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首页> 外文期刊>Antibodies >Pyrrolobenzodiazepine Antibody-Drug Conjugates Designed for Stable Thiol Conjugation
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Pyrrolobenzodiazepine Antibody-Drug Conjugates Designed for Stable Thiol Conjugation

机译：吡咯并苯二氮杂卓抗体-药物偶联物设计用于稳定的硫醇偶联。

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Thiosuccinimide-linked antibody-drug conjugates (ADCs) are susceptible to drug loss over time due to a retro-Michael reaction, which can be prevented by selecting stable conjugation positions or hydrolysis of the thiosuccinimide. Here, we investigate pyrrolobenzodiazepine (PBD) ADC drug-linkers equipped with N -phenyl maleimide functionality for stable thiol conjugation via thiosuccinimide hydrolysis. Two PBD drug-linker formats (enzyme-cleavable and non-cleavable) were evaluated following site-specific conjugation to an engineered cysteine incorporated at position T289, which is known to be unstable for N -alkyl maleimide conjugates. N -phenyl maleimide PBDs conjugated to antibodies with similar efficiencies as N -alkyl maleimide PBDs and enhanced thiosuccinimide hydrolysis for N -phenyl maleimide PBDs was confirmed by mass spectrometry, capillary isoelectric focusing, and a SYPRO Orange dye binding assay. All of the PBD ADCs were highly potent in vitro regardless of maleimide- or linker-type, exhibiting low pM EC 50 values. Thiol conjugation to N -phenyl maleimide PBD minimized the retro-Michael reaction in both rat and mouse serum. However, cleavage of the valine-alanine dipeptide in mouse serum for ADCs containing cleavable drug-linker led to drug loss regardless of maleimide type, which impacted ADC potency in tumor growth inhibition studies that were conducted in mouse models. Therapeutic improvement in mouse tumor models was realized for ADCs prepared with non-cleavable PBD drug-linkers that were conjugated through N -phenyl maleimide, where a stronger tumor growth inhibition (TGI) response was achieved when compared to the analogous N -alkyl maleimide drug-linker ADC. Altogether, our findings highlight the stability and efficacy benefits of N -phenyl maleimide functionality for ADCs that are produced with thiol-maleimide conjugation chemistry.
机译：硫代琥珀酰亚胺连接的抗体-药物共轭物（ADC）随时间的流逝容易遭受药物逆流反应的影响，这可以通过选择稳定的缀合位置或硫代琥珀酰亚胺的水解来防止。在这里，我们研究吡咯并苯二氮杂（PBD）ADC药物连接器，配备N-苯基马来酰亚胺功能，可通过硫代琥珀酰亚胺水解稳定硫醇结合。在与位置T289处掺入的工程化半胱氨酸发生位点特异性缀合后，评估了两种PBD药物接头形式（酶可裂解和不可裂解），已知该半胱氨酸对N-烷基马来酰亚胺缀合物不稳定。通过质谱，毛细管等电聚焦和SYPRO Orange染料结合测定法确认了与抗体结合的N-苯基马来酰亚胺PBD与N-烷基马来酰亚胺PBD具有相似的效率，并增强了N-苯基马来酰亚胺PBD的硫代琥珀酰亚胺水解。不论马来酰亚胺或接头类型如何，所有的PBD ADC都具有很强的体外活性，表现出低的pM EC 50值。硫醇与N-苯基马来酰亚胺PBD的结合使大鼠和小鼠血清中的逆迈克尔反应最小化。但是，无论是否含有马来酰亚胺类型，对于含有可裂解药物连接子的ADC，小鼠血清中缬氨酸-丙氨酸二肽的裂解都会导致药物丢失，从而影响ADC在小鼠模型中抑制肿瘤生长的功效。对于通过N-苯基马来酰亚胺偶联的不可裂解的PBD药物连接子制备的ADC，小鼠肿瘤模型的治疗性改善得以实现，与类似的N-烷基马来酰亚胺药物相比，该药物可实现更强的肿瘤生长抑制（TGI）反应-链接器ADC。总之，我们的发现突出了N-苯基马来酰亚胺官能团对于用硫醇-马来酰亚胺共轭化学生产的ADC的稳定性和功效。

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