McSAF, 1 rue Claude Thion, Tours 37000 France.
University of Tours, GICC, Team IMT EA7501, 31 avenue, Monge, Tours 37200 France.
Bioconjug Chem. 2021 Mar 17;32(3):595-606. doi: 10.1021/acs.bioconjchem.1c00058. Epub 2021 Feb 25.
To overcome stability and heterogeneity issues of antibody-drug conjugates (ADCs) produced with existing bioconjugation technologies incorporating a maleimide motif, we developed McSAF Inside, a new technology based on a trifunctionalized di(bromomethyl)pyridine scaffold. Our solution allows the conjugation of a linker-payload to previously reduced interchain cysteines of a native antibody, resulting in disulfide rebridging. This leads to highly stable and homogeneous ADCs with control over the drug-to-antibody ratio (DAR) and the linker-payload position. Using our technology, we synthesized an ADC, , built from anti-CD30 antibody cAC10 (brentuximab), and compared it to Adcetris, the first line treatment against CD30-positive lymphoma, in a CD30-positive lymphoma model. displayed improved DAR homogeneity, with a solid batch-to-batch reproducibility, as well as enhanced stability in thermal stress conditions or in the presence of a free thiol-containing protein, such as human serum albumin (HSA). showed antigen-binding, cytotoxicity, efficacy, and tolerability similar to Adcetris. Therefore, in accordance with current regulatory expectations for the development of new ADCs, McSAF Inside technology gives access to relevant ADCs with improved characteristics and stability.
为了克服采用包含马来酰亚胺基序的现有生物偶联技术生产的抗体药物偶联物 (ADC) 的稳定性和异质性问题，我们开发了 McSAF Inside，这是一种基于三功能化双（溴甲基）吡啶支架的新技术。我们的解决方案允许将接头 - 有效载荷连接到天然抗体先前还原的链间半胱氨酸上，从而重新桥接二硫键。这导致具有控制药物抗体比（DAR）和接头 - 有效载荷位置的高度稳定和均一的 ADC。使用我们的技术，我们合成了一种 ADC， ，由抗 CD30 抗体 cAC10（ Brentuximab ）构建，并在 CD30 阳性淋巴瘤模型中与 Adcetris（针对 CD30 阳性淋巴瘤的一线治疗药物）进行了比较。 显示出改善的 DAR 均一性，具有稳定的批间重现性，以及在热应激条件下或存在游离含巯基蛋白（如人血清白蛋白（HSA））时的增强稳定性。 显示出与 Adcetris 相似的抗原结合、 细胞毒性、 疗效和耐受性。因此，根据新 ADC 开发的当前监管期望，McSAF Inside 技术可获得具有改善特性和稳定性的相关 ADC。
