Oncotarget

Research Papers:

In silico-designed mutations increase variable new-antigen receptor single-domain antibodies for VEGF165 neutralization

Dalia Millán-Gómez, Salvador Dueñas, Patricia L. A. Muñoz, Tanya Camacho-Villegas, Carolina Elosua, Olivia Cabanillas-Bernal, Teresa Escalante, Almudena Perona, David Abia, Florian Drescher, Pierrick G.J. Fournier, Marco A. Ramos, Rosa E. Mares, Jorge Paniagua-Solis, Teresa Mata-Gonzalez, Jorge Gonzalez-Canudas, Robert M. Hoffman, Alexei Licea-Navarro and Noemí Sánchez-Campos _

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Oncotarget. 2018; 9:28016-28029. https://doi.org/10.18632/oncotarget.25549

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Abstract

Dalia Millán-Gómez1, Salvador Dueñas1, Patricia L.A. Muñoz2, Tanya Camacho-Villegas3, Carolina Elosua4, Olivia Cabanillas-Bernal1, Teresa Escalante5, Almudena Perona6, David Abia6, Florian Drescher1, Pierrick G.J. Fournier1, Marco A. Ramos2, Rosa E. Mares2, Jorge Paniagua-Solis4, Teresa Mata-Gonzalez7, Jorge Gonzalez-Canudas7, Robert M. Hoffman8,9, Alexei Licea-Navarro1 and Noemí Sánchez-Campos1

1Departamento de Innovación Biomédica, Centro de Investigación Científica y de Educación Superior de Ensenada (CICESE), Ensenada, Baja California, México

2Facultad de Ciencias Químicas e Ingeniería, Universidad Autónoma de Baja California, Tijuana, Baja California, México

3CONACYT- Unidad de Biotecnología Médica y Farmacéutica, Centro de Investigación y Asistencia en Tecnología y Diseño Del Estado de Jalisco (CIATEJ), Guadalajara, Jalisco, México

4Teraclon IDF, Parque Científico de Madrid, Tres Cantos, Madrid, Spain

5Instituto Clodomiro Picado, Facultad de Microbiología, Universidad de Costa Rica, San José, Costa Rica

6Grupo de Biotecnología Aplicada, Universidad Europea de Madrid, Madrid, Spain

7Laboratorios Silanes S.A. de C.V., Ciudad de México, México

8AntiCancer Inc., San Diego, CA, USA

9Department of Surgery, University of California, San Diego, CA, USA

Correspondence to:

Noemí Sánchez-Campos, email: [email protected]

Alexei Licea-Navarro, email: [email protected]

Keywords: VNAR; shark antibody; VEGF neutralization; in silico mutation; angiogenesis

Received: November 16, 2017     Accepted: May 14, 2018     Published: June 15, 2018

ABSTRACT

The stability, binding, and tissue penetration of variable new-antigen receptor (VNAR) single-domain antibodies have been tested as part of an investigation into their ability to serve as novel therapeutics. V13 is a VNAR that recognizes vascular endothelial growth factor 165 (VEGF165). In the present study V13 was used as a parental molecule into which we introduced mutations designed in silico. Two of the designed VNAR mutants were expressed, and their ability to recognize VEGF165 was assessed in vitro and in vivo. One mutation (Pro98Tyr) was designed to increase VEGF165 recognition, while the other (Arg97Ala) was designed to inhibit VEGF165 binding. Compared to parental V13, the Pro98Tyr mutant showed enhanced VEGF165 recognition and neutralization, as indicated by inhibition of angiogenesis and tumor growth. This molecule thus appears to have therapeutic potential for neutralizing VEGF165 in cancer treatment.


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