Multivalency: the hallmark of antibodies used for optimization of tumor targeting by design

Abstract

High-precision tumor targeting with conventional therapeutics is based on the concept of the ideal drug as a "magic bullet"; this became possible after techniques were developed for production of monoclonal antibodies (mAbs). Innovative DNA technologies have revolutionized this area and enhanced clinical efficiency of mAbs. The experience of applying small-size recombinant antibodies (monovalent binding fragments and their derivatives) to cancer targeting showed that even high-affinity monovalent interactions provide fast blood clearance but only modest retention time on the target antigen. Conversion of recombinant antibodies into multivalent format increases their functional affinity, decreases dissociation rates for cell-surface and optimizes biodistribution. In addition, it allows the creation of bispecific antibody molecules that can target two different antigens simultaneously and do not exist in nature. Different multimerization strategies used now in antibody engineering make it possible to optimize biodistribution and tumor targeting of recombinant antibody constructs for cancer diagnostics and therapy.

Targeting cancer cells by using an antireceptor antibody-photosensitizer fusion protein

“…scFv antibody fragments are ideal for use as targeting moieties in selective delivery applications and offer significant advantages over full-size antibodies because of their smaller size and rational design (20,21). Using a rational approach to the recombinant protein construction, we studied molecular structures of both proteins.…”

“…The latter consideration can be important to avoid spatial constraints that could interrupt proper folding of fused 4D5scFv fragment. It is well known that conversion of scFv antibody fragments into multivalent format increases their functional affinity and decreases cell surface dissociation rates (20). Considering the intrinsic dimeric nature of KillerRed, we exploit it to design a bivalent supramolecular construct (Fig.…”

A fibronectin scaffold approach to bispecific inhibitors of epidermal growth factor receptor and insulin-like growth factor-I receptor

“…The ability to combine multiple activities into a single molecular entity has the potential to improve therapeutic outcomes, simplifying drug development and improving patient compliance. 1 Targeting multiple essential pathways that drive cell growth and survival may enhance the spectrum of treatable tumor types or increase treatment response by limiting the impact of resistance mechanisms. 2 The design of a dual specific antibody targeting human epidermal growth factor receptor 2 (HER2 or Erb-B2) and vascular endothelial growth factor (VEGF) by the mutation Engineered domains of human fibronectin (Adnectins TM ) were used to generate a bispecific Adnectin targeting epidermal growth factor receptor (EGFR) and insulin-like growth factor-I receptor (IGF-IR), two transmembrane receptors that mediate proliferative and survival cell signaling in cancer.…”

“…6 Bispecific or multi-specific single molecular entities could avoid the increased time and higher cost associated with clinical evaluation of separate biologics and provide equivalent or greater potencies at lower doses compared to antibody combinations. 1,7 ©2 0 1 1 L a n d e s B i o s c i e n c e .…”

Feasibility study of the optical imaging of a breast cancer lesion labeled with upconversion nanoparticle biocomplexes

“…A recombinant scFv4D5 mini-antibody is an example of such a high-efficiency HER2/neu-targeting vector that represents a single chain variable fragment of immunoglobulin (Ig) and exhibits lower cross-reactivity and immunogenicity in comparison with the corresponding full-size antibody. 7 The use of contrast agents, exploiting their fluorescent or, more generally, luminescent properties, is widespread in biomedical optical imaging. These luminescent molecular probes allow high-sensitivity and high-resolution imaging, since the absorbed excitation light is re-emitted as luminescence in a different spectral band, which can be spectrally discriminated from the excitation light and also from intrinsic tissue fluorescence termed autofluorescence.…”