RESUMO
We report a general approach to engineering multivalent d-proteins with antibody-like activities in vivo. Mirror-image phage display and structure-guided design were utilized to create a d-protein that uses receptor mimicry to antagonize vascular endothelial growth factor A (VEGF-A). Selections against the d-protein form of VEGF-A using phage-displayed libraries of two different domain scaffolds yielded two proteins that bound distinct receptor interaction sites on VEGF-A. X-ray crystal structures of the d-protein/VEGF-A complexes were used to guide affinity maturation and to construct a heterodimeric d-protein VEGF-A antagonist with picomolar activity. The d-protein VEGF-A antagonist prevented vascular leakage in a rabbit eye model of wet age-related macular degeneration and slowed tumor growth in the MC38 syngeneic mouse tumor model with efficacies comparable to those of approved antibody drugs, and in contrast with antibodies, the d-protein was non-immunogenic during treatment and following subcutaneous immunizations.
Assuntos
Antineoplásicos/química , Neoplasias/tratamento farmacológico , Peptídeos/química , Receptores de Fatores de Crescimento do Endotélio Vascular/química , Vasos Retinianos/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Antineoplásicos/farmacologia , Bevacizumab/farmacologia , Sítios de Ligação , Avaliação Pré-Clínica de Medicamentos , Olho/efeitos dos fármacos , Feminino , Humanos , Camundongos , Modelos Moleculares , Biblioteca de Peptídeos , Peptídeos/farmacologia , Ligação Proteica , Conformação Proteica , Multimerização Proteica , Coelhos , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
With the growing importance of optical techniques in medical diagnosis and treatment, there exists a pressing need to develop and optimize materials platform for biophotonic applications. Particularly, the design of biocompatible and biodegradable materials with desired optical, mechanical, chemical, and biological properties is required to enable clinically relevant biophotonic devices for translating in vitro optical techniques into in situ and in vivo use. This technological trend propels the development of natural and synthetic polymeric biomaterials to replace traditional brittle, nondegradable silica glass based optical materials. In this review, we present an overview of the advances in polymeric optical material development, optical device design and fabrication techniques, and the accompanying applications to imaging, sensing and phototherapy.