉霖和汉康生技子公司FBD Biologics Limited签订合作协议，复宏汉霖将获得由汉康生技自主开发的SIRPα-Fc融合蛋白HCB101在中国（除台湾地区）、东南亚特定国家及中东和北非地区（MENA）特定国家的开发、生产及商业化独家许可权益，以及在日本市场的优先谈判权。汉康生技有望获得1000万美元的首付款以及1.92亿美元的潜在里程碑付款等。 HCB101作为一种SIRPα-Fc融合蛋白，具备高选择性的肿瘤靶向结合能力，同时降低红细胞结合，减少贫血和血小板减少等常见副作用，在早期临床中展现出了优异的血液安全性。目前正在中国大陆、美国等多地开展HCB101联合标准疗法治疗晚期实体瘤的Ib/IIa期研究。本次交易采取了低首付+高里程碑的风险分担模式，表明只要分子设计能有效解决“红细胞毒性”这一问题，产业资本便愿意为安全性支付溢价， 2025年8月，浙江昂利康制药股份有限公司宣布与亚飞(上海)生物医药科技有限公司、上海亲合力生物医药科技股份有限公司签署《战略合作协议之授权许可协议》，公司将获得靶向CD47的IMD-1005药物分子在中国(包括中国大陆、香港、澳门特别行政区以及中国台湾地区)的研发、生产、商业化独家权益。昂利康拟分阶段向亚飞生物与亲合力支付合计1.5亿元人民币的首付款，以及最高不超过6.2亿元人民币的里程碑付款和产品上市后支付12.8%的销售分成。 IMD-1005是一种全球创新的肿瘤微环境激活型的遮罩型抗体药物，抗体部分为CD47单抗。该CD47抗体对CD47靶点的结合活性因偶联了遮罩而大大降低，在血液中高度稳定，从而避免了CD47抗体活性所导致的血液毒性。药物被运送到肿瘤微环境中，连接遮罩和抗体之间的连接子（Linker）被肿瘤微环境高表达的酶切断后，遮罩效果消失，CD47抗体恢复活性，从而在肿瘤局部促进巨噬细胞攻击肿瘤细胞，同时抗体依赖的细胞介导的细胞毒性作用（ADCC）也被增强，从而达到双重抗肿瘤免疫治疗的作用效果。宜明昂科的IMM01是一款靶向CD47的SIRPα-Fc融合蛋白，其与CD47结合区域采用了一个工程化的人类SIRPα结构域，在体外研究中，该结构域大大抑制了药物与人体红细胞结合。目前，该产品拟开发适应症为骨髓增生异常综合征（MDS）、经典霍奇金淋巴瘤（cHL）和慢性粒单核细胞白血病（CMML）以及心血管领域疾病，并已率先进入临床后期阶段，前期研究表明IMM01的不良反应都在可控范围内。康方生物的AK117是一款抗CD47人源化IgG4单克隆抗体，在红细胞凝集试验中，AK117在高达3000nM的浓度下也不诱导红细胞凝集，预示着显著的安全性。康方生物开展了AK117联合阿扎胞苷治疗初诊较高危MDS的全球II期临床试验等。另外，信达生物布局了CD47/PD-L1双抗、德昇济医药布局了HER2/CD47双抗等等。在CD47领域虽有不少失败案例在前，但仍有不少成功案例在陆续披露。在巨头们频频受挫时，产业资本已悄然开始新一轮的逆向布局，与2020年那波热潮不同，这次资本的理性回归是在为已验证的疗效和安全性付费。在这波热潮中，药企们提出了一系列创新性的解决方案：或减少CD47药物与红细胞的结合，或放弃CD47抗体的直接杀伤作用寻求新的作用机制，或开发双抗、融合蛋白以及探索联合用药策略，等等。多样化的药物分子，展现了药企们在面对CD47挑战时不屈不挠的创新精神。未来1—2年，CD47领域将迎来关键数据读出，届时，CD47靶点或不再是制药界的“意难平”。 END 往期精彩内容倒计时2天！创新药“华山奖”即将揭晓倒计时3天！创新药“华山奖”即将揭晓三生制药15亿美元创纪录首付款：解码中国创新药出海核心价值

ASCO会议临床结果临床1期

2026-01-08

·ir.alxoncology.com

ALX Oncology Advances Separate Clinical Trials Evaluating Investigational CD47-Inhibitor Evorpacept and Novel EGFR-Targeted Antibody-Drug Conjugate ALX2004

- First patient dosed in Phase 2 ASPEN-09-Breast trial evaluating evorpacept in combination with trastuzumab and physician’s choice of chemotherapy in HER2-positive metastatic breast cancer; interim analysis anticipated Q3 2026 – - Third dose cohort initiated in Phase 1 trial of ALX 2004; study remains on track to provide initial safety data in 1H 2026 - SOUTH SAN FRANCISCO, Calif., Jan. 08, 2026 (GLOBE NEWSWIRE) -- ALX Oncology Holdings Inc. ("ALX Oncology," Nasdaq: ALXO), a clinical-stage biotechnology company advancing a pipeline of novel therapies designed to treat cancer and extend patients’ lives, announced that the first patient has been dosed in the Company’s Phase 2 ASPEN-09-Breast trial evaluating its investigational CD47-inhibitor evorpacept. This trial will evaluate the combination of evorpacept with trastuzumab and physicians’ choice of chemotherapy in patients with HER2-positive metastatic breast cancer whose disease has progressed after ENHERTU® (T-DXd). Additionally, after successfully clearing the second dose cohort, the Phase 1 trial evaluating the Company’s epidermal growth factor receptor (EGFR)-targeted antibody-drug conjugate (ADC) ALX2004 for the treatment of EGFR-expressing solid tumors has begun enrolling patients in the third dose cohort at 4mg/kg. No dose-limiting toxicities were observed in the prior two dose cohorts. "We are extremely pleased with the progress we are making on these clinical trials," said Jason Lettmann, Chief Executive Officer at ALX Oncology. "We believe both evorpacept and ALX2004 have the potential to fill significant gaps in the standard of care for many types of cancer." Evorpacept is the first CD47 inhibitor to show substantial tumor response and a well-tolerated safety profile in a randomized trial. Data from this prior gastric cancer trial, ASPEN-06, show that evorpacept demonstrated benefit across all efficacy parameters in patients with HER2-positive disease and high CD47 expression levels. Research has demonstrated that increased CD47 expression is correlated with poor patient outcomes in many tumor types, including breast cancer. The Phase 2 ASPEN-09-Breast clinical trial (NCT07007559) is a single-arm, open-label, multicenter study evaluating evorpacept plus trastuzumab and physicians’ choice of chemotherapy in 80 patients with HER2-positive breast cancer previously treated with ENHERTU® (fam-trastuzumab deruxtecan-nxki), which was recently approved as first-line therapy. The trial will utilize participants’ CD47 expression levels as a biomarker to assess responses. The primary endpoint of the trial is overall response rate (ORR) in patients who are confirmed HER2 positive by circulating tumor DNA (ctDNA). Key secondary endpoints are ORR in the HER2 ctDNA+ subpopulation by level of CD47 expression, clinical benefit rate (CBR), duration of response (DOR), progression-free survival (PFS) and overall survival (OS), and safety. ORR in the HER2 ctDNA-negative subpopulation is an exploratory endpoint. ALX Oncology anticipates sharing interim data from the trial in Q3 2026. The ALX2004 Phase 1 clinical trial (NCT07085091) is a first-in-human, open-label, multicenter trial evaluating ALX2004 in participants with advanced or metastatic select EGFR-expressing solid tumors. The study consists of a Phase 1a dose escalation portion followed by optional dose exploration, and a Phase 1b dose expansion. The dose escalation portion of the trial is enrolling patients with previously treated advanced or metastatic non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), esophageal squamous cell carcinoma (ESCC) and colorectal cancer (CRC). "Preclinical data suggest that ALX2004 has the potential to overcome the toxicity challenges associated with earlier generation EGFR-targeted ADCs," said Lettmann. "It is encouraging that, after clearing the second dose cohort in our Phase 1 trial at 2mg/kg, we are able to double the dosage to 4mg/kg in the third cohort." ALX Oncology expects to provide an initial safety update from the Phase 1 ALX2004 trial during 1H 2026. About ALX Oncology ALX Oncology (Nasdaq: ALXO) is a clinical-stage biotechnology company advancing a pipeline of novel therapies designed to treat cancer and extend patients’ lives. ALX Oncology’s lead therapeutic candidate, evorpacept, has demonstrated potential to serve as a cornerstone therapy upon which the future of immuno-oncology can be built. Evorpacept is currently being evaluated across multiple ongoing clinical trials in a wide range of cancer indications. ALX Oncology’s second pipeline candidate, ALX2004, is a novel EGFR-targeted antibody-drug conjugate with a differentiated mechanism of action. A Phase 1, dose-escalation trial of ALX2004 is ongoing in patients with EGFR-expressing solid tumors. Cautionary Note Regarding Forward-Looking Statements This press release contains forward-looking statements that involve substantial risks and uncertainties. Forward-looking statements include statements regarding future results of operations and financial position, business strategy, product candidates, planned preclinical studies and clinical trials, results of clinical trials, research and development costs, regulatory approvals, timing and likelihood of success, plans and objects of management for future operations, as well as statements regarding industry trends. Such forward-looking statements are based on ALX Oncology’s beliefs and assumptions and on information currently available to it on the date of this press release. Forward-looking statements may involve known and unknown risks, uncertainties and other factors that may cause ALX Oncology’s actual results, performance or achievements to be materially different from those expressed or implied by the forward-looking statements. These and other risks are described more fully in ALX Oncology’s filings with the Securities and Exchange Commission (SEC), including ALX Oncology’s Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q and other documents ALX Oncology files with the SEC from time to time. Except to the extent required by law, ALX Oncology undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made. More information is available at www.alxoncology.com and on LinkedIn @ALX Oncology. Investor Relations Contact: Elhan Webb, CFA, IR Consultant ewebb@alxoncology.com Media Contact: Michele Parisi, SparkPoint Healthcare Communications mparisi@sparkpointpr.com (925) 864-5028

临床1期抗体药物偶联物临床2期上市批准免疫疗法

2026-01-07

·有驾

抗癌新突破！CD47靶点药物如何破解“别吃我”信号难题

科学界历经十余年攻坚，曾经因血液毒性险些被放弃的CD47靶点，如今正成为肿瘤免疫治疗的新希望。2009年，斯坦福大学Irving Weissman教授团队在《细胞》杂志上发表两项开创性研究，首次揭示癌细胞通过表面高表达的CD47蛋白与巨噬细胞表面的SIRPα结合，发出“别吃我”信号，从而逃避免疫系统的吞噬清除。这一发现点燃了科学界对CD47靶点的研发热情。CD47作为肿瘤免疫治疗的新星靶点，其发展历程却充满挑战与突破。从最初因血液毒性险些被放弃，到如今第三代技术带来新的希望，CD47靶向药物的研发历程堪称一部创新药发展的缩影。 01 靶点机制：癌细胞如何利用“别吃我”信号逃避免疫监视 CD47是一种广泛表达于多种细胞表面的跨膜糖蛋白，也被称为整合素相关蛋白（IAP）。它通过与免疫细胞上的信号调节蛋白α（SIRPα）结合，发出“别吃我”的信号，抑制巨噬细胞的吞噬作用，从而保护健康细胞不被免疫系统破坏。研究表明，大多数肿瘤细胞均存在CD47的过度表达，且CD47高表达与患者不良预后密切相关。肿瘤细胞利用这一机制，伪装成“自己人”，逃避免疫系统的攻击。CD47靶向药物的核心作用机制是通过阻断CD47-SIRPα信号通路，解除肿瘤细胞的“别吃我”信号，同时通过抗体Fc段介导的效应功能，如抗体依赖性细胞吞噬作用（ADCP），激活巨噬细胞杀伤肿瘤细胞。 02 发展历程：CD47靶点药物研发的三代技术演进第一代CD47抗体：血液毒性成绊脚石 CD47药物研发初期，最大的挑战是红细胞表面也大量表达CD47，导致抗体在攻击肿瘤细胞的同时也会误伤红细胞，引起严重贫血和血小板减少等副作用。最具代表性的第一代CD47抗体是吉利德公司的Magrolimab（原Hu5F9-G4）。为解决血液毒性问题，研究人员采用了预激给药策略：先给予低剂量（1mg/kg）清除衰老红细胞，刺激新红细胞生成，再逐步增加剂量。这一策略在早期临床试验中显示出 promise。2019年美国血液学会（ASH）年会上公布的数据显示，Magrolimab与阿扎胞苷联合治疗骨髓增生异常综合征（MDS）和急性髓系白血病（AML）患者，客观缓解率（ORR）分别高达92%和64%。然而，2023年，Magrolimab在三期临床研究中因疗效不足接连受挫，吉利德终止了其针对MDS和AML的多项临床试验。第二代CD47抗体：优化设计降低毒性第二代CD47抗体致力于通过分子优化减少与红细胞的结合。信达生物的IBI188和ALX Oncology的Evorpacept（ALX-148）是这一代代表作品。Evorpacept采用Fc结构域灭活策略，完全消除了Fc效应功能，虽然避免了血液毒性，但单药治疗效果不佳，必须依赖联合用药。2023年，ALX Oncology宣布终止Evorpacept治疗MDS和AML的临床研究，主因疗效不足。第三代CD47抗体：精准靶向突破毒性瓶颈第三代CD47抗体通过精准靶向技术，实现了对肿瘤细胞的特异性识别，同时最小化对红细胞的影响。天境生物的开发团队采用噬菌体展示技术筛选CD47抗体，并通过负向筛选找到与红细胞低亲和力的抗体。在约200个CD47结合阳性克隆中，他们发现了唯一一个同时具有高肿瘤结合力和低红细胞结合力的抗体——来佐利单抗（lemzoparlimab，TJC4）。来佐利单抗的独特之处在于它能识别CD47的特殊表位，该表位在红细胞上因糖基化修饰而无法充分暴露，从而大大降低了与红细胞的结合能力。临床数据显示，来佐利单抗无需预激给药，在高达30mg/kg的剂量下仍表现出良好安全性。康方生物的AK117则采用不同的策略，通过在IgG4抗体基础上改造Fc结构，调整CD47结合的表位及复合物角度，减少红细胞凝集现象。 03 研究意义：CD47靶点为何成为必争之地 CD47靶点被誉为继PD-1/PD-L1之后最具潜力的肿瘤免疫治疗靶点，其研究意义重大。CD47信号通路在多种血液肿瘤和实体瘤中发挥关键作用。特别是在目前治疗选择有限的MDS和AML领域，CD47靶向药物展现出巨大潜力。CD47靶点的重要性还体现在其与现有疗法的协同作用。临床前研究显示，CD47抗体与阿扎胞苷联用可产生协同抗肿瘤效应。阿扎胞苷可增强“吃我”信号，而CD47抗体则阻断“别吃我”信号，共同增强对肿瘤细胞的吞噬作用。此外，CD47靶向药物在解决肿瘤耐药性问题方面也展现出潜力。研究表明，CD47在肿瘤干细胞上高表达，这可能是导致肿瘤复发和治疗抵抗的重要原因之一。靶向CD47有望消除肿瘤干细胞，从而防止肿瘤复发。 04 未来发展方向：联合治疗与创新策略尽管CD47靶点研发遭遇挫折，但未来仍有多条路径可能引领这一领域走向成功。联合治疗策略 CD47靶向药物与其它疗法的联合应用是主要发展方向。目前研究的联合策略包括： (1) 与化疗药物联用：如与阿扎胞苷、维奈克拉等联合治疗血液肿瘤 (2) 与免疫检查点抑制剂联用：如与PD-1/PD-L1抗体联合，同时激活先天性和适应性免疫 (3) 与靶向药物联用：如与CD20抗体、HER2抗体等联合应用 ALX Oncology的Evorpacept在联合治疗方面已取得初步成功。其与曲妥珠单抗、雷莫西尤单抗和紫杉醇联用治疗HER2阳性胃癌/胃食管结合部癌的二期研究显示，客观缓解率达到52%，显著优于对照组的22%。双特异性抗体开发双特异性抗体是CD47靶点发展的另一重要方向。天境生物开发的TJ-L1C4（靶向PD-L1和CD47）和TJ-C4GM（靶向CD47和GM-CSF）等双特异性抗体，可同时阻断多个免疫抑制信号，增强抗肿瘤效果。实体瘤治疗探索虽然CD47抗体在血液肿瘤中效果更为明确，但实体瘤才是CD47靶向药物的终极目标。目前，多个CD47靶向药物已在实体瘤中展开临床研究。例如，Evorpacept联合帕博利珠单抗一线治疗头颈部鳞状细胞癌的客观缓解率达到38.5%。这些早期数据为CD47靶向药物在实体瘤中的应用提供了初步证据。创新分子设计未来的CD47靶向药物将更加注重分子设计的创新。宜明昂科开发的IMM01采用SIRPα-Fc融合蛋白设计，选择具有较强Fc效应功能的IgG1亚型，同时通过改造避免与红细胞结合。IMM01已在中国进入三期临床试验，早期数据显示其在不使用低初始剂量的情况下，联合阿扎胞苷治疗较高危MDS患者的客观缓解率达到64.7%。据医药魔方NextPharma数据库显示，全球共有65款CD47靶点药物进入临床阶段，其中超过半数来自中国药企。天境生物、康方生物、宜明昂科等国内企业的创新研发，正使中国在CD47靶点领域跻身世界前列。CD47靶向药物的研发历程印证了创新药开发的普遍规律：真正的突破往往源于对失败经验的深刻理解。随着对CD47生物学机制的深入理解和药物技术的持续创新，CD47靶点有望在未来五年内迎来重要突破，为肿瘤患者提供新的治疗选择。科学界历经十余年攻坚，曾经因血液毒性险些被放弃的CD47靶点，如今正迎来新的曙光。文章来源于网络、如有侵权请联系作者删除

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
HER2表达胃腺癌	临床3期	美国	Eli Lilly & Co.	2022-01-15
HER2表达胃腺癌	临床3期	美国	ALX Oncology, Inc.	2022-01-15
HER2表达胃腺癌	临床3期	日本	Eli Lilly & Co.	2022-01-15
HER2表达胃腺癌	临床3期	日本	ALX Oncology, Inc.	2022-01-15
HER2表达胃腺癌	临床3期	澳大利亚	ALX Oncology, Inc.	2022-01-15
HER2表达胃腺癌	临床3期	澳大利亚	Eli Lilly & Co.	2022-01-15
HER2表达胃腺癌	临床3期	比利时	ALX Oncology, Inc.	2022-01-15
HER2表达胃腺癌	临床3期	比利时	Eli Lilly & Co.	2022-01-15
HER2表达胃腺癌	临床3期	捷克	ALX Oncology, Inc.	2022-01-15
HER2表达胃腺癌	临床3期	捷克	Eli Lilly & Co.	2022-01-15

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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


NCT05025800 (ASH2025)	临床2期	惰性B细胞非霍奇金淋巴瘤一线	24	Evorpacept (ALX148) + Lenalidomide + Rituximab	膚構積醖艱願觸窪築餘(遞糧遞築鏇製獵壓鹽衊) = 獵鬱鬱餘觸艱網願憲餘襯餘築鹹醖夢選鹹積醖 (齋構願窪遞獵蓋廠夢憲 ) 更多	积极	2025-12-06
NCT04675333 (ASPEN-04, ESMO2025)	临床2期	复发性头颈部鳞状细胞癌	165	Evorpacept (evo) + Pembrolizumab + Chemotherapy	夢窪廠襯醖窪選膚選齋(築餘構鹽構簾鬱醖襯廠) = 齋範壓選網襯製網餘齋衊鬱積淵遞廠顧憲積憲 (獵願鏇繭鹽廠餘網遞餘, 28.2 ~ 47.0)	不佳	2025-10-17
				Pembrolizumab + Chemotherapy	夢窪廠襯醖窪選膚選齋(築餘構鹽構簾鬱醖襯廠) = 築齋觸築鬱鹽構衊襯繭衊鬱積淵遞廠顧憲積憲 (獵願鏇繭鹽廠餘網遞餘, 32.0 ~ 59.4)
ASPEN-09-03 (ESMO2025)	临床2期	HER2阳性转移性乳腺癌 HER2-positive	80	Evorpacept + Trastuzumab + Chemotherapy	獵淵繭淵窪淵餘築窪繭(網憲願憲壓範淵構廠夢) = 鏇餘餘膚鑰網淵構鹹糧願觸窪鑰醖顧鹹衊糧鹹 (顧廠遞遞願鑰憲夢觸鹽 )	积极	2025-10-17
NCT04675294 (ASPEN-03, ESMO2025)	临床2期	PD-L1阳性头颈部鳞状细胞癌 PD-L1 positive	181	Evorpacept (evo) + Pembrolizumab	餘積遞齋糧繭製獵網構(構壓築鹽網鏇構糧蓋繭) = 夢鏇膚淵遞壓艱淵窪積獵餘獵憲築憲鹽蓋齋顧 (築膚遞觸願選遞鑰鬱遞, 18.8 ~ 35.2)	不佳	2025-10-17
				Pembrolizumab	餘積遞齋糧繭製獵網構(構壓築鹽網鏇構糧蓋繭) = 鬱構鑰鏇鏇壓遞憲鏇鹽獵餘獵憲築憲鹽蓋齋顧 (築膚遞觸願選遞鑰鬱遞 )
NCT05787639 (Phase II trial of neoadjuvant SBRT followed by combination evorpacept/pembrolizumab in HPV+ HNSCC, ASCO2025)	临床2期	头颈部鳞状细胞癌新辅助 HPV+	27	evorpacept (Neoadjuvant SBRT)	窪鬱蓋窪範構淵壓艱觸(蓋觸鬱窪廠網淵範製積) = 齋醖窪簾壓築觸齋憲鬱鏇鹹憲顧繭餘繭簾鑰構 (醖積餘鬱淵築製衊蓋齋 )	积极	2025-05-30
NCT05025800 (AACR2025) 人工标引	临床1期	非霍奇金淋巴瘤	20	Evorpacept + lenalidomide + rituximab	齋選壓觸淵範衊願餘蓋(鏇糧願夢範觸鏇積範鹹) = 糧艱築築齋鹹蓋鑰衊襯廠鹹蓋廠襯觸製積觸廠 (夢鬱壓願窪壓獵衊鏇鹽 ) 更多	积极	2025-04-29
NCT04675333 (ASPEN-04, Company_Website) 人工标引	临床2期	晚期头颈部鳞状细胞癌	-	evorpacept + pembrolizumab + chemotherapy	鹽鏇膚鹽膚憲願繭襯獵(鑰築簾蓋糧鏇顧鹽鑰構) = Not Meet Primary Endpoints. 願願顧醖鏇鹽遞憲膚膚 (憲築窪糧網醖構遞醖壓 ) 未达到	不佳	2025-04-25
				pembrolizumab + chemotherapy
NCT04675294 (ASPEN-03, Company_Website) 人工标引	临床2期	晚期头颈部鳞状细胞癌一线 PD-L1 Positive	-	Evorpacept + pembrolizumab	積蓋衊網選繭夢獵齋夢(窪鹹壓獵膚築窪繭範鹹) = Not Meet Primary Endpoints 蓋衊鹹膚獵鏇窪鏇艱繭 (製觸蓋簾製獵襯壓齋簾 ) 未达到	不佳	2025-04-25
				pembrolizumab
NCT05002127 (ASPEN-06, Corporate Publications) 人工标引	临床2/3期	HER2阳性胃食管交界处癌 \| HER2阳性胃癌 HER2 Positive	127	Evorpacept + Trastuzumab + Ramucirumab + Paclitaxel	鹹範膚選繭網網憲製蓋(齋繭窪簾夢繭憲齋憲獵) = 壓壓製廠窪憲遞積範膚遞膚壓繭襯憲鑰艱鏇壓 (簾鏇築簾選蓋選顧積衊, 29.0 ~ 54.4) 更多	积极	2025-01-23
				Trastuzumab + Ramucirumab + Paclitaxel	鹹範膚選繭網網憲製蓋(齋繭窪簾夢繭憲齋憲獵) = 齋網衊觸遞糧淵淵餘製遞膚壓繭襯憲鑰艱鏇壓 (簾鏇築簾選蓋選顧積衊, 16.3 ~ 39.1) 更多
NCT05002127 (ASPEN-06, ASCO_GI2025) 人工标引	临床2/3期	HER2阳性胃食管腺癌 \| HER2阳性胃癌 HER2+	127	EvorpaceptEvorpacept (ALX148) + Trastuzumab (T) + Ramucirumab (R) + Paclitaxel (P)	衊顧範襯壓獵鹽簾艱遞(餘壓餘膚衊範鑰憲鹹鏇) = 襯觸壓鏇醖艱醖鏇範積齋鹽艱壓觸顧夢糧壓齋 (廠簾淵鹹網獵淵夢夢夢 ) 更多	积极	2025-01-23
				Trastuzumab (T) + Ramucirumab (R) + Paclitaxel (P)	衊顧範襯壓獵鹽簾艱遞(餘壓餘膚衊範鑰憲鹹鏇) = 構鹽選窪鏇醖襯願網鹽齋鹽艱壓觸顧夢糧壓齋 (廠簾淵鹹網獵淵夢夢夢 ) 更多