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Redirecting adenoviruses to tumour cells using therapeutic antibodies: Generation of a versatile human bispecific adaptor.

Abstract：

:Effective use of adenovirus-5 (Ad5) in cancer therapy is heavily dependent on the degree to which the virus's natural tropism can be subverted to one that favours tumour cells. This is normally achieved through either engineering of the viral fiber knob or the use of bispecific adaptors that display both adenovirus and tumour antigen receptors. One of the main limitations of these strategies is the need to tailor each engineering event to any given tumour antigen. Here, we explore bispecific adaptors that can utilise established anti-cancer therapeutic antibodies. Conjugates containing bacterially derived antibody binding motifs are efficient at retargeting virus to antibody targets. Here, we develop a humanized strategy whereby we synthesise a re-targeting adaptor based on a chimeric Ad5 ligand/antibody receptor construct. This adaptor acts as a molecular bridge analogous to therapeutic antibody mediated cross-linking of cytotoxic effector and tumour cells during immunotherapy. As a proof or principle, we demonstrate how this adaptor allows efficient viral recognition and entry into carcinoma cells through the therapeutic monoclonal antibodies Herceptin/trastuzumab and bavituximab. We show that targeting can be augmented by use of contemporary antibody enhancement strategies such as the selective elimination of competing serum IgG using "receptor refocusing" enzymes and we envisage that further improvements are achievable by enhancing the affinities between the adaptor and its ligands. Humanized bispecific adaptors offer the promise of a versatile retargeting technology that can exploit both clinically approved adenovirus and therapeutic antibodies.

journal_name

Mol Immunol

journal_title

Molecular immunology

authors

Vasiljevic S,Beale EV,Bonomelli C,Easthope IS,Pritchard LK,Seabright GE,Caputo AT,Scanlan CN,Dalziel M,Crispin M

doi

10.1016/j.molimm.2015.08.014

subject

Has Abstract

pub_date

2015-12-01 00:00:00

pages

234-43

issue

2 Pt A

eissn

0161-5890

issn

1872-9142

pii

S0161-5890(15)30062-6

journal_volume

68

pub_type

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