AMB-302

//  国内不少公司已尝试寻找新靶点，并从单靶点向双靶点、联合用药等方向拓展。国内已有恒瑞医药、科伦博泰、荣昌生物等多家企业开始了ADC联合疗法研究，其中ADC+免疫检查点抑制剂成为热门尝试组合。国内ADC研发目标靶点过于集中时常被诟病。研发客统计发现，国内企业推进到临床阶段的ADC，有63%集中于HER2、Trop-2、Claudin 18.2三个靶点。因此，国内不少公司已在往新靶点ADC研发方向使劲，寻找更新、更有针对性的靶点，并将ADC研发从单靶点向双靶点、联合用药等方向拓展。全球新靶点仍在少数中国ADC技术不断革新，给ADC新靶点开发孕育了合适的机会，但目前国内已披露靶点的ADC中，目标全球新靶点的产品仍属少数。除上述三大靶点产品外，剩余的37%临床试验中，大部分还是针对国外已开发靶点，例如Nectin-4、FRα、EGFR、CD79b等。也有少数企业开发全新靶点产品。礼新医药的LM-305是全球首个获批临床的GPRC5D靶向ADC药物。该产品还获得跨国药企青睐，礼新医药今年5月与阿斯利康达成总价6亿美元的合作，授出LM-305全球开发权益。智康弘义的BC3195也是一款全球首创靶向CDH3的ADC药物，近期在中美同步获批开展临床。另外，启德医药与AimedBio合作开发的AMB302/GR1017，是一种新型FGFR3靶向ADC，还处于临床前阶段，全球尚无同类ADC产品进入临床。（其他产品见下表）上表中部分产品的研发进度趋于全球前列水平。翰森制药布局了靶向B7-H3的HS-20093，与第一三共的DS-7300同处于临床2期；另一款靶向B7-H4的HS-20089，正在开展1期临床，同类产品进展最快的阿斯利康的AZD8205，处于2期临床阶段。国内企业在多年的ADC研发摸索中，已经积累了新靶点ADC的研发经验。科伦博泰副总经理、首席科学官谭向阳博士告诉研发客，通常在筛选ADC适合开发的靶点时，会集中在肿瘤细胞表达量高、正常组织低表达或不表达的靶点，“但随着有效载荷和连接子设计技术越加成熟，可以放宽靶点筛选要求，从肿瘤微环境的角度去考虑靶点开发，提高新靶点的维度与深度。”另外，ADC的创新设计也不再局限于肿瘤，开始向自身免疫疾病等其他领域发展。近期国内也掀起了自免疾病研发的小高潮，研发客也观察到已有ADC企业开始探索自身免疫领域，拓展更多的创新靶点。拓展阅读国内“自免一哥” 是谁 ？例如，映恩生物利用其免疫ADC平台“DIMAC”开发了两款自免产品DB-2304和DB-2306。其中，DB-2304靶向表达于浆细胞样树突状细胞（pDC）特异靶点BDCA2，是全球首款针对系统性红斑狼疮（SLE）的ADC。谭向阳认为，随着对偶联药物作用机理的研究更加深入，可以在ADC基础上探索更多蓝海。例如，抗体与核酸药物、抗生素、或蛋白降解靶向联合体（PROTAC）偶联，靶点和适应症的选择都将更加广泛。双抗ADC之“新”逐渐拥挤的ADC赛道中，双抗ADC也成为拓宽思路的新方向之一。双抗ADC的研发方向包含两类，一类是针对两个不同靶点，一类是针对同一靶点的两个表位。当前国内也有多家公司解锁了双抗ADC技能，部分产品的靶点创新也走在全球前列。百利天恒的BL-B01D1是全球首个靶向EGFR/HER3的双抗ADC，正在开展2期临床；百奥赛图也有多款临床前双抗ADC产品，如靶向HER2xTrop-2的YH012、EGFRxMET的YH013，同时还有另外三款授权给思道医药；同宜医药的两款产品CBP-1018和CBP-1008，分别靶向PSMAxFRα和TRPV6xFRα，均为全球首创；映恩生物也引进达石药业的DS005，加码双抗ADC开发。双抗ADC的多重优势是吸引越来越多玩家进入这一领域的关键。恒瑞医药副总经理张连山在接受研发客采访时表示，基于现有靶点的双抗（或双表位）研究，通过巧妙的双抗ADC设计，可以进一步提升ADC的治疗窗口，从而展现出更优的杀伤效果，产生新的知识产权。双抗和双表位ADC也是科伦博泰的布局方向之一。谭向阳阐述道，双抗ADC的两个抗体端能够结合两个相同或不同靶点，递送更多毒素弹头至肿瘤细胞，增加对肿瘤细胞的杀伤效率。此外，同时靶向两个靶点或表位，增加抗体与不同肿瘤细胞结合的特异性，不仅能克服因单靶点表达下降而产生的耐药性问题，还可以降低单靶点亲和力低引发的脱靶毒性。目前中国双抗ADC的临床研究都在早期，但初步数据已显露出优势。百利天恒BL-B01D1的1期临床数据显示，在EGFR突变非小细胞肺癌患者中ORR达到61.8%，DCR为91.2%；鼻咽癌的ORR和DCR数据分别达到45.8%和100%。康宁杰瑞JSKN003在HER2高表达和低表达的肿瘤模型中均表现出良好的安全性以及与DS-8201a相似疗效，目前处于临床1期。但不可否认，双抗ADC作为尚未成熟验证的产品，还存在一些难题需要攻克，例如安全性问题。阿斯利康的双表位HER2 ADC MEDI4276，就因毒性问题终止临床开发。受访专家均表示，双抗ADC的研发门槛很高，如何平衡双靶点中单一靶点的贡献、以及连接子和有效载荷对细胞的作用，对产品的成药性、有效性和安全性都提出更高要求。此外，在产品的CMC、临床、生产等各环节都更加复杂。联合用药新趋势与PD-1/PD-L1联合用药的研发思路相似，ADC也从单药治疗拓展到了联合治疗。国内已有恒瑞医药、科伦博泰、荣昌生物等多家企业开始了ADC联合疗法研究，其中ADC+免疫检查点抑制剂成为热门尝试组合。ADC与免疫检查点抑制剂联用可能达到双向疗效提升的效果。谭向阳提到，免疫检查点抑制剂在大部分肿瘤治疗中应答低，单药疗效相对有限，而与ADC联用能诱导免疫原性细胞死亡、募集肿瘤浸润淋巴细胞，增强免疫应答，另一方面免疫激活也能反向推动ADC的治疗活性。张连山认为，联合用药的拓展能够释放HER2、Trop-2等老靶点的更多可能性，各公司可根据自身管线的实际情况开展联合研究。例如科伦开展了Trop-2 ADC SKB264与PD-L1单抗KL-A167、或与PD-1抗体帕博利珠单抗联合用药的研究。恒瑞尝试了ADC+双抗的联用方案，将靶向HER2的ADC SHR-A1811联合PD-L1/TGF-β双功能融合蛋白SHR-1701，用于HER2阳性胃癌治疗。张连山表示，从单个产品来看，SHR-A1811和SHR-1701在胃癌的研究进度不占优势，但强强联合后或有弯道超车的可能性。礼新医药也在探索ADC与双抗的联合疗法。今年3月，礼新医药与康方生物达成合作，共同推进靶向Claudin 18.2的ADC药物LM-302与PD-1/VEGF双抗AK112的一系列临床研究。事实上，不论是创新的单靶点、双靶点ADC药物开发，还是联合用药的ADC策略研究，国内这些ADC产品大多仍处于早期临床阶段，真实表现如何，需要进一步的临床数据予以验证，才能在竞争激烈的赛道中找到真正差异化的生存空间。编辑｜施樱子shi.yingzi@PharmaDJ.com 总第1925期访问研发客网站可浏览更多文章www.PharmaDJ.com

SUZHOU, China, July 6, 2023 /PRNewswire/ -- GeneQuantum Healthcare, a leader in the innovative bioconjugation technologies for ADC new drug development, announced the expansion of its partnership with a South Korean biotech company Aimed Bio today. This strategic collaboration aims to jointly develop up to five new ADC drugs to address unmet clinical needs. Since April of last year, GeneQuantum and Aimed Bio have been collaborating on the joint development of a FGFR3-targeting ADC named GQ1011/AMB302. The progress of this development was presented at the 13th World ADC 2022 and the American Association for Cancer Research (AACR) 2023 Annual Meeting. The published results showcased the exceptional anti-cancer effects of this FGFR3-targeting ADC in in vivo models of bladder cancer and glioblastoma. Safety evaluations conducted in monkey models also showed positive results. Encouraged by these development achievements, the two companies have made the decision to expand their partnership in the joint development of up to five additional ADCs. Dr. Gang Qin, the founder and CEO of GeneQuantum, stated, "The innovative ADC drug GQ1011 developed in collaboration with Aimed Bio has demonstrated excellent preclinical druggability data, fully showcasing the wide applicability and competitive advantage of GeneQuantum's leading site-specific conjugation and linker-payload technologies. GeneQuantum has always adhered to the vision of open collaboration and innovative empowerment for ecosystem construction. With an integrated and holistic innovative conjugation solution as the hub, we gather advantages and resources from all parties, breaking fundamental bioconjugate drug development barrier through wide cooperation. This enables us to focus on the development of high-quality innovative ADC drugs that better meet the growing unmet clinical demand and provide improved treatment options for patients worldwide. The collaboration with Aimed Bio in the development of a series of innovative ADC drugs fully embodies GeneQuantum's core technology and integration of various high-quality innovative resources from both international and domestic upstream and downstream sectors, presents a promising outlook for the revolutionary ADC therapy innovation." Dr. Do-Hyun Nam, Aimed Bio's CTO, commented " Through our collaboration with GeneQuantum, we aim to optimize resources by leveraging big data analysis and addressing high unmet needs to identify novel targets. We will utilize our proprietary translation platform to develop the most effective ADC platforms together." Dr. Nam highlighted the potential of this collaboration to deliver innovative treatments for patients who has no other therapeutic options. About GeneQuantum Healthcare GeneQuantum is a global innovative biopharmaceutical company and one of the pioneers dedicated to the development of ADC drugs using enzyme-mediated site-specific conjugation technology. It has established comprehensive proprietary techniology system, iLDC® and iGDC®, which can provide end-to-end solutions for development and commercialization of multiple bioconjugate drug modalities including ADC. Based on the unique technology platform, GeneQuantum has successfully developed multiple clinically advanced innovative ADC products. GeneQuantum is committed to bringing revolutionized cancer therapy to patients worldwide through bioconjugate drug ecosystem construction. For more information, please visit: . About Aimed Bio: Aimed Bio is an innovative biotechnology company that was spun off from Samsung Medical Center (SMC) in August 2018. The company aims to provide treatment solutions for patients with severe brain diseases, including neuro-oncology and neurodegenerative diseases, to save lives and improve patients' quality of life. With a strong global network of key opinion leaders in the field of neuro-oncology and neurodegenerative diseases, an excellent research team, and a pipeline layout, Aimed Bio has emerged as an emerging leader in innovative therapies for brain diseases. SOURCE GeneQuantum Healthcare