HY0001a

2026年AACR年会现场，国内生物药企百奥赛图公布其CDCP1靶向ADC候选药物BCG046的完整研究数据。CDCP1 在肺癌、结直肠癌、胰腺癌等多种实体瘤中异常高表达，参与调控肿瘤增殖、侵袭转移及化疗耐药进程。 肿瘤细胞膜表面的CDCP1胞外区可被蛋白酶剪切，分为远膜ATF片段和近膜CTF片段；ATF可能存在脱落的风险，游离ATF会中和靶向该区域的抗体，削弱药物靶向杀伤效果。BCG046完整结构由三部分构成：靶向CDCP1近膜CTF结构域的全人源抗体Ab.168、Val-Cit（vc）可裂解连接子、MMAE 微管抑制剂毒素。Ab.168经定向筛选仅特异性结合CTF，从机制层面规避了脱落的抗原造成的药效损耗。 体内药效数据显示，在非小细胞肺癌、结直肠癌PDX模型中，BCG046抗肿瘤活性优于或对标同类参比抗体-vcMMAE ADC，凭借差异化CTF表位布局，为CDCP1实体瘤靶向治疗开辟全新开发方向[1]。 BCG046 poster[1] 结构与功能 CDCP1 CUB结构域蛋白1（CUB Domain-Containing Protein 1，CDCP1），又称为CD318、gp140、SIMA135和Trask[2]，全长CDCP1（fl-CDCP1），是一种I型跨膜蛋白，分子量为135kD，其胞外段含3个CUB样结构域和14个N-糖基化位点，胞内含5个酪氨酸磷酸化位点。在正常组织中fl-CDCP1的表达受到限制[3]，但在多种恶性肿瘤中，如转移性三阴性乳腺癌（TNBC）、转移性HER2阳性乳腺癌、肺腺癌、结直肠癌、前列腺癌、胰腺导管腺癌、非小细胞肺癌等，其表达显著上调[4]。 fl-CDCP1结构示意图[4] 在肿瘤细胞中，肿瘤微环境中蛋白酶水平的升高使得fl-CDCP1被纤溶酶、基质蛋白酶和uPA等丝氨酸蛋白酶诱导裂解，生成切割型CDCP1（c-CDCP1），即一个约65kD的氨基末端片段（CDCP1-ATF）和一个约70kD的跨膜羧基末端片段（CDCP1-CTF)[5]，切割位点主要发生在R368和K369之间。切割后的CTF能够被SRC家族激酶识别并磷酸化，特别是734位的酪氨酸（Y734）。磷酸化的CTF能够招募PKCδ，进一步激活MAPK和PI3K/AKT等下游信号通路。切割后的CTF可以发生同源二聚化，也可以与β1整合素等其他膜蛋白形成异源二聚体，这种异源二聚体化不仅增强了信号传导，还能够整合细胞外基质（ECM）的信号，促进细胞的迁移和侵袭[4]。 研究表明，切割生成的ATF可以从多种前列腺癌细胞系表面脱落，且在结直肠癌患者的血清中被检测到[3]。若抗体靶向ATF，游离抗原会中和药物，可能会削弱药物的抗肿瘤杀伤活性；也有研究指出，ATF被切割后仍保留在细胞表面，并与CTF紧密结合[6]。 基于CDCP1病理条件下可能存在的特殊结构形式，其靶向药物开发主要存在两种策略：一是特异性靶向CTF或切割后形成的新表位，以精准阻断其下游促癌信号传导；二是靶向fl-CDCP1，直接破坏其表达或阻断其被切割。在免疫、筛选阶段，可使用CTF、CTF&ATF、通过长linker连接的CTF&ATF或fl-CDCP1等不同形式的抗原蛋白。 CDCP1的蛋白水解过程[4] 药物进展 CDCP1 IDP-001是InduPro开发的EGFR×CDCP1 双特异性ADC。针对单EGFR ADC脱靶毒性、耐药缺陷，该药物依靠EGFR、CDCP1双抗原协同识别机制，仅对双阳性肿瘤细胞实现特异性内吞杀伤。在结直肠癌、非小细胞肺癌CDX细胞移植模型中， IDP-001展现出剂量依赖性抗肿瘤活性，小鼠体内半衰期约16小时，全剂量组耐受性良好，同等给药条件下抑瘤效果显著优于EGFR、CDCP1单靶点ADC； 在非小细胞肺癌PDX模型中，8例双阳性肿瘤模型给药后有6例实现肿瘤完全消退。临床前体内数据充分验证了IDP-001具备广谱强效的抗肿瘤潜力，目前该药物正开展I/II期临床试验。 IDP-001结构[7] 汇宇制药的HY0001a于2025年6月获批临床，是全球首个披露的针对CDCP1推向临床的项目，适应症是晚期实体瘤，是一款ADC药物。HY0001a能够将增殖的癌细胞阻滞在G2M期，在MDA-MB-231 CDX模型的肿瘤组织中显著诱导了凋亡通路[8]。 除了前文提及的BCG046，还有多款ADC药物处于临床前阶段。如The University of Queensland开发的ch10D7-MMAE靶向fl-CDCP1-ATF的aa30-aa358，阻断fl-CDCP1被切割，在胰腺癌、结直肠癌和卵巢癌的小鼠异种移植模型中显示出强大的抗肿瘤效果[3]。 10D7抗体靶向fl-CDCP1[3] 单抗方面，UCSF开发的CL-03靶向c-CDCP1新表位，结合在ATF的C末端附近。CL03能特异性杀伤表达c-CDCP1的肿瘤细胞，而对健康细胞无毒性。 CL03单抗靶向c-CDCP1[6] 药物名称 靶点 适应症 药物类型 最高研发阶段 公司 IDP-001 CDCP1 x EGFR EGFR突变的非小细胞肺癌 ADC 临床I/II期 InduPro, Inc. RC-278 CDCP1 晚期恶性实体瘤 ADC 临床I/II期 荣昌生物 HY0001a CDCP1 晚期恶性实体瘤 ADC 临床I/II期 四川汇宇 DB-1329 CDCP1 肿瘤 ADC 临床前 映恩生物 Chi2B5×4F11 CDCP1 x TIGHT 胰腺癌 双抗 临床前 Ajou university ch10D7-MMAE CDCP1 三阴性乳腺癌 ADC 临床前 the university of Queensland CL-03 CDCP1 胰腺癌 单抗 临床前 UCSF TAVO605 CDCP1 三阴性乳腺癌等 ADC 临床前 拓创生物 h14A043-ATAC CDCP1 前列腺癌 ADC 临床前 Chiome Bioscience AMB-304 CDCP1 实体瘤 ADC 临床前 AimedBio BCG046 CDCP1 实体瘤 ADC 临床前 百奥赛图 部分CDCP1靶向药物 恺佧生物供应高品质的CDCP1 CTF domain蛋白 CDCP1是当下实体瘤 ADC 赛道极具潜力的热门靶点，已有多款靶向药物进入临床阶段。肿瘤微环境中蛋白酶切割全长CDCP1生成ATF和CTF，而ATF存在脱落的风险，可能会中和抗体、大幅削弱药效。因此，靶向CTF可成为CDCP1药物开发的差异化策略。基于对CDCP1结构的理解，恺佧生物重磅推出核心特色产品—CDCP1 CTF domain蛋白，助力客户免疫、筛选得到靶向CTF表位的抗体。此外，我们还供应ATF&CTF复合物、ATF domain、fl-CDCP1等不同形式的抗原蛋白，蛋白标签设计合理，不遮挡重要表位；且产品覆盖多个种属，适用于不同的应用场景。 产品数据 Human CDCP1 CTF, hFc Tag immobilized on CM5 Chip can bind Anti-CDCP1 CTF Antibody1 with an affinity constant of 59.11 nM as determined in SPR assay (Biacore T200). Human CDCP1 CTF, hFc Tag immobilized on CM5 Chip can bind Anti-CDCP1 CTF Antibody2 with an affinity constant of 153.23 nM as determined in SPR assay (Biacore T200). Immobilized Human CDCP1 at 2μg/ml (100μl/Well). Dose response curve for Anti-CDCP1 Antibody, hFc Tag with the EC50 of 5.4ng/ml determined by ELISA. (QC Test) Immobilized Human CDCP1 ATF&CTF (fused by polypeptide linker), His Tag at 1μg/ml (100μl/well) on the plate. Dose response curve for Anti-CDCP1 Antibody, hFc Tag with the EC50 of 4.2ng/ml determined by ELISA. (QC Test) Immobilized Human CDCP1 ATF&CTF (co-transfected complex), His Tag at 2 μg/ml (100 μl/well) on the plate. Dose response curve for Anti-CDCP1 Antibody, hFc Tag with the EC50 of 17.1 ng/ml determined by ELISA (QC Test). The purity of Human Human CDCP1 ATF&CTF (co-transfected complex) is greater than 90%. The molecular weight of this protein is around 80-101 kDa as determined by SEC-MALS, which is similar to that of fl-CDCP1 (QC Test). Immobilized Human CDCP1 ATF (30-368), His Tag at 2 μg/ml (100 μl/well) on the plate. Dose response curve for Anti-CDCP1 Antibody, hFc Tag with the EC50 of 4.6 ng/ml determined by ELISA (QC Test). 产品列表 Cat. No. Product Name CDC-HM20C Human CDCP1 CTF Protein, hFc(IgG1) Tag CDC-HM101 Human CDCP1 Protein, His Tag CDC-HM101-UL Human CDCP1 Protein, His Tag,  Ultra Low Endotoxin CDC-HM201 Human CDCP1 Protein, hFc(IgG1) Tag CDC-HM201-UL Human CDCP1 Protein, hFc(IgG1) Tag, Ultra Low Endotoxin CDC-HM401B Biotinylated Human CDCP1 Protein, His-Avi Tag CDC-HM102 Human CDCP1 ATF&CTF Protein(fused by polypeptide linker), His Tag CDC-HM102-UL Human CDCP1 ATF&CTF Protein(fused by polypeptide linker), His Tag,  Ultra Low Endotoxin CDC-HM104 Human CDCP1 ATF&CTF(co-transfected complex) Protein, HA,His Tag CDC-HM20D Human CDCP1 (30-440) Protein, hFc(IgG1) Tag CDC-HM1D2 Human CDCP1 (338-667) Protein, His Tag CDC-HM203 Human CDCP1 (338-667) Protein, hFc(IgG1) Tag CDC-HM11D Human CDCP1 ATF (30-368) Protein, His Tag CDC-MM101 Mouse CDCP1 Protein, His Tag CDC-MM101-UL Mouse CDCP1 Protein, His Tag, Ultra Low Endotoxin CDC-MM401B Biotinylated Mouse CDCP1 Protein, His-Avi Tag CDC-CM102 Cynomolgus CDCP1 Protein,, His Tag CDC-CM102-UL Cynomolgus CDCP1 Protein,, His Tag, Ultra Low Endotoxin CDC-CM402B Biotinylated Cynomolgus CDCP1 Protein, His-Avi Tag CDC-CM101 Rhesus macaque CDCP1 Protein, His Tag CDC-CM101-UL Rhesus macaque CDCP1 Protein, His Tag, Ultra Low Endotoxin CDC-CM401B Biotinylated Rhesus macaque CDCP1 Protein, His-Avi Tag CDC-CM401B-UL Biotinylated Rhesus macaque CDCP1 Protein, His-Avi Tag, Ultra Low Endotoxin CDC-RM101 Rat CDCP1 Protein,His Tag CDC-RM101-UL Rat CDCP1 Protein,His Tag,Ultra Low Endotoxin 参考文献 [1]BCG046, a CDCP1 ADC that targets CTF, has demonstrated potent  in vitro  and  in vivo  efficacy [2] Donahue, Katelyn L, and Marina Pasca di Magliano. “Cleaved CDCP1 marks the spot: a neoepitope for RAS-driven cancers.” The Journal of clinical investigation vol. 132,4 (2022): e157168. doi:10.1172/JCI157168 [3] Khan, Tashbib et al. “CUB Domain-Containing Protein 1 (CDCP1) is a rational target for the development of imaging tracers and antibody-drug conjugates for cancer detection and therapy.” Theranostics vol. 12,16 6915-6930. 3 Oct. 2022, doi:10.7150/thno.78171 [4] Khan, Tashbib et al. “The CDCP1 Signaling Hub: A Target for Cancer Detection and Therapeutic Intervention.” Cancer research vol. 81,9 (2021): 2259-2269. doi:10.1158/0008-5472.CAN-20-2978 [5]Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674. [6]Lim, Shion A et al. “Targeting a proteolytic neoepitope on CUB domain containing protein 1 (CDCP1) for RAS-driven cancers.” The Journal of clinical investigation vol. 132,4 (2022): e154604. doi:10.1172/JCI154604 [7]IDP-001 is a potent bispecific ADC with in vivo activity against mouse xenograft tumors models expressing EGFR and CDCP1 [8]Abstract 4256: HY0001a: A novel antibody-drug conjugate (ADC) targeting CUB domain containing protein 1 (CDCP1) | Cancer Research | American Association for Cancer Research  服务号                  公众号 恺佧生物科技（上海）有限公司 电话：400-614-0008 官网：www.kactusbio.cn 邮箱：support@kactusbio.com