Site-Specific Lysine Arylation as an Alternative Bioconjugation Strategy for Chemically Programmed Antibodies and Antibody-Drug Conjugates.
Site-Specific Lysine Arylation as an Alternative Bioconjugation Strategy for Chemically Programmed Antibodies and Antibody-Drug Conjugates.
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DOI：
10.1021/acs.bioconjchem.9b00609
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发表时间：
2019-11-20
影响因子：
4.7
通讯作者：
Rader C
中科院分区：
文献类型：
--
作者：
Hwang D;Tsuji K;Park H;Burke TR Jr;Rader C
通过利用独特的活性赖氨酸残基（Lys99）进行小分子的位点特异性附着，人源化催化抗体h38C2已被用作生物偶联模块，用于化学编程抗体和抗体-药物偶联物的组装。用β-内酰胺功能化的小分子处理h38C2，通过选择性地与Lys99残基的ε-氨基形成稳定的酰胺键，导致共价偶联。在这里，我们报道了杂芳基甲基磺酰（MS-PODA）功能化的小分子代表了一种替代的生物偶联策略，通过对Lys99残基进行高效、位点特异性和稳定的芳基化。一组化学编程抗体和由Lys99芳基化组装的抗体-药物偶联物为这种替代生物偶联策略的治疗效用提供了概念证明。虽然与β-内酰胺功能化配体一样有效地与催化抗体h38C2进行生物偶联，但MS-PODA片段具有明显的合成优势，使其具有很高的吸引力。
By exploiting a uniquely reactive lysine residue (Lys99) for site-specific attachment of small molecules, the humanized catalytic antibody h38C2 has been used as bioconjugation module in the assembly of chemically programmed antibodies and antibody-drug conjugates. Treatment of h38C2 with β-lactam-functionalized small molecules has been previously shown to result in covalent conjugation by selective formation of a stable amide bond with the ε-amino group of the Lys99 residue. Here we report that heteroaryl methylsulfonyl (MS-PODA)-functionalized small molecules represent an alternative bioconjugation strategy through highly efficient, site-specific, and stable arylation of the Lys99 residue. A set of chemically programmed antibodies and antibody-drug conjugates assembled by Lys99 arylation provided proof-of-concept for the therapeutic utility of this alternative bioconjugation strategy. While being equally effective as β-lactam-functionalized ligands for bioconjugation with catalytic antibody h38C2, the MS-PODA moiety offers distinct synthetic advantages, making it highly attractive.
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