Increased Tumor Penetration of Single-Domain Antibody-Drug Conjugates Improves In Vivo Efficacy in Prostate Cancer Models

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 therapeut...

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Veröffentlicht in:Cancer research (Chicago, Ill.) Ill.), 2020-03, Vol.80 (6), p.1268-1278
Hauptverfasser: 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
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container_end_page 1278
container_issue 6
container_start_page 1268
container_title Cancer research (Chicago, Ill.)
container_volume 80
creator 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
description 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 potency resulted in higher efficacy than other protein-drug conjugates. Biodistribution data, tumor histology images, spheroid experiments, 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 efficacy. In conclusion, these results provide evidence that reaching the maximum number of cells with a lethal payload dose correlates more strongly with efficacy than total tumor uptake or 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 than other agents with equal tumor uptake due to improved tissue penetration and cellular distribution.
doi_str_mv 10.1158/0008-5472.can-19-2295
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subjects Animals
Antineoplastic Agents, Alkylating - chemistry
Antineoplastic Agents, Alkylating - pharmacology
Antineoplastic Agents, Alkylating - therapeutic use
Cell Line, Tumor
Computer Simulation
Humans
Immunoconjugates - chemistry
Immunoconjugates - pharmacokinetics
Immunoconjugates - therapeutic use
Male
Mice
Microscopy, Confocal
Models, Biological
Prostatic Neoplasms - diagnostic imaging
Prostatic Neoplasms - drug therapy
Prostatic Neoplasms - pathology
Single-Domain Antibodies - chemistry
Single-Domain Antibodies - pharmacology
Single-Domain Antibodies - therapeutic use
Spheroids, Cellular
Structure-Activity Relationship
Tissue Distribution
Xenograft Model Antitumor Assays
title Increased Tumor Penetration of Single-Domain Antibody-Drug Conjugates Improves In Vivo Efficacy in Prostate Cancer Models
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