Abstract 950: Targeting B7-H3 in squamous cell carcinoma of the head and neck: Preclinical proof-of-concept with the investigational anti-B7-H3 antibody-drug conjugate, MGC018
Juniper A Scribner, Francine Z Chen, Ying Li, M. Chiechi, T. Son, J. Hooley, S. Koenig, P. Moore, E. Bonvini, C. Bohac, D. Loo
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引用次数: 0
Abstract
Introduction: Squamous cell carcinoma of the head and neck (SCCHN) is the seventh most common cancer worldwide, accounting for ~ 4% of all cancers in the United States. Although PD-1-directed therapy has efficacy in SCCHN, 85-95% of patients progress following initial response. B7-H3 is a member of the B7 family of immunomodulatory molecules, is overexpressed in SCCHN, and correlates with disease severity and poor clinical outcome. Furthermore, consistent with its putative coinhibitory function, B7-H3 expression in SCCHN is inversely correlated with the number of tumor infiltrating CD8+ T-cells. We are developing therapeutics targeting B7-H3, including enoblituzumab, an Fc-engineered anti-B7-H3 monoclonal antibody, and MGC018, a duocarmycin-based B7-H3 ADC, both of which are currently being evaluated in clinical studies. Here the potential of MGC018 was explored in preclinical models as a proof of concept for targeting B7-H3 in SCCHN. Methods: Immunohistochemistry studies were performed to define the expression of B7-H3 in SCCHN tissue microarrays (TMA). Single and repeat-dose in vivo efficacy studies were conducted in CD-1 nude mice with cell line-derived SCCHN human tumor xenografts to explore the relationship between Cmax, exposure and antitumor activity, and to define the minimal efficacious dose in these models. Based on results in these cell-derived xenograft (CDX) studies, in vivo efficacy studies were extended to a panel of SCCHN patient-derived xenograft (PDX) models, which more closely mimic the biological characteristics of the patient tumor and exhibit heterogenous expression of B7-H3. Results: Analysis of B7-H3 expression on a SCCHN TMA confirmed and extended previously reported expression of B7-H3 in SCCHN. Of the SCCHN samples evaluated, 90% (36/40) of the tumor samples were positive for B7-H3: 35% (14/40) had H-scores greater than 200, with the remaining 22 samples equally distributed between the H-score range of 101-200 and 1-100 (~ 28% each). MGC018 demonstrated specific, dose-dependent in vitro cytotoxicity toward SCCHN human tumor cell lines. The in vitro cytotoxicity translated to potent antitumor activity in vivo against SCCHN CDX models, with a single administration of 3 mg/kg resulting in complete responses in 7/7 mice in the FaDu model. In the PDX setting (H-scores 120-283), repeat dose administration every week or two weeks with MGC018 at 3 mg/kg/dose, led to regressions and/or stable disease in 10/18 models, and a delay in tumor growth in 5 additional models. Conclusion: B7-H3 is frequently overexpressed in SCCHN. At clinically relevant dose levels, MGC018 demonstrated potent antitumor activity in vivo toward SCCHN CDX mouse models and the majority of SCCHN PDX mouse models examined. These results support SCCHN as a potential indication that may be responsive to ADC-based treatments directed toward B7-H3. Citation Format: Juniper A. Scribner, Francine Z. Chen, Ying Li, Michael Chiechi, Thomas Son, Jeff Hooley, Scott Koenig, Paul A. Moore, Ezio Bonvini, Chet Bohac, Deryk Loo. Targeting B7-H3 in squamous cell carcinoma of the head and neck: Preclinical proof-of-concept with the investigational anti-B7-H3 antibody-drug conjugate, MGC018 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 950.
头颈部鳞状细胞癌(SCCHN)是全球第七大常见癌症,占美国所有癌症的4%。虽然pd -1定向治疗对SCCHN有效,但85-95%的患者在初始反应后进展。B7- h3是免疫调节分子B7家族的成员,在SCCHN中过表达,与疾病严重程度和不良临床预后相关。此外,与推测的共抑制功能一致,B7-H3在SCCHN中的表达与肿瘤浸润CD8+ t细胞的数量呈负相关。我们正在开发针对B7-H3的治疗药物,包括enoblituzumab(一种fc工程抗B7-H3单克隆抗体)和MGC018(一种基于多卡霉素的B7-H3 ADC),这两种药物目前都在临床研究中进行评估。本研究在临床前模型中探索了MGC018的潜力,作为靶向B7-H3治疗SCCHN的概念证明。方法:采用免疫组化方法确定B7-H3在SCCHN组织微阵列(TMA)中的表达。在CD-1裸鼠身上进行单次和重复剂量的体内药效研究,探讨Cmax、暴露与抗肿瘤活性之间的关系,并确定这些模型的最小有效剂量。基于这些细胞源性异种移植物(CDX)研究的结果,体内疗效研究扩展到一组SCCHN患者源性异种移植物(PDX)模型,这些模型更接近于模拟患者肿瘤的生物学特性,并表现出B7-H3的异质表达。结果:B7-H3在SCCHN TMA上的表达分析证实并扩展了先前报道的B7-H3在SCCHN中的表达。在评估的SCCHN样本中,90%(36/40)的肿瘤样本B7-H3阳性,35%(14/40)的肿瘤样本h评分大于200,其余22个样本平均分布在101-200和1-100之间(各约28%)。MGC018对SCCHN人肿瘤细胞系具有特异性、剂量依赖性的体外细胞毒性。体外细胞毒性转化为体内对SCCHN CDX模型的有效抗肿瘤活性,单次给药3mg /kg, FaDu模型中7/7只小鼠完全缓解。在PDX组(h评分120-283)中,每周或每两周重复给药3mg /kg/剂量的MGC018,在10/18模型中导致疾病消退和/或稳定,在另外5个模型中导致肿瘤生长延迟。结论:B7-H3在SCCHN中高表达。在临床相关剂量水平下,MGC018在体内对SCCHN CDX小鼠模型和大多数SCCHN PDX小鼠模型显示出有效的抗肿瘤活性。这些结果支持SCCHN作为一种潜在的适应症,可能对针对B7-H3的adc治疗有反应。引文格式:Juniper A. Scribner, Francine Z. Chen, Ying Li, Michael Chiechi, Thomas Son, Jeff Hooley, Scott Koenig, Paul A. Moore, Ezio Bonvini, Chet Bohac, Deryk Loo。靶向B7-H3治疗头颈部鳞状细胞癌:抗B7-H3抗体-药物偶联物MGC018的临床前概念验证[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志,2021;81(13 -增刊):摘要第950期。