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Increased Tumor Penetration of Single-Domain Antibody-Drug Conjugates Improves In Vivo Efficacy in Prostate Cancer Models.
Nessler, Ian; Khera, Eshita; Vance, Steven; Kopp, Anna; Qiu, Qifeng; Keating, Thomas A; Abu-Yousif, Adnan O; Sandal, Thomas; Legg, James; Thompson, Lorraine; Goodwin, Normann; Thurber, Greg M.
Afiliação
  • Nessler I; Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan.
  • Khera E; Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan.
  • Vance S; Crescendo Biologics, Cambridge, United Kingdom.
  • Kopp A; Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan.
  • Qiu Q; ImmunoGen, Waltham, Massachusetts.
  • Keating TA; ImmunoGen, Waltham, Massachusetts.
  • Abu-Yousif AO; Takeda Pharmaceuticals, Cambridge, Massachusetts.
  • Sandal T; Crescendo Biologics, Cambridge, United Kingdom.
  • Legg J; Crescendo Biologics, Cambridge, United Kingdom.
  • Thompson L; Crescendo Biologics, Cambridge, United Kingdom.
  • Goodwin N; Crescendo Biologics, Cambridge, United Kingdom.
  • Thurber GM; Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan. gthurber@umich.edu.
Cancer Res ; 80(6): 1268-1278, 2020 03 15.
Article em En | MEDLINE | ID: mdl-31941698
Targeted delivery of chemotherapeutics aims to increase efficacy and lower toxicity by concentrating drugs at the site-of-action, a method embodied by the seven current FDA-approved antibody-drug conjugates (ADC). However, a variety of pharmacokinetic challenges result in relatively narrow therapeutic windows for these agents, hampering the development of new drugs. Here, we use a series of prostate-specific membrane antigen-binding single-domain (Humabody) ADC constructs to demonstrate that tissue penetration of protein-drug conjugates plays a major role in therapeutic efficacy. Counterintuitively, a construct with lower in vitro potency resulted in higher in vivo efficacy than other protein-drug conjugates. Biodistribution data, tumor histology images, spheroid experiments, in vivo single-cell measurements, and computational results demonstrate that a smaller size and slower internalization rate enabled higher tissue penetration and more cell killing. The results also illustrate the benefits of linking an albumin-binding domain to the single-domain ADCs. A construct lacking an albumin-binding domain was rapidly cleared, leading to lower tumor uptake (%ID/g) and decreased in vivo efficacy. In conclusion, these results provide evidence that reaching the maximum number of cells with a lethal payload dose correlates more strongly with in vivo efficacy than total tumor uptake or in vitro potency alone for these protein-drug conjugates. Computational modeling and protein engineering can be used to custom design an optimal framework for controlling internalization, clearance, and tissue penetration to maximize cell killing. SIGNIFICANCE: A mechanistic study of protein-drug conjugates demonstrates that a lower potency compound is more effective in vivo than other agents with equal tumor uptake due to improved tissue penetration and cellular distribution.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias da Próstata / Imunoconjugados / Antineoplásicos Alquilantes / Anticorpos de Domínio Único / Modelos Biológicos Limite: Animals / Female / Humans / Male Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias da Próstata / Imunoconjugados / Antineoplásicos Alquilantes / Anticorpos de Domínio Único / Modelos Biológicos Limite: Animals / Female / Humans / Male Idioma: En Ano de publicação: 2020 Tipo de documento: Article