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Human Antibody V(H) Domains Targeting GPNMB and VCAM-1 as Candidate Therapeutics for Cancers

[Image: see text] The elevated expression of GPNMB and VCAM-1 has been observed in many cancers including breast cancer, melanoma, and prostate cancers. Such overexpression of GPNMB and VCAM-1 has been associated with poor prognosis and increased cancer metastasis. Thus, GPNMB and VCAM-1 are potenti...

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Autores principales: Chu, Xiaojie, Li, Wei, Hines, Margaret G., Lyakhov, Ilya, Mellors, John W., Dimitrov, Dimiter S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2023
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10155206/
https://www.ncbi.nlm.nih.gov/pubmed/37067377
http://dx.doi.org/10.1021/acs.molpharmaceut.3c00173
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author Chu, Xiaojie
Li, Wei
Hines, Margaret G.
Lyakhov, Ilya
Mellors, John W.
Dimitrov, Dimiter S.
author_facet Chu, Xiaojie
Li, Wei
Hines, Margaret G.
Lyakhov, Ilya
Mellors, John W.
Dimitrov, Dimiter S.
author_sort Chu, Xiaojie
collection PubMed
description [Image: see text] The elevated expression of GPNMB and VCAM-1 has been observed in many cancers including breast cancer, melanoma, and prostate cancers. Such overexpression of GPNMB and VCAM-1 has been associated with poor prognosis and increased cancer metastasis. Thus, GPNMB and VCAM-1 are potential targets for immunotherapies across multiple cancers. In this study, two high-affinity specific human V(H) domain antibody candidates, 87 (GPNMB) and 1B2 (VCAM-1), were isolated from our in-house proprietary phage-displayed human V(H) antibody domain libraries. The avidity was increased after conversion to VH-Fc. Domain-based bispecific T-cell engagers (DbTE) based on these two antibodies combined with the anti-CD3ε OKT3 antibody exhibited potent killing against GPNMB and VCAM-1-positive cancer cells, respectively. Hence, these two domain antibodies are promising therapeutic candidates for cancers expressing GPNMB or VCAM-1.
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spelling pubmed-101552062023-05-04 Human Antibody V(H) Domains Targeting GPNMB and VCAM-1 as Candidate Therapeutics for Cancers Chu, Xiaojie Li, Wei Hines, Margaret G. Lyakhov, Ilya Mellors, John W. Dimitrov, Dimiter S. Mol Pharm [Image: see text] The elevated expression of GPNMB and VCAM-1 has been observed in many cancers including breast cancer, melanoma, and prostate cancers. Such overexpression of GPNMB and VCAM-1 has been associated with poor prognosis and increased cancer metastasis. Thus, GPNMB and VCAM-1 are potential targets for immunotherapies across multiple cancers. In this study, two high-affinity specific human V(H) domain antibody candidates, 87 (GPNMB) and 1B2 (VCAM-1), were isolated from our in-house proprietary phage-displayed human V(H) antibody domain libraries. The avidity was increased after conversion to VH-Fc. Domain-based bispecific T-cell engagers (DbTE) based on these two antibodies combined with the anti-CD3ε OKT3 antibody exhibited potent killing against GPNMB and VCAM-1-positive cancer cells, respectively. Hence, these two domain antibodies are promising therapeutic candidates for cancers expressing GPNMB or VCAM-1. American Chemical Society 2023-04-17 /pmc/articles/PMC10155206/ /pubmed/37067377 http://dx.doi.org/10.1021/acs.molpharmaceut.3c00173 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Chu, Xiaojie
Li, Wei
Hines, Margaret G.
Lyakhov, Ilya
Mellors, John W.
Dimitrov, Dimiter S.
Human Antibody V(H) Domains Targeting GPNMB and VCAM-1 as Candidate Therapeutics for Cancers
title Human Antibody V(H) Domains Targeting GPNMB and VCAM-1 as Candidate Therapeutics for Cancers
title_full Human Antibody V(H) Domains Targeting GPNMB and VCAM-1 as Candidate Therapeutics for Cancers
title_fullStr Human Antibody V(H) Domains Targeting GPNMB and VCAM-1 as Candidate Therapeutics for Cancers
title_full_unstemmed Human Antibody V(H) Domains Targeting GPNMB and VCAM-1 as Candidate Therapeutics for Cancers
title_short Human Antibody V(H) Domains Targeting GPNMB and VCAM-1 as Candidate Therapeutics for Cancers
title_sort human antibody v(h) domains targeting gpnmb and vcam-1 as candidate therapeutics for cancers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10155206/
https://www.ncbi.nlm.nih.gov/pubmed/37067377
http://dx.doi.org/10.1021/acs.molpharmaceut.3c00173
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