Payload-Binding Fab Fragments Increase the Therapeutic Index of MMAE Antibody-Drug Conjugates.
Payload-Binding Fab Fragments Increase the Therapeutic Index of MMAE Antibody-Drug Conjugates.
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DOI：
10.1158/1535-7163.mct-22-0440
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发表时间：
2023-04-03
影响因子：
5.7
通讯作者：
中科院分区：
文献类型：
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单甲基金黄色E(MMAE)是一种有效的微管蛋白抑制剂，用于FDA批准的四种抗体药物结合物(ADCs)的有效载荷。去结合的MMAE很容易扩散到非靶向细胞，导致非靶向毒性。在这里，我们报告了一种人源化Fab片段(ABC3315)的开发和评估，该片段可以增强MMAE ADC的治疗选择性。ABC3315将MMAE对人癌细胞的IC50提高了500倍，而对包括Polatuzumab vedotin和曲妥珠单抗-vc-MMAE(TvcMMAE)在内的MMAE ADCs的细胞毒性没有影响。联合应用ABC3315不会降低Polatuzumab vedotin或TvcMMAE在异种移植瘤模型中的疗效。ABC3315与80 mg/kg TvcMMAE联合给药显著增加了0-4天后尿中MMAE的累积排泄量，从789.4±19.0ng(单独给予TvcMMAE)增加到2625±206.8纳克(对于同时服用TvcMMAE和ABC3315的小鼠)。与对照组相比，接受80 mg/kg TvcMMAE和PBS的小鼠的白细胞计数(p=0.025)和红细胞计数(p=0.0083)显著下降。与对照组相比，服用80 mg/kg TvcMMAE和ABC3315的小鼠在白细胞计数(p=0.15)或红细胞计数(p=0.23)方面没有显著差异。ABC3315120 mg/kgpolatuzumab vedotin联合给药后，小鼠体重下降率由11.9±7.0%降至4.1±2.1%(p=0.045)。我们的结果表明，抗MMAE Fab片段ABC3315在不降低抗肿瘤疗效的同时，降低了靶外毒性，增加了MMAE ADC的治疗窗口。
Monomethyl auristatin E (MMAE) is a potent tubulin inhibitor that is used as the payload for four FDA-approved antibody drug conjugates (ADCs). Deconjugated MMAE readily diffuses into untargeted cells resulting in off-target toxicity. Here we report the development and evaluation of a humanized Fab fragment (ABC3315) that enhances the therapeutic selectivity of MMAE ADCs. ABC3315 increased the IC50 of MMAE against human cancer cell-lines by >500-fold with no impact on the cytotoxicity of MMAE ADCs, including polatuzumab vedotin and trastuzumab-vc-MMAE (TvcMMAE). Co-administration of ABC3315 did not reduce the efficacy of polatuzumab vedotin or TvcMMAE in xenograft tumor models. Co-administration of ABC3315 with 80 mg/kg TvcMMAE significantly (p<0.0001) increased the cumulative amount of MMAE that was excreted in urine 0-4-days after administration from 789.4 ±19.0 nanograms (TvcMMAE alone) to 2625±206.8 nanograms (for mice receiving TvcMMAE with co-administration of ABC3315). Mice receiving 80 mg/kg TvcMMAE and PBS exhibited a significant drop in white blood cell counts (p=0.025) and red blood cell counts (p=0.0083) in comparison to control mice. No significant differences, relative to control mice, were found for white blood cell counts (p=0.15) or for red blood cell counts (p=0.23) for mice treated with 80 mg/kg TvcMMAE and ABC3315. Co-administration of ABC3315 with 120 mg/kg polatuzumab vedotin significantly (p=0.045) decreased the percentage body weight loss at nadir for treated mice from 11.9 ± 7.0% to 4.1 ± 2.1%. Our results demonstrate that ABC3315, an anti-MMAE Fab fragment, decreases off-target toxicity while not decreasing anti-tumor efficacy, increasing the therapeutic window of MMAE ADCs.
DOI：
10.1177/1076029618755947
发表时间：
2018-07
期刊：
Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis
影响因子：
--
作者：
Glund S;Gan G;Moschetti V;Reilly P;Honickel M;Grottke O;Van Ryn J
通讯作者：
Van Ryn J
影响因子：
2.5
作者：
Shah DK;Balthasar JP
通讯作者：
Balthasar JP