PO.CL06.01 · 临床研究

ABBV-706（一种SEZ6靶向的拓扑异构酶1抑制剂ADC）的疗效：来自儿童临床前体内测试（PIVOT）项目的报告

Efficacy of ABBV-706, a SEZ6-targeted topoisomerase 1 inhibitor ADC: A report from the Pediatric Preclinical In Vivo Testing (PIVOT) Program

编号 7815 展板 18 时间 4/22 09:00–12:00 区域 Section 44 主讲 Elizabeth Stewart, MD

分会场 Immunotherapies in Pediatric Cancers

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作者与单位 Authors & Affiliations

Elizabeth A. Stewart¹, Michael A. Dyer¹, Yael P. Mosse², John M. Maris², Xiao-Nan Li³, Stefan Atkinson¹, Chen He¹, David N. Groff², Alvin Farrel², Yuchen Du³, Jinnan Chen³, Steven B. Neuhauser⁴, Timothy M. Stearns⁴, Emily L. Jocoy⁵, Jee Young Kwon⁶, Jeffrey H. Chuang⁶, Emily Faivre⁷, Kelly Doyle⁷, Kimberly E. Ellison⁷, Joshua F. Hernandez⁷, Joann P. Palma⁷, Michael Barnes⁷, Pooja Hingorani⁷, Nandini Rudra-Ganguly⁷, Beverly A. Teicher⁸, Carol J. Bult⁴, Malcolm A. Smith⁸

¹St. Jude Children's Research Hospital, Memphis, TN,²Children's Hospital of Philadelphia, Philadelphia, PA,³Ann & Robert H. Lurie Children's Hosp. of Chicago, Chicago, IL,⁴The Jackson Laboratory, Bar Harbor, ME,⁵The Jackson Laboratory, Sacramento, CA,⁶The Jackson Laboratory, Farmington, CT,⁷AbbVie Inc, North Chicago, IL,⁸National Cancer Institute, Bethesda, MD

摘要 Abstract

中文摘要

引言：ABBV-706是一种抗体药物偶联物（ADC），由靶向癫痫相关同源物6（SEZ6）表面蛋白的单克隆抗体连接拓扑异构酶1抑制剂载荷组成。ABBV-706的1期临床试验正在SEZ6表达的复发性实体瘤成人患者中进行（NCT05599984）。由于SEZ6在许多儿童癌症中高表达，ABBV-706引起了关注。目标是评估ABBV-706在具有显著SEZ6表达的儿童癌症模型中的作用：神经母细胞瘤（NB）、髓母细胞瘤（MB）、视网膜母细胞瘤（RB）和腺泡状横纹肌肉瘤（ARMS），并将其活性与溶媒对照和同型非靶标对照ADC（IC-ADC）进行比较。方法：筛查儿童异种移植模型的SEZ6表达。在具有不同SEZ6表达的NB、MB、RB和ARMS模型中完成了单药体内研究。移植成功后，以两个剂量水平（DL1、DL2）通过腹腔注射间隔3周给予共2剂ABBV-706或IC-ADC。通过中位无事件生存期（KM med，以天为单位）和客观反应指标（ORM，Ped Blood Cancer 2007;49:928-940）评估疗效。ORM将客观反应定义为部分、完全或维持性完全缓解（PR、CR和MCR），与疾病稳定（SD）或疾病进展（伴或不伴生长延迟，分别为PD2和PD1）相比较。结果：ABBV-706在广泛的SEZ6表达的非中枢神经系统（NB、RB、ARMS）模型中显示出疗效。在DL1时，11个模型中有8个出现PR、CR或MCR反应。在DL2时，11个模型中有9个出现PR、CR或MCR反应。对于大多数模型，ABBV-706比IC-ADC更有活性。在2个MB模型中的1个中观察到生存优势。结论：我们展示了ABBV-706在多个SEZ6表达模型中的高抗肿瘤活性以及相对于IC-ADC增强的疗效。由于SEZ6在多种儿童组织学类型中的高表达，ABBV-706在这些癌症患者中具有临床活性的潜力。模型 SEZ6 mRNA (FPKM) 癌症类型溶媒 KM med 溶媒 ORM ABBV-706 DL1 KM med ABBV-706 DL1 ORM ABBV-706 DL2 KM med ABBV-706 DL2 ORM IC-ADC DL1 KM med IC-ADC DL1 ORM IC-ADC DL2 KM med IC-ADC DL2 ORM COG-N-424x 46.1 NB 8.6 PD 82.8* MCR >99* MCR 6 PD1 13.6 PD1 COG-N-496x 59.9 NB 11.1 PD >103* MCR >103 MCR 8.3 PD1 >103 MCR COG-N-561x 13 NB 8.2 PD 78.4* PR 101* MCR 13.7 PD1 37 PD2 NB-1691 17.9 NB 7.9 PD 19.4* PD2 34.3* PD2 10.7 PD1 10.8 PD1 SK-N-AS 0.06 NB 9.7 PD 9.4 PD1 10.5 PD1 8.74 PD1 12.3 PD1 SJRB012408_X2 53.8 RB 35 PD 126* MCR 108.5 PR 42 PD1 70 PD1 SJRB063836_X1 78.6 RB 35 PD 140* MCR 140* MCR 35 PD1 87.5 SD SJRHB030765_X1 119.8 ARMS 35 PD 63* PD1 140* PR 42 PD1 70 PD1 SJRHB030787_X1 129.3 ARMS 35 PD 105* CR 91 CR 63 PD1 84 SD SJRHB031320_X1 21.8 ARMS 35 PD 98* PR 108.5* PR 66.5 PD1 91 SD SJRHB046156_X1 111.7 ARMS 14 PD 84 PR 105* CR 21 PD1 21 PD1 Icb-2164MB 166.4 MB 69.5 - 76 - 91* - 77.5 - 72 - Icb-3130MB 46.1 MB 90 - 137 - 148.5 - 121.5 - 117.5 - *表示与匹配的IC-ADC相比p值<0.05。

查看英文原文 English abstract

Introduction: ABBV-706 is an antibody-drug conjugate (ADC) composed of a monoclonal antibody targeting the seizure-related homolog 6 (SEZ6) surface protein linked to topoisomerase 1 inhibitor payload. A Phase 1 trial of ABBV-706 is underway in adults with SEZ6 expressing relapsed solid tumors (NCT05599984). ABBV-706 became of interest as SEZ6 is highly expressed in many pediatric cancers. The goal was to evaluate ABBV-706 in models of childhood cancers with notable SEZ6 expression: neuroblastoma (NB), medulloblastoma (MB), retinoblastoma (RB), and alveolar rhabdomyosarcoma (ARMS) and compare the activity to vehicle and isotype non-target control ADC (IC-ADC). Methods: Pediatric xenograft models were screened for SEZ6 expression. Single agent in vivo studies were completed in NB, MB, RB, and ARMS models with varying SEZ6 expression. After engraftment, 2 total doses of ABBV-706 or IC-ADC were given by IP injection 3 weeks apart at 2 dose levels (DL1, DL2). Efficacy was assessed by median event free survival (KM med, in days) and objective response measure (ORM, Ped Blood Cancer 2007;49:928-940). ORM defines an objective response as partial, complete, or maintained complete response (PR, CR, and MCR) compared to stable disease (SD) or progressive disease, with or without growth delay (PD2 and PD1, respectively). Results: ABBV-706 showed efficacy in a broad range of SEZ6 expressing non-CNS (NB, RB, ARMS) models. At DL1, PR, CR, or MCR responses were seen in 8 of 11 models. At DL2, 9 of 11 models had PR, CR, or MCR responses. For most models, ABBV-706 was more active than IC-ADC. Survival advantage was observed in 1 of 2 MB models. Conclusion: We showed high anti-tumor activity for ABBV-706 in multiple SEZ6 expressing models and enhanced efficacy versus IC-ADC. Due to high expression of SEZ6 in several pediatric histologies, ABBV-706 has potential for clinical activity in patients with these cancers. Model SEZ6 mRNA (FPKM) Cancer Type Vehicle KM med Vehicle ORM ABBV-706 DL1 KM med ABBV-706 DL1 ORM ABBV-706 DL2 KM med ABBV-706 DL2 ORM IC-ADC DL1 KM med IC-ADC DL1 ORM IC-ADC DL2 KM med IC-ADC DL2 ORM COG-N-424x 46.1 NB 8.6 PD 82.8* MCR >99* MCR 6 PD1 13.6 PD1 COG-N-496x 59.9 NB 11.1 PD >103* MCR >103 MCR 8.3 PD1 >103 MCR COG-N-561x 13 NB 8.2 PD 78.4* PR 101* MCR 13.7 PD1 37 PD2 NB-1691 17.9 NB 7.9 PD 19.4* PD2 34.3* PD2 10.7 PD1 10.8 PD1 SK-N-AS 0.06 NB 9.7 PD 9.4 PD1 10.5 PD1 8.74 PD1 12.3 PD1 SJRB012408_X2 53.8 RB 35 PD 126* MCR 108.5 PR 42 PD1 70 PD1 SJRB063836_X1 78.6 RB 35 PD 140* MCR 140* MCR 35 PD1 87.5 SD SJRHB030765_X1 119.8 ARMS 35 PD 63* PD1 140* PR 42 PD1 70 PD1 SJRHB030787_X1 129.3 ARMS 35 PD 105* CR 91 CR 63 PD1 84 SD SJRHB031320_X1 21.8 ARMS 35 PD 98* PR 108.5* PR 66.5 PD1 91 SD SJRHB046156_X1 111.7 ARMS 14 PD 84 PR 105* CR 21 PD1 21 PD1 Icb-2164MB 166.4 MB 69.5 - 76 - 91* - 77.5 - 72 - Icb-3130MB 46.1 MB 90 - 137 - 148.5 - 121.5 - 117.5 - *indicates p-value <0.05 compared to matched IC-ADC

利益披露 Disclosure

E. A. Stewart, None.. M. A. Dyer, None.. Y. P. Mosse, None.. J. M. Maris, None.. S. Atkinson, None.. C. He, None.. D. N. Groff, None.. A. Farrel, None.. Y. Du, None.. J. Chen, None.. S. B. Neuhauser, None.. T. M. Stearns, None.. E. L. Jocoy, None.. J. Kwon, None.. J. H. Chuang, None. E. Faivre, AbbVie Inc Employment. K. Doyle, AbbVie Inc Employment. K. E. Ellison, AbbVie Inc Employment. J. F. Hernandez, AbbVie Inc Employment. J. P. Palma, AbbVie Inc Employment. M. Barnes, AbbVie Inc Employment. P. Hingorani, AbbVie Inc Employment. N. Rudra-Ganguly, AbbVie Inc Employment. B. A. Teicher, None.. M. A. Smith, None.

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