| DOI | Resolve DOI: https://doi.org/10.1016/j.bbrc.2021.05.030 |
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| Author | Search for: Henry, Kevin A.1ORCID identifier: https://orcid.org/0000-0003-0477-0558; Search for: Nguyen, Thanh-Dung1; Search for: Baral, Toya Nath1; Search for: Hussack, Greg1; Search for: Raphael, Shalini1; Search for: Arbabi-Ghahroudi, Mehdi1; Search for: Robert, Alma1; Search for: Durocher, Yves1; Search for: Wu, Cunle1; Search for: Jaramillo, Maria L.1; Search for: MacKenzie, C. Roger1 |
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| Affiliation | - National Research Council of Canada. Human Health Therapeutics
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| Funder | Search for: National Research Council of Canada |
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| Format | Text, Article |
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| Subject | single-domain antibody; nanobody; VHH; cancer; Axl; receptor tyrosine kinase; TAM family |
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| Abstract | Overexpression of Axl, a TAM-family receptor tyrosine kinase, plays key roles in the formation, growth, and spread of tumors as well as resistance to targeted therapies and chemotherapies. We identified novel llama VHHs against human Axl using multiple complementary phage display selection strategies and characterized a subset of high-affinity VHHs. The VHHs targeted multiple sites in Ig-like domains 1 and 2 of the Axl extracellular domain, including an immunodominant epitope overlapping the site of Gas6 interaction and two additional non-Gas6 competitive epitopes recognized by murine monoclonal antibodies. Only a subset of VHHs cross-reacted with cynomolgus monkey Axl and none recognized mouse Axl. As fusions to human IgG1 Fc, VHH-Fcs bound Axl+ tumor cell lines and mertansine-loaded VHH-Fcs were cytotoxic in vitro against Axl+ cells in proportion to their binding affinities. Engineered biparatopic VHH-VHH heterodimers bound Axl avidly, and a subset of molecules showed dramatically enhanced association rates indicative of intramolecular binding. These VHHs may have applications as modular elements of biologic drugs such as antibody-drug conjugates. |
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| Publication date | 2021-05-28 |
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| Publisher | Elsevier |
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| In | |
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| Language | English |
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| Peer reviewed | Yes |
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| Identifier | S0006291X21008019 |
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| Export citation | Export as RIS |
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| Report a correction | Report a correction (opens in a new tab) |
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| Record identifier | 6875c0a7-0ed5-4122-9ea2-81b34a675d11 |
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| Record created | 2022-09-23 |
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| Record modified | 2023-03-16 |
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