Panikar Sandeep Surendra, Berry Na-Keysha, Shmuel Shayla, Keltee Nai, Pereira Patrícia M R
Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
bioRxiv. 2023 Nov 6:2023.09.05.556426. doi: 10.1101/2023.09.05.556426.
Antibody-drug conjugates (ADCs) have emerged as promising therapeutics for cancer treatment; however, their effectiveness has been limited by single antigen targeting, potentially leading to resistance mechanisms triggered by tumor compensatory pathways or reduced expression of the target protein. Here, we present antibody-ADC click, an approach that harnesses bioorthogonal click chemistry for dual receptor targeting, irrespective of the levels of the tumor's expression of the ADC-targeting antigen. Antibody-ADC click enables targeting heterogeneity and enhances antibody internalization and drug delivery inside cancer cells, resulting in potent toxicity. We conjugated antibodies and ADCs to the bioorthogonal click moieties tetrazine (Tz) and trans-cyclooctene (TCO). Through sequential antibody administration in living biological systems, we achieved dual receptor targeting by clicking of antibody-TCO with antibody-Tz. We show that the clicked antibody therapy outperformed conventional ADC monotherapy or antibody combinations in preclinical models mimicking ADC-eligible, ADC-resistant, and ADC-ineligible tumors. Antibody-ADC click enables dual-antigen targeting without extensive antibody bioengineering, sustains tumor treatment, and enhances antibody-mediated cytotoxicity.
抗体药物偶联物（ADCs）已成为癌症治疗中颇具前景的疗法；然而，其有效性受到单一抗原靶向的限制，这可能会引发由肿瘤补偿途径或靶蛋白表达降低所触发的耐药机制。在此，我们介绍抗体 - ADC点击技术，这是一种利用生物正交点击化学进行双受体靶向的方法，无论肿瘤中ADC靶向抗原的表达水平如何。抗体 - ADC点击技术能够实现靶向异质性，并增强抗体在癌细胞内的内化和药物递送，从而产生强效毒性。我们将抗体和ADCs与生物正交点击基团四嗪（Tz）和反式环辛烯（TCO）偶联。通过在活体生物系统中顺序给药抗体，我们通过抗体 - TCO与抗体 - Tz的点击实现了双受体靶向。我们表明，在模拟适合ADC治疗、对ADC耐药和不适合ADC治疗的肿瘤的临床前模型中，点击抗体疗法优于传统的ADC单一疗法或抗体联合疗法。抗体 - ADC点击技术无需进行广泛的抗体生物工程改造就能实现双抗原靶向，维持肿瘤治疗效果，并增强抗体介导的细胞毒性。
