Antibodies as Magic Bullets

Little, Melvyn

doi:10.1007/978-3-030-72599-0_7

Antibodies for Treating Cancer 2021

DOI: 10.1007/978-3-030-72599-0_7

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Antibodies as Magic Bullets

Melvyn Little¹

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Cited by 2 publications

(2 citation statements)

References 26 publications

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“…2 Tumor-targeting antibodies have been exploited for the selective delivery of highly potent cytotoxic payloads to tumor lesions. 3 Thirteen antibody−drug conjugate (ADC) products gained marketing authorization for the treatment of patients with a variety of solid and liquid cancers. 4 The therapeutic performance of ADCs is hampered by their slow extravasation, heterogeneous diffusion in solid tumors, and significant liver uptake at early and late time points after systemic administration.…”

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confidence: 99%

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A Comparative Analysis of Fibroblast Activation Protein-Targeted Small Molecule–Drug, Antibody–Drug, and Peptide–Drug Conjugates

et al. 2023

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We present the first in vivo comparative evaluation of chemically defined antibody–drug conjugates (ADCs), small molecule–drug conjugates (SMDCs), and peptide–drug conjugates (PDCs) targeting and activated by fibroblast activation protein (FAP) in solid tumors. Both the SMDC (OncoFAP-Gly-Pro-MMAE) and the ADC (7NP2-Gly-Pro-MMAE) candidates delivered high amounts of active payload (i.e., MMAE) selectively at the tumor site, thus producing a potent antitumor activity in a preclinical cancer model.

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mentioning

confidence: 99%

“…Tumor-targeting antibodies have been exploited for the selective delivery of highly potent cytotoxic payloads to tumor lesions . Thirteen antibody–drug conjugate (ADC) products gained marketing authorization for the treatment of patients with a variety of solid and liquid cancers .…”

mentioning

confidence: 99%

A Comparative Analysis of Fibroblast Activation Protein-Targeted Small Molecule–Drug, Antibody–Drug, and Peptide–Drug Conjugates

et al. 2023

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Fibroblast Activation Protein Triggers Release of Drug Payload from Non-internalizing Small Molecule Drug Conjugates in Solid Tumors

Zana

Galbiati

Gilardoni

et al. 2022

Clinical Cancer Research

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Purpose: Small Molecule-Drug Conjugates (SMDCs) are modular anti-cancer pro-drugs that include a tumor-targeting small organic ligand, a cleavable linker and a potent cytotoxic agent. Most of the SMDC products that have been developed for clinical applications target internalizing tumor-associated antigens on the surface of tumor cells. We have recently described a novel non-internalizing small organic ligand (named OncoFAP) of Fibroblast Activation Protein (FAP), a tumor-associated antigen highly expressed in the stroma of most of solid human malignancies. Experimental Design: In this article, we describe a new series of OncoFAP-Drug derivatives based on monomethyl auristatin E (MMAE, a potent cytotoxic tubulin poison) and dipeptide linkers that are selectively cleaved by FAP in the tumor microenvironment. Results: The tumor targeting potential of OncoFAP was confirmed in cancer patients using Nuclear Medicine procedures. We used mass spectrometry methodologies in order to quantify the amount of pro-drug delivered to tumors and normal organs, as well as the efficiency of the drug release process. Linkers previously exploited for anticancer drug conjugates were used as benchmark. We identified OncoFAP-Gly-Pro-MMAE as the best performing SMDC, which has now been prioritized for further clinical development. OncoFAP-Gly-Pro-MMAE selectively delivered more than 10% injected dose per gram of MMAE to FAP-positive tumors, with a tumor-to-kidney ratio of 16:1 at 24-hours post-injection. Conclusions: The FAP-specific drug conjugates described in this article promise to be efficacious for the targeting of human malignancies. The extracellular release of potent anticancer payloads mediates durable complete remission in difficult-to-treat animal models of cancer.

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Antibodies as Magic Bullets

Cited by 2 publications

References 26 publications

A Comparative Analysis of Fibroblast Activation Protein-Targeted Small Molecule–Drug, Antibody–Drug, and Peptide–Drug Conjugates

A Comparative Analysis of Fibroblast Activation Protein-Targeted Small Molecule–Drug, Antibody–Drug, and Peptide–Drug Conjugates

Fibroblast Activation Protein Triggers Release of Drug Payload from Non-internalizing Small Molecule Drug Conjugates in Solid Tumors

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