Preclinical assessment of a novel human antibody VH domain targeting mesothelin as an antibody-drug conjugate
© 2023 The Author(s)..
Mesothelin (MSLN) has been a validated tumor-associated antigen target for several solid tumors for over a decade, making it an attractive option for therapeutic interventions. Novel antibodies with high affinity and better therapeutic properties are needed. In the current study, we have isolated and characterized a novel heavy chain variable (VH) domain 3C9 from a large-size human immunoglobulin VH domain library. 3C9 exhibited high affinity (KD [dissociation constant] <3 nM) and binding specificity in a membrane proteome array (MPA). In a mouse xenograft model, 3C9 fused to human IgG1 Fc was detected at tumor sites as early as 8 h post-infusion and remained at the site for over 10 days. Furthermore, 3C9 fused to a human Fc domain drug conjugate effectively inhibited MSLN-positive tumor growth in a mouse xenograft model. The X-ray crystal structure of full-length MSLN in complex with 3C9 reveals interaction of the 3C9 domains with two distinctive residue patches on the MSLN surface. This newly discovered VH antibody domain has a high potential as a therapeutic candidate for MSLN-expressing cancers.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:31 |
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| Enthalten in: |
Molecular therapy oncolytics - 31(2023) vom: 19. Dez., Seite 100726 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Sun, Zehua [VerfasserIn] |
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| Links: |
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| Themen: |
ADC |
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| Anmerkungen: |
Date Revised 03.10.2023 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1016/j.omto.2023.09.002 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM362675872 |
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| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a © 2023 The Author(s). | ||
| 520 | |a Mesothelin (MSLN) has been a validated tumor-associated antigen target for several solid tumors for over a decade, making it an attractive option for therapeutic interventions. Novel antibodies with high affinity and better therapeutic properties are needed. In the current study, we have isolated and characterized a novel heavy chain variable (VH) domain 3C9 from a large-size human immunoglobulin VH domain library. 3C9 exhibited high affinity (KD [dissociation constant] <3 nM) and binding specificity in a membrane proteome array (MPA). In a mouse xenograft model, 3C9 fused to human IgG1 Fc was detected at tumor sites as early as 8 h post-infusion and remained at the site for over 10 days. Furthermore, 3C9 fused to a human Fc domain drug conjugate effectively inhibited MSLN-positive tumor growth in a mouse xenograft model. The X-ray crystal structure of full-length MSLN in complex with 3C9 reveals interaction of the 3C9 domains with two distinctive residue patches on the MSLN surface. This newly discovered VH antibody domain has a high potential as a therapeutic candidate for MSLN-expressing cancers | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a ADC | |
| 650 | 4 | |a MSLN | |
| 650 | 4 | |a VH domain | |
| 650 | 4 | |a in vivo distribution | |
| 650 | 4 | |a library | |
| 650 | 4 | |a structure | |
| 700 | 1 | |a Chu, Xiaojie |e verfasserin |4 aut | |
| 700 | 1 | |a Adams, Cynthia |e verfasserin |4 aut | |
| 700 | 1 | |a Ilina, Tatiana V |e verfasserin |4 aut | |
| 700 | 1 | |a Guerrero, Michel |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Guowu |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Chuan |e verfasserin |4 aut | |
| 700 | 1 | |a Jelev, Dontcho |e verfasserin |4 aut | |
| 700 | 1 | |a Ishima, Rieko |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Mellors, John W |e verfasserin |4 aut | |
| 700 | 1 | |a Calero, Guillermo |e verfasserin |4 aut | |
| 700 | 1 | |a Dimitrov, Dimiter S |e verfasserin |4 aut | |
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