Single-Domain Antibodies and the Promise of Modular Targeting in Cancer Imaging and Treatment

IEZZI, MARÍA ELENA; POLICASTRO, LUCÍA; WERBAJH, SANTIAGO; PODHAJCER, OSVALDO; CANZIANI, GABRIELA ALICIA

Frontiers in Immunology

Frontiers Media

Año: 2018 vol. 9

Monoclonal antibodies and their fragments have significantly changed the outcomeof cancer in the clinic, effectively inhibiting tumor cell proliferation, triggering antibodydependentimmune effector cell activation and complement mediated cell death. Alongwith a continued expansion in number, diversity, and complexity of validated tumor targetsthere is an increasing focus on engineering recombinant antibody fragments for leaddevelopment. Single-domain antibodies (sdAbs), in particular those engineered from thevariable heavy-chain fragment (VHH gene) found in Camelidae heavy-chain antibodies(or IgG2 and IgG3), are the smallest fragments that retain the full antigen-binding capacityof the antibody with advantageous properties as drugs. For similar reasons, growingattention is being paid to the yet smaller variable heavy chain new antigen receptor(VNAR) fragments found in Squalidae. sdAbs have been selected, mostly from immuneVHH libraries, to inhibit or modulate enzyme activity, bind soluble factors, internalize cellmembrane receptors, or block cytoplasmic targets. This succinct review is a compilationof recent data documenting the application of engineered, recombinant sdAb in theclinic as epitope recognition ?modules? to build monomeric, dimeric and multimericligands that target, tag and stall solid tumor growth in vivo. Size, affinity, specificity, andthe development profile of sdAbs drugs are seemingly consistent with desirable clinicalefficacy and safety requirements. But the hepatotoxicity of the tetrameric anti-DR5-VHHdrug in patients with pre-existing anti-drug antibodies halted the phase I clinical trial andcalled for a thorough pre-screening of the immune and poly-specific reactivities of thesdAb leads.