PDL1 x CD3 x 5T4

2024 年 ESMO 年会正在进行中。根据 Insight 数据库，本届大会上有 30 多项双特异性抗体的临床研究数据入选，其中包括许多尚未获批的在研双抗新药，靶点涵盖 PD-L1/VEGFA、TIGIT/PD-1、CD3/STEAP1、CD20/CD47、CD3/CEACAM5、CD47/PD-L1、4-1BB/5T4、DLL3/CD3、4-1BB/CLDN-18.2、EGFR/FCGR3A 等等。本文将分享其中 5 项首次披露临床数据的在研双抗研究，仅供读者参阅。 阿斯利康首次公布TIGIT/PD-1 双抗胃癌研究数据 Rilvegostomig 是一种在研 PD-1 / TIGIT 双抗，全球和国内的最高研究进度均为 Ⅲ 期临床。本次大会上，阿斯利康首次公布了 Rilvegostomig (以下简称 Rilve) + 化疗治疗 HER2–局部晚期不可切除或转移性胃或胃食管交界腺癌的 GEMINI-Gastric (NCT05702229) 研究结果。 截图来源：ESMO 官网 在该研究中，患者接受 Rilve 750 mg Q3W IV + XELOX（奥沙利铂 + 卡培他滨）或 FOLFOX（奥沙利铂 + 5-FU + 亚叶酸）治疗。主要终点是 ORR（通过基线 PD-L1 综合阳性评分 (CPS) <5 vs ≥5 进行分析）和 6 个月时 PFS；次要终点是安全性。  在数据截止时（2023 年 12 月 27 日），40 名患者接受了 Rilve+ XELOX（n=27）或 Rilve + FOLFOX（n=13）治疗，并有机会进行≥3 个月的随访（2 次治疗期间扫描）；27 名患者（67.5%）正在接受治疗。72.5% 的患者为亚洲人，52.5% 的患者 ECOG PS 为 0。所有患者均患有 IV 期疾病且伴有远处转移。 有效性数据显示，未证实的 ORR 为 67.5%（PD-L1 CPS ≥5 和 CPS <5 的患者分别为 81.3% 和 59.1%），证实的 ORR 为 52.5%（详见下表）。所有患者均有疾病控制（客观反应或疾病稳定）；无原发性进展性疾病。 截图来源：ESMO 官网 所有患者均有治疗引起的不良事件 (TEAE) 和治疗相关 AE（TRAE，60.0% 与治疗相关）。最常见的 TEAE 是恶心、中性粒细胞计数减少和食欲下降。≥3 级 TEAE 发生率为 45.0%，TRAE 发生率为 37.5%（7.5% 与 Rilve  有关）。未发生与 Rilve 有关的严重 AE (SAE)，任何原因的 SAE 均未导致死亡。 研究认为，Rilve +化疗显示出初步疗效和可控的 AE。该研究正在进行中，阿斯利康会在未来提供更新的疗效数据。 BMS 首次公布 TCER 双抗 Ⅰ 期临床数据 IMA401 是一种新一代 TCER 双特异性抗体，最初由 Immatics 公司研发。BMS 在 2021 年与 Immatics 公司达成一项高达 9.2 亿美元的合作，获得了该药的全球独家许可。本届大会上，研究人员以口头报告形式首次公布了该药在 I 期剂量递增中的初始安全性、药代动力学和抗肿瘤活性数据。 截图来源：ESMO 官网 IMA401 结合了针对 HLA-A*02:01 呈递的 MAGEA4/8 肽的高亲和力 TCR 结构域、低亲和力 T 细胞募集抗体和用于延长半衰期的 Fc 部分。MAGEA4/8 在多种实体瘤中表达，包括鳞状非小细胞肺癌、头颈部鳞状细胞癌、膀胱癌、子宫癌、食道癌和卵巢癌、黑色素瘤等等。 这项正在进行的 1a/1b 期首次人体临床试验评估了 IMA401 对复发/难治性实体瘤患者的初步效果和安全性。HLA-A*02:01+ 和 MAGEA4/8+ 患者最初接受 一周一次治疗（QW），然后接受两周一次（Q2W）静脉输注 IMA401。研究主要目标是确定 MTD 和/或 RP2D，次要目标是安全性、耐受性、PK、初始抗肿瘤活性。 截至 2024 年 4 月 1 日，25 名接受过大量前期治疗的癌症患者接受了第一剂量水平（DL1-7、6.6 μg-2.5 mg）的 IMA401。IMA401 表现出可控的耐受性，最常见的（≥30%）治疗相关不良事件是短暂性淋巴细胞减少症（G1-4）和 CRS（G1/2）。在引入地塞米松预处理后，在 DL7 观察到的高级（G3/4）中性粒细胞减少症没有复发。未达到 MTD/RP2D，并且剂量递增研究正在进行中。中位终末半衰期为 15.0 天。 在剂量递增阶段接受治疗的疗效可评估患者中，55% (11/20) 的患者实现了疾病控制 (SD/PR)，其中包括卵巢癌、鳞状非小细胞肺癌、胃癌、头颈部鳞状细胞癌、黑色素瘤和神经内分泌癌患者。45% (9/20) 的患者靶病变缩小（中位数 -21.7%），其中 3 名患者在首次输注后 4+月、10+个月 和 11+ 个月时确认持续 PR。 综合上述数据，研究认为 IMA401 耐受性良好，其单药抗肿瘤活性通过持久的客观反应和疾病控制得到证实，半衰期延长促使患者在剂量递增期间每 2 周切换一次治疗。研究表示，这项正在进行的 1 期剂量递增试验的数据为下一代半衰期延长 TCER® 形式及其在多种实体瘤中的潜力提供了第一个临床 PoC。 普米斯首次公布 PD-L1/VEGFA 双抗 NSCLC II 期研究数据 PM8002（BNT327）是普米斯开发的一种 PD-L1 /VEGF-A 双抗。本届大会上，PM8002 联合化疗治疗 EGFR 突变非小细胞肺癌 (NSCLC) 患者的单臂 II 期研究入选了口头报告。2023 年 11 月，BioNTech 公司曾与普米斯达成一项超 10.55 亿美元的授权合作，获得了该药在大中华区之外的全球其它地区的开发、生产和商业化权利。 截图来源：ESMO 官网 在该研究中，患者接受 PM8002 加卡铂和培美曲塞 Q3W 治疗 4 个周期，随后接受 PM8002 和培美曲塞维持治疗。主要终点是 ORR（RECIST v1.1）。通过免疫组织化学法对 EGFR-TKI 治疗进展后采集的活检样本进行 PD-L1 表达分析，并根据肿瘤比例评分 (TPS) 分为阴性（<1%）、低表达（1 %至 49%）或高表达（≥50%）。 截至 2024 年 4 月 12 日，64 名患者接受了 PD-L1 TPS 检测：28 名为 TPS<1%，23 名 为 TPS 1%-49%，13 名为 TPS ≥50%。所有患者均可评估安全性和疗效。数据显示： 总体 ORR 为 54.7% (35/64)，DCR 为 95.3% (61/64)。PD-L1 TPS＜1% 组 ORR 为 35.7%，DCR 为 92.9%；TPS 1%-49% 组 ORR 为 56.5%，DCR 为 100%；TPS≥50% 组 ORR 为 92.3%，DCR 为 92.3%。  95.3% 的患者发生了任何级别的治疗相关不良事件 (TRAE)，54.7% 的患者发生了 3 级以上 TRAE。28.1% 的患者发生了任何级别的免疫相关 AE (irAE)，4.7%  的患者发生了 3 级以上 irAE。6 名患者因 TRAE 停止使用 PM8002 和/或化疗，其中 1 例 TRAE 相关死亡。 Insight 数据库显示，PM8002 是国内首个也是目前唯一一个进入 Ⅲ 期临床的 PD-L1 /VEGF 双抗，正在开展治疗三阴性乳腺癌的 Ⅲ 期研究。此外，该药也已在今年 7 月获 CDE 批准开展联合紫杉醇注射液对比化疗二线治疗免疫经治的小细胞肺癌的注册性 Ⅲ 期临床。 宜明昂科首次公布 CD47/PD-L1 双抗Ⅰ 期临床数据 IMM2520 是一种在研 CD47/PD-L1 双特异性抗体，正在国内开展Ⅰ期临床。本次大会上，宜明昂科公布了 IMM2520 的 Ⅰ 期研究结果，该研究旨在评估 IMM2520 对晚期实体瘤患者的安全性、RP2D/MTD 和抗肿瘤作用。IMM2520 每周给药一次，每 28 天为一个周期。本次大会展示的是剂量递增阶段的结果。 截图来源：ESMO 官网 截至 2024 年 4 月 4 日，18 名患者接受了 5 个剂量水平（从 0.1mpk 到 4mpk）的治疗。大多数患者 (61%) 之前接受过 ≥ 3 线全身抗肿瘤治疗，其中 9 名患者有 PD-(L)1 疗法治疗史。研究尚未观察到 DLT。所有患者均报告了治疗相关不良事件 (TRAE)，其中 10 名 (56%) 患者为 ≥ 3 级。任何级别最常见的 TRAE 是血小板减少、贫血、白细胞减少和输液相关反应 。≥ 3 级的最常见 TRAE 是淋巴细胞减少、血小板减少和厌食症。未观察到导致治疗停止的 AE。 在 11 名可评估疗效的患者中，在 2mpk 治疗后，小细胞肺癌 (SCLC) 患者中观察到 1 例未证实的部分缓解（之前接受过 2 种疗法，包括免疫疗法和 PD-L1 表达阴性）和 5 例病情稳定，其中包括 1 例宫颈癌 (肿瘤缩小 21.1%），1 例结直肠癌（肿瘤缩小 11.1%）。药效学生物标志物包括外周循环 CD3+T 细胞上的 CD47 靶标占有率 (TO)。CD47 TO 率较轻，呈剂量依赖性趋势。 研究认为，IMM2520 在评估剂量下表现出耐受性，并且在晚期实体瘤中表现出初步的抗肿瘤活性，尤其是对于 SCLC。目前该研究的剂量递增研究正在进行中。 2024 年 8 月，Instil Bio 公司曾与宜明昂科达成授权合作，Instil 全资子公司 SynBioTx 获得 IMM2510 和 CTLA4 单抗 IMM27M 在大中华区以外的全球其它地区开发和商业化权利。该项交易包括高达 5000 万美元的首付款及潜在近期付款，以及总计超过 20 亿美元的里程碑付款。 石药集团/康宁杰瑞首次公布 HER2 双抗+化疗胃癌 II 期数据 KN026 是石药集团旗下津曼特生物从康宁杰瑞引进的一种新型 HER2 靶向双抗，可结合 HER2 的两个不同结构域。本次大会上，石药集团首次公布了 KN026 与化疗联合治疗无法切除或转移性 HER2 阳性胃癌或胃食管癌 (GC/GEJC) 患者的 II 期研究数据（NCT05427383）。 截图来源：ESMO 官网 在这项多中心、开放标签、II 期研究中，接受含曲妥珠单抗方案一线治疗后，HER2 阳性 GC/GEJC 患者根据既往治疗情况由研究者酌情分配接受 KN026（30 mg/kg，D1，Q3W）+紫杉醇（175 mg/m2，D1，Q3W）或伊立替康（125 mg/m2，D1 和 D8，Q3W）治疗。主要终点是 IRC 确定的安全性和 ORR 。 在数据截止时（2024 年 3 月 26 日），39 名患者入组并接受了至少一剂治疗。34 名患者观察到 HER3+染色。分别有 35 名和 37 名患者符合 IRC 和研究者评估疗效的条件。 IRC 确认的 ORR为 40.0% (14例PR) ，  DCR 为 80.0% (8例SD)。研究者确认的 ORR 为 45.9%(17例PR)  ， DCR 为 81.1% (13例SD)。 中位缓解时间为 1.38 个月，缓解持续时间为 11.7 个月。中位无进展生存期为 8.6 个月，总生存期为 13.2 个月。 最常见的≥3 级 TRAE（≥5%）为中性粒细胞减少症、白细胞减少症、贫血、疲劳、腹泻、淋巴细胞减少症、发热性中性粒细胞减少症、低钾血症和咳嗽。未发生与治疗相关的死亡。未观察到新的安全信号。 研究认为，KN026 联合化疗对一线治疗后 HER2 阳性 GC/GEJC 患者具有良好的抗肿瘤疗效，且安全性良好。KN026 与化疗联合治疗的 III 期研究正在进行中。 封面来源：站酷海洛 Plus 免责声明：本文仅作信息分享，不代表 Insight 立场和观点，也不作治疗方案推荐和介绍。如有需求，请咨询和联系正规医疗机构。 编辑：馨药 PR 稿对接：微信 insightxb 投稿：微信 insightxb；邮箱 insight@dxy.cn 多样化功能、可溯源数据…… Insight 数据库网页版等你体验 点击阅读原文，立刻解锁！

过去十几年，ADC技术逐渐成熟，并在实体瘤和血液瘤取得了很大突破。目前，有超过140多款ADC药物进入临床阶段，15款已经获批上市。不过，传统以单抗为基础的ADC也面临着一些困境，包括非预期毒性、耐药的出现等。造成这一局面的原因很多，比如实体瘤的异质性导致靶向单一抗原的临床有效性有限；靶抗原下调、抗体结合表位突变、旁路激活、靶抗原内吞抵抗等引发的耐药；抗原在正常组织的表达、连接子的不稳定等引发的脱靶毒性。解决以上问题的一个策略是双抗ADC路线，如下图所示，较单抗ADC额外增加一种抗原结合能力，可以是同一抗原的不同表位，也可以是不同抗原的不同表位。目前已经至少有12款双抗ADC处于临床不同阶段，超过50款双抗ADC处于临床前不同阶段，临床阶段的产品多以表皮生长因子家族的靶点为主，如HER2、HER3、EGFR，其次是c-MET、MUC1和TROP2靶点。目前进展最快的产品均是由我国生物医药企业开发，四川百利天恒的HER3*EGFR双靶ADC伦康依隆妥单抗、康宁杰瑞的HER2*HER2双表位ADC JSKN-003已经处于临床Ⅲ期研究阶段，紧随其后的是正大天晴开发的TQB2102，同样是靶向HER2不同表位。下表是统计的临床和临床前阶段的双抗ADC产品清单。伦康依隆妥单抗（Izalontamab Brengitecan; BL-B01D1）伦康依隆妥单抗由四川百利天恒子公司Systimmune开发，是一款EGFR*HER3双靶点的抗体-药物偶联物，结构如下图所示。2023年ASCO，Systimmune公布了在NSCLC、鼻咽癌等瘤种中的数据，如下表所示，在NSCLC中的数据非常惊艳。其中，34例EGFR突变的患者，30例前期已经用过三代EGFR TKI治疗，ORR还有61.2%，DCR高达91.2%。42例EGFR野生型患者中，37例一线已经用过PD-1/L1联合铂类为基础的化疗，ORR为40.5%，DCR高达95.2%，明显优于多西他赛标准化疗方案。2023 年12月11日， SystImmune与BMS就 BL-B01D1项目达成独家许可与合作协议。BMS 将向SystImmune 支付8 亿美元的高额首付款，和最高可达5 亿美元的近期或有付款；达成开发、注册和销售里程碑后，SystImmune 将获得最高可达71 亿美元的额外付款；潜在总交易额最高可达84亿美元。根据协议，双方将合作推动BL-B01D1在美国的开发和商业化。SystImmune将通过其关联公司独家负责BL-B01D1在中国大陆的开发、商业化以及在中国大陆的生产，并负责生产部分供中国大陆以外地区使用的药品。BMS将独家负责BL-B01D1在全球其他地区的开发和商业化。协议签订以后，从2023年底到现在，SystImmune /BMS连续启动了 6项Ⅲ期临床研究，分别是PD-1/L1抑制剂+铂类联用治疗失败的EGFR野生型NSCLC、与铂类化疗联用治疗EGFR TKI经治失败的EGFR突变型NSCLC、二线以上鼻咽癌、紫杉醇治疗失败的三阴乳腺癌、PD-1/L1抑制剂+铂类联用治疗失败的复发或转移性食管鳞癌、一线化疗失败的HR+HER2-乳腺癌。JSKN003JSKN003是由康宁杰瑞开发的HER2双表位ADC，结构如下图所示。抗体部分是共轻链结构，重链则由已上市的HER2单抗曲妥珠单抗、帕妥珠单抗组成，靶向HER2胞外区的ECD2和ECD4两个表位，连接子为可切割dibenzocyclooctyne tetrapeptide，毒素为TOP I抑制剂，通过糖基定点偶联，DAR值约为4。JSKN003-101是该产品的首次临床试验，在晚期实体瘤患者中开展剂量爬升+扩组，1-8.4mg/kg，Q3W。截止2024年3月15日，共入组32例患者，大部分为经过3线及以上治疗的患者，ORR为56.3%、DCR为90.6%。按照HER2表达进行分级，IHC 1+、2+、3+的ORR分别为66.7%（6/9）、37.5%（6/16）、85.7%（6/7）。HER2+乳腺癌、HER2-乳腺癌患者中的ORR分别为100%（5/5）、50%（5/10）。安全性方面，27例患者（84.4%）出现治疗相关的AE，4例患者出现3级AE。常见AE为腹泻、恶心、乏力、呕吐和食欲减退等，直至剂量达到8.4mg/kg，尚未达到MTD剂量。康宁杰瑞已经于2023年12月启动了JSKN003的Ⅲ期临床研究，用于治疗HER2低表达的、一线或二线治疗失败的复发或转移性乳腺癌。TQB2102TQB2102由正大天晴开发，与JSKN003有点类似，也是靶向HER2胞外区的ECD2和ECD4两个表位，采用酶切割连接子，毒素为TOP I抑制剂氘代DXd，DAR约为5.8。未披露太多临床数据。目前进展最快的临床试验处于Ⅱ期阶段，2024年2月启动，用于HER2阳性乳腺癌患者的新辅助治疗。与康宁杰瑞同靶点产品JSKN003的临床开发策略区别还挺大的。处于临床阶段的HER2双表位ADC还有MEDI4276、ZW49（Zanidatamab zovodotin）、KM501MEDI4276结合HER2 ECD2和ECD4两个表位，由可切割多肽连接子经半胱氨酸残基偶联微管蛋白抑制剂tubulysin毒素（AZ13599185），DAR约为4。Ⅰ期临床数据显示，胃癌和乳腺癌患者中，0.05-0.9mg/kg，Q3W，剂量爬升，探索安全性和初步有效性。结果发现，0.4、0.6、0.9mg/kg均出现了剂量限制性毒性（DLT）。0.5mg/kg出现1例乳腺癌患者CR，0.6和0.75mgkg出现2例乳腺癌患者PR。MEDI4276人体MTD剂量<0.3mg/kg，出现药效的剂量均高于该剂量，安全窗口几乎没有。本品自2015年启动Ⅰ期临床，2021年披露数据后，就再无进展。ZW49结构如下图所示，是由HER2双抗ZW25，经v-c连接子偶联微管蛋白抑制剂ZD02044而成，DAR值为2，不算高。ZW49公布的Ⅰ期临床数据显示，在前线已经经过曲妥珠单抗、帕妥珠单抗或者T-DM1治疗的HER2+肿瘤患者中，增加给药频率并未体现出ORR的改善，2.5mg/kg Q3W是其RP2D剂量。该剂量下的ORR约为30%，中位DOR约为6.8个月。有句老话说的好，“不怕不识货，就怕货比货”，ZW49这个数据跟第一三共的DS8201、康宁杰瑞的JSKN003一比，就有些不够看了。百济神州2018年拿到的亚太区权益，已经于2023年下半年退回给了Zymeworks。ZW49单药的竞争力和前景比较有限。还有一款国内轩主生物/康明百奥开发的KM501，结合HER2 ECD2和ECD4两个表位，比较有特色的是抗体部分采用的去岩藻糖设计，ADCC活性会显著增强，动物试验中看到在中低HER2表达肿瘤中显示出不错的抑瘤效果。未见临床数据披露。REGN5093-M114REGN5093-M114由Regeneron开发，也是一个针对单靶点双表位的ADC，只不过不是HER2靶点，换成了MET靶点，抗体端的赖氨酸残基通过可切割连接子，与微管蛋白抑制剂美登素衍生物M24共价偶联，DAR约为3.2。MET是一个单跨膜酪氨酸激酶受体，约24-75%的非鳞NSCLC过表达MET。REGN5093-M114正在开展MET过表达NSCLC的Ⅰ/Ⅱ期临床研究，截至2023年6月26日，已经完成5个剂量的爬升，共入组18例患者，未披露太多其他数据。AZD9592AZD9592由阿斯利康开发，是一款MET/EGFR双靶点ADC。MET和EGFR在NSCLC和头颈鳞癌中共表达。阿斯利康在EGFR靶点领域有一款明星产品，即第三代EGFR抑制剂奥希替尼，临床发现奥希替尼耐药的患者多出现MET受体过表达，故AZD9592这款双靶ADC有可能对奥希替尼耐药的患者有效。其实，百利天恒的那款HER3/EGFR双靶ADC，其中一个临床开发策略也是针对三代EGFR耐药的患者。但是，二者的设计有明显不同，百利天恒选择的是高EGFR亲和力、低HER3亲和力，阿斯利康为降低EGFR在正常组织表达引入的毒性，选择的高MET亲和力、低EGFR亲和力设计，相差>15倍。AZD9592采用的可切割连接子，毒素选择是TOP I抑制剂AZ14170132。AZD9592正处于临床Ⅰ期研究阶段，考察在EGFR突变型或野生型NSCLC、复发/转移性头颈鳞癌患者中安全性、有效性情况。EGFR不只与MET可以组合，还有1款EGFR/MUC1 ADC、1款EGFR-B7H3 ADC处于临床Ⅰ期阶段。M1231是由Merck开发的一款EGFR/MUC1双抗ADC，比较有特色的是引入了非天然氨基酸进行定点偶联，毒素为新型微管蛋白抑制剂，连接子为可切割型的ValCit-PABA。MUC1和EGFR在很多肿瘤中共表达，如食管鳞癌、NSCLC、头颈鳞癌、宫颈癌等。MUC1/EGFR在正常组织的共表达比例很低。双靶的预期是降低在正常组织中的毒性。不过，从进度看，M1231于2021年启动Ⅰ期临床研究后，再无数据更新。根据其合作方SUTRO BIOPHARMA披露的信息，2014年5月双方达成合作协议，2020年第二季度递交IND，2023年，Merck子公司EMD Serono宣布关闭Ⅰa期临床，且不再进行扩组研究，给出的解释是出于strategic portfolio考虑。2023年9月，M1231还在Merck产品管线中，随后没多久，就从管线中消失了，基本宣告失败。IBI3001是信达生物开发的一款糖基化定点偶联，针对EGFR/B7H3的双抗ADC，抗体部分为IBI334，毒素部分为TOP I抑制剂Exatecan，DAR值约为4。B7H3除了与EGFR在某些肿瘤表面共表达以外，还能增强EGFR信号的阻断。临床前研究证实，IBI30031对B7H3lowEGFRlow、B7H3lowEGFRhigh、B7H3highEGFRlow、B7H3highEGFRhigh细胞系均有杀伤作用，对B7H3-EGFR-也有旁观者杀伤效果。体内异源移植瘤模型可以看到对NSCLC、结直肠癌、胰腺癌、乳腺癌明显抑瘤作用。在小鼠体内的PK可达到282h。食蟹猴给药剂量高达90mg/kg/week依然耐受良好。目前本品正在开展Ⅰ期临床研究，尚无临床数据披露。临床前阶段的双抗ADC总体看，临床前双抗ADC国内企业研发比较多，布局最多的应该是百奥赛图/多玛医药/思道医药3家关联企业，前2家公司董事长都是沈月雷博士，第3家公司思道医药由多玛医药全资控股，3家公司合计至少15款双抗ADC产品在推进，靶点主要是EGFR、TROP2、HER3、MUC1、5T4、PTK7、MET的两两组合。感觉像是从原来的OX40、CD40、CTLA-4、4-1BB免疫检查点单抗管线，转而全面拥抱双抗ADC这条火热赛道。有前期大量抗体储备，这种转型确实要快上很多。除以上公司外，国内还有爱科瑞思、康源久远、多禧生物、复宏汉霖、科弈药业、普米斯、普方生物、橙帆生物、祥耀生物等有双抗ADC布局。由于临床前的管线比较早期，很多公司其实并未对外披露，很多之前做单抗、双抗的企业，将双抗ADC视为一次难得的弯道超车的机会。毕竟，单抗技术门槛太低，很难做出差异化，CD3/TAA双抗受限于实体瘤的突破难度，获批的还是以血液瘤为主。单抗ADC算是抗体药物的一条出路，但肿瘤异质性很强，且单靶会出现耐药，其中一种耐药机制是旁路信号的激活，所以双抗ADC理论上能更大程度解决单抗ADC的问题，更何况单抗ADC才上市了15款而已，双抗ADC的对手还不是单抗ADC，而是传统的标准治疗如化疗等。  写在最后  ADC这条赛道近两年很是火热，但实际上还是需要保持理性，毕竟那么多年仅上市了15款，临床失败了近100款，不要被幸存者偏差所误导，大部分其实成了前浪，全倒在了沙滩上。单抗ADC大戏还没唱完，双抗ADC赛道又开始蠢蠢欲动，硝烟四起。但其实回顾下目前在研的双抗ADC，只有百利天恒的EGFR/HER3、康宁杰瑞的HER2双表位两款ADC产品还算顺利，其它产品虽比较早期，但已经有产品（MEDI4276、ZW49）遇到问题，先后推出，后续产品究竟临床表现如何，尚未可知。另外，双抗ADC绝对不是简单的两个靶点的自由组合，即使是共表达靶点如德国默克的EGFR/MUC1双靶ADC M1231，也还是未能如愿推进。目前开发双靶ADC的企业，国内占了大半，如果说国内企业在靶点方面的认知超过Merck、AZ这些MNC，几乎不太可能，更多还是基于竞争对手管线、单抗ADC数据、靶点共表达等进行靶点筛选和组合。这其中，由于EGFR背后涉及的适应症是NSCLC这类大适应症，尤其受欢迎，开发以EGFR为基础的双靶ADC的企业占比很高，靶点组合包括EGFR/HER3、EGFR/c-MET、EGFR/MUC1、EGFR/TROP2、EGFR/PTK7等。毕竟有百利天恒与BMS的EGFR/HER3双抗ADC的重磅交易在前，使这一赛道更具诱惑。ADC的门槛很低，单抗大部分抗体企业都会做，连接子和毒素也已经有商业化CRO成熟供应，想开发个ADC产品的难度较前几年容易很多，所以做抗体的企业趋之若鹜。ADC的门槛也很高，高到虽未开始，但结局已定，现实情况是90多个临床失败，成功上市的仅10多个。想要成功渡劫，就要有真功夫，既需要对靶点有深刻认知，也需要对分子设计有独到理解。尤其后者，同样靶点，为何有些成功，有些失败，是毒素原因（如本文中提到的几款HER2双表位ADC）、偶联原因（如DAR值）、亦或是抗体原因（如两个靶点的亲和力调节），都要深入分析。对于双抗ADC，还是要保持敬畏之心。  BiG 十周年预告  6月26-29日，苏州，将召开BiG十周年庆典，此次会议将首次分为国内和国际篇章，以原创科学和临床需求为出发点，讨论创新技术平台和创新疗法（PROTACT/分子胶、双抗/ADC、siRNA/ASO、CGT、AI制药）的重大进展和发展前景，十年一药曙光现，大浪淘沙始见金！▼架构&完整议程（点击图片，跳转链接）论坛2:  抗体&ADC：从创新靶点到临床进展冠名支持：东曜药业策划：田  丰、刘  军B2皇冠宴会厅C上半场：抗体&ADC，新靶点与新技术14:00-14:30 肺癌领域：双抗&ADC最新临床开发进展周彩存：同济大学附属东方医院肿瘤科主任14:30-15:00 全球ADC新一代技术亮点梳理田   丰：Luxvitae Therapeutics 联合创始人/CEO15:00-15:30 肿瘤全新免疫检查点CD3L1：从源头发现到新药研发许  杰：柏全生物创始人15:30-15:50 善用糖定点偶联技术构建创新ADC分子段  清：东曜药业药物研发及技术开发负责人15:50-16:10 Break下半场：CD3双抗与双抗ADC16:10-16:40 CD3双抗：全球进展&创新设计思路康小强：维立志博董事长/CEO16:40-17:00 高通量仿临床研究平台，如何加速双抗/ADC开发陈大为：创模生物联合创始人、CSO17:00-17:40 Panel：如何开发一款双抗ADC？靶点选择vs.CMC开发vs.临床&市场潜力刘    军：东曜药业CEO兼执行董事（主持）李    竞：橙帆医药联合创始人/CEO周    辉：信达生物集团高级副总裁更多讨论嘉宾邀请中公开会议报名参会 会议门票：审核制(免费)；含主论坛+分论坛，不含餐；优先biotech/Pharma、临床、院校科学家。共建Biomedical创新生态圈！如何加入BiG会员？

Breast cancer patient who improved from a progressive disease diagnosis to an over nine-month sustained stable disease diagnosis has now successfully transitioned to a higher dose level, accessing the potential for greater clinical benefit in the ALG.APV-527 clinical trial Cohort 5 dosing imminent, trial more than 50% enrolled APVO436 Phase 1b/2 dose optimization trial initiation expected 1H 2024 Premier CRO, Prometrika, engaged as partner for dose optimization trial to evaluate APVO436 in frontline AML in combination with venetoclax + azacitidine in venetoclax naïve patients APVO711 demonstrates its ability to induce tumor killing properties in preclinical studies APVO711 dual mechanism checkpoint inhibitor with unique precision targeting capabilities progressing towards IND SEATTLE, WA / ACCESSWIRE / April 10, 2024 /Aptevo Therapeutics Inc. (NASDAQ:APVO), a clinical-stage biotechnology company focused on developing novel immune-oncology therapeutics based on its proprietary ADAPTIR™ and ADAPTIR-FLEX™ platform technologies, today announced advancements in both clinical programs and one preclinical program. A heavily pretreated breast cancer patient, enrolled in the ALG.APV-527 Phase 1 open-label, multi-center, multi-cohort trial for the treatment of multiple solid tumor types, entered the trial and improved from progressive disease to long-lasting stable disease (SD) while on therapy. The patient has remained on study for more than nine months and been successfully transitioned to a higher dose level, which may allow for increased clinical benefit. The trial is more than 50% enrolled and dosing in cohort five (of six) is imminent. "I'm encouraged by the promise that ALG.APV-527 brings to the treatment of solid tumor patients. Witnessing a patient maintaining a stable disease, especially for more than nine months, and then moving to a higher dose level within a Phase 1 trial is uncommon, but we believe it can be therapeutically beneficial for this patient and is a testament to the drug's clinical potential," stated Dirk Huebner, MD, Chief Medical Officer at Aptevo. The Company is on track to initiate part 1 of its upcoming two-part Phase 1b/2 trial in 1H 2024. The study will further evaluate APVO436 for the treatment of acute myeloid leukemia (AML). Aptevo has partnered with premier CRO, Prometrika, for the upcoming study. The first part is a dose optimization trial evaluating standard of care venetoclax + azacitidine along with APVO436 as a frontline treatment for AML patients. It is planned as an open-label, multi-center, multi-cohort study. The trial will evaluate safety/tolerability and efficacy of the triplet combination at multiple dose levels. The therapeutic combination of venetoclax + azacitidine + APVO436 was selected based on outcomes from the Company's dose expansion trial that showed promising outcomes across all categories of evaluation including safety, efficacy, and duration of remission. "We are eager to initiate the next phase of development in support of lead candidate APVO436 as a therapeutic option in combination therapy for the treatment of AML," said Marvin White, President and CEO of Aptevo. "APVO436 results have been positive across the board. For example, we demonstrate an exemplary safety profile, noting that patients experienced cytokine release syndrome at rates that are about one-third the benchmarks demonstrated in literature. Similarly, efficacy results demonstrate clinical responses that are almost double the benchmarks in literature. We anticipate that our dose optimization results will reinforce our growing body of data and demonstrate the clinical potential of APVO436 in patients with frontline AML." APVO711 is currently progressing through preclinical evaluation intended to target a broad range of solid tumors. The Company continues to move this anticancer checkpoint inhibitor with added dual mechanism of action functionality toward the clinic. Key learnings to date include: APVO711 imparts beneficial attributes to both antigen presenting cells and T cells that boost the immune response targeted at controlling tumor cells Experiments in cultured cells have confirmed that APVO711 enhances tumor cell killing by T cells In vivo studies have confirmed that APVO711 reduces the size of PD-L1-expressing tumors "We are pleased with the progress we have made to date in preclinical studies for our dual mechanism checkpoint inhibitor APVO711. This PD-L1 x CD40 molecule, represents an anticancer approach that combines a checkpoint inhibitor with a potent immune mediator. This innovative therapeutic strategy holds promise for unleashing the full potential of the immune system to combat cancer, offering new hope for patients in need of more effective treatments," said Michelle H. Nelson, Ph.D., Director of Immunobiology at Aptevo Therapeutics. More About the Programs ALG.APV-527 ALG.APV-527 is a conditional 4-1BB agonist bispecific that is designed for activation only upon simultaneous binding to 4-1BB and 5T4. It is designed to target cancer cells by activating both T cells and natural killer cells and is intended to bind to tumor-specific antigens while sparing healthy cells and maximizing immune response. This has the potential to be clinically important because 4-1BB can stimulate the immune cells (antitumor-specific T cells and NK cells) involved in tumor control, making 4-1BB a particularly compelling target for cancer immunotherapy. The compound is currently being evaluated for multiple solid tumor types in a multi-center, dose escalation trial that is more than 50% enrolled. Additional promising preliminary data includes: In addition to the patient described above, a second heavily pretreated breast cancer patient who was progressing prior to enrolling in the trial has sustained long lasting stable disease and remained on study drug for seven months. Analysis demonstrated measurable level of drug in circulation (pharmacokinetic) and reproducible elevation of serum pharmacodynamic markers with dosing, suggesting the drug is biologically active Treatment to date has been overall well-tolerated, and a maximum tolerated dose has not yet been determined, dose-escalation in higher-dose cohorts is ongoing as the Company moves into cohort five (of six) ALG.APV-527 has been measurable in all patients with plasma concentration of ALG.APV-527 consistent with the administered dose Biomarker analyses indicate the expression of the targets (4-1BB and 5T4) in tumor biopsies and confirm biological activity of ALG.APV-527 "We are excited by the emerging data from the ALG.APV-527 clinical trial, indicating biological activity and generating stable disease even at the lowest dose levels tested in heavily pretreated patients. This molecule is engineered to target cancer cells while preserving healthy tissues, all the while amplifying a specific immune response. We eagerly anticipate sharing forthcoming data and continuing to unveil the immense potential of this bispecific candidate in the solid tumor space," expressed Dirk Huebner, MD, Chief Medical Officer at Aptevo. APVO436 Aptevo's wholly owned lead proprietary drug candidate, APVO436 is targeting AML and is differentiated by design to redirect the immune system of the patient to destroy leukemic cells and leukemic stem cells expressing the target antigen CD123, which is a compelling target for AML due to its overexpression on leukemic stem cells and AML blasts . This antibody-like recombinant protein therapeutic is designed to engage both leukemic cells and T cells of the immune system and bring them closely together to trigger the destruction of leukemic cells. APVO436 is purposefully designed to reduce the likelihood and severity of CRS by use of a unique CD3 derived from CRIS-7 vs. the CD3 used by other competitors. APVO436 has received orphan drug designation ("orphan status") for AML according to the Orphan Drug Act. The Phase 1b Dose escalation trial results showed a 91% clinical benefit rate in combination with venetoclax + azacitidine in venetoclax naïve patients, a 27% incidence of CRS across all trial cohorts (the majority were grades 1 & 2) and meaningful duration of remission, including three patients who transitioned to transplant after receiving therapy, the best possible outcome for AML patients. The Company is planning to commence the first part of the Phase 1b/2 dose optimization program in the first half of 2024. APVO711 APVO711, a bispecific checkpoint inhibitor with added functionality, targets PD-L1 and CD40, and is designed to function to synergistically induce a biological response. This is achieved by simultaneously engaging in two clinically validated T cell activating mechanisms: 1) blocking of PD-L1/PD-1 inhibitory pathway and 2) CD40 signaling augments APC maturation resulting in enhanced T cell stimulation. APVO711 is designed to activate CD40 only in the presence of PD-L1 binding for an improved safety profile. The Company believes APVO711 has the potential to positively impact the treatment paradigm of multiple solid tumor types for which there is currently significant unmet medical need. About Aptevo Therapeutics Inc. Aptevo Therapeutics Inc. is a clinical-stage biotechnology company focused on developing novel immuno-oncology therapies for the treatment of cancer. Aptevo is seeking to improve treatment outcomes for cancer patients. For more information, please visit . Safe Harbor Statement This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements, other than statements of historical fact, including, without limitation, Aptevo's expectations about the activity, efficacy, safety, tolerability and durability of its therapeutic candidates and potential use of any such candidates, including in combination with other drugs, as therapeutics for treatment of disease, its expectations regarding the effectiveness of its ADAPTIR and ADAPTIR-FLEX platforms, statements related to the progress of Aptevo's clinical programs, including statements related to anticipated clinical and regulatory milestones such as Phase 1b/2 trial initiation for APVO436 in frontline, venetoclax naïve AML patients, whether further study of APVO436 in a Phase 1b dose optimization trial focusing on multiple doses of APVO436 in combination with venetoclax + azacitidine on a targeted patient population will continue to show clinical benefit, whether Aptevo's final trial results will vary from its earlier assessment, whether biomarker analyses will continue to confirm biological activity of ALG.APV-527, whether higher dose ranges will result in increased signs of clinical activity, whether further study of ALG.APV-527 across a cross section of multiple tumor types will continue to show clinical benefit, the possibility and timing of interim data readouts for ALG.APV-527, whether Aptevo's final trial results will vary from its preliminary or interim assessments, the possibility and timing of preliminary or interim data readouts for ALG.APV-527, statements related to the progress of and enthusiasm for Aptevo's clinical programs, whether pre-clinical studies of APVO711 will show the desired anti-tumor efficacy, mechanism of action and safety profile, whether APVO711 will demonstrate the ability to fight a range of solid malignancies, statements related to the progress towards an IND filing for APVO711, statements related to Aptevo's ability to generate stockholder value, whether Aptevo will continue to have momentum in its business in the future, and any other statements containing the words "may," "continue to," "believes," "knows," "expects," "optimism," "potential," "designed," "promising," "plans," "will" and similar expressions are intended to identify forward-looking statements. These forward-looking statements are based on Aptevo's current intentions, beliefs, and expectations regarding future events. Aptevo cannot guarantee that any forward-looking statement will be accurate. Investors should realize that if underlying assumptions prove inaccurate or unknown risks or uncertainties materialize, actual results could differ materially from Aptevo's expectations. Investors are, therefore, cautioned not to place undue reliance on any forward-looking statement. There are several important factors that could cause Aptevo's actual results to differ materially from those indicated by such forward-looking statements, including a deterioration in Aptevo's business or prospects; further assessment of preliminary or interim data or different results from later clinical trials; adverse events and unanticipated problems, adverse developments in clinical development, including unexpected safety issues observed during a clinical trial; and changes in regulatory, social, macroeconomic and political conditions. For instance, actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including the uncertainties inherent in the results of preliminary or interim data and preclinical studies being predictive of the results of later-stage clinical trials, initiation, enrollment and maintenance of patients, and the completion of clinical trials, the availability and timing of data from ongoing clinical trials, the trial design includes combination therapies that may make it difficult to accurately ascertain the benefits of APVO436, expectations for the timing and steps required in the regulatory review process, expectations for regulatory approvals, the impact of competitive products, our ability to enter into agreements with strategic partners or raise funds on acceptable terms or at all and other matters that could affect the availability or commercial potential of Aptevo's product candidates, business or economic disruptions due to catastrophes or other events, including natural disasters or public health crises such as the coronavirus (referred to as COVID-19), geopolitical risks, including the current war between Russia and Ukraine and the rising conflict in the Middle East, and macroeconomic conditions such as economic uncertainty, rising inflation and interest rates, continued market volatility and decreased consumer confidence. These risks are not exhaustive, Aptevo faces known and unknown risks. Additional risks and factors that may affect results are set forth in Aptevo's filings with the Securities and Exchange Commission, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2023, and its subsequent reports on Form 10-Q and current reports on Form 8-K. The foregoing sets forth many, but not all, of the factors that could cause actual results to differ from Aptevo's expectations in any forward-looking statement. Any forward-looking statement speaks only as of the date of this press release, and, except as required by law, Aptevo does not assume any obligation to update any forward-looking statement to reflect new information, events, or circumstances. CONTACT: Miriam Weber Miller Head, Investor Relations & Corporate Communications Aptevo Therapeutics Email: IR@apvo.com or Millerm@apvo.com Phone: 206-859-6628 SOURCE: Aptevo Therapeutics View the original press release on accesswire.com