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Improving Intracellular Delivery of an Antibody-Drug Conjugate Targeting Carcinoembryonic Antigen Increases Efficacy at Clinically Relevant Doses In Vivo.
Nessler, Ian; Rubahamya, Baron; Kopp, Anna; Hofsess, Scott; Cardillo, Thomas M; Sathyanarayan, Nalini; Donnell, Jennifer; Govindan, Serengulam V; Thurber, Greg M.
Afiliação
  • Nessler I; Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan.
  • Rubahamya B; Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan.
  • Kopp A; Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan.
  • Hofsess S; Gilead Sciences, Inc., Morris Plains, New Jersey.
  • Cardillo TM; Gilead Sciences, Inc., Morris Plains, New Jersey.
  • Sathyanarayan N; Gilead Sciences, Inc., Morris Plains, New Jersey.
  • Donnell J; Gilead Sciences, Inc., Morris Plains, New Jersey.
  • Govindan SV; Gilead Sciences, Inc., Morris Plains, New Jersey.
  • Thurber GM; Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan.
Mol Cancer Ther ; 23(3): 343-353, 2024 Mar 04.
Article em En | MEDLINE | ID: mdl-37913500
Solid tumor antibody-drug conjugates (ADC) have experienced more clinical success in the last 5 years than the previous 18-year span since the first ADC approval in 2000. While recent advances in protein engineering, linker design, and payload variations have played a role in this success, high expression and readily internalized targets have also been crucial to solid tumor therapy. However, these factors are also paradoxically connected to poor tissue penetration and lower efficacy. Previous work shows that potent ADCs can benefit from slower internalization under subsaturating doses to improve tissue penetration and increase tumor response. In contrast, faster internalization is predicted to increase efficacy under higher, tumor saturating doses. In this work, the intracellular delivery of SN-38 conjugated to an anti-carcinoembryonic antigen (anti-CEA) antibody (Ab) is increased by coadministering a noncompeting (cross-linking) anti-CEA Ab to improve efficacy in a colorectal carcinoma animal model. The SN-38 payload enables broad tumor saturation with clinically-tolerable doses, and under these saturating conditions, using a second CEA receptor cross-linking Ab yields faster internalization, which increases tumor killing efficacy. Our spheroid results show indirect bystander killing can also occur, but the more efficient direct cell killing from targeted intracellular payload release drives a greater tumor response. These results provide a strategy to increase therapeutic effectiveness with improved intracellular delivery under tumor saturating doses with the potential to expand the ADC target repertoire.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Imunoconjugados / Antineoplásicos Limite: Animals Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Imunoconjugados / Antineoplásicos Limite: Animals Idioma: En Ano de publicação: 2024 Tipo de documento: Article