Developments in therapy with monoclonal antibodies and related proteins

Abstract

Monoclonal antibody therapeutics have been approved for over 30 targets and diseases, most commonly cancer. Antibodies have become the new backbone of the pharmaceutical industry, which previously relied on small molecules. Compared with small molecules, monoclonal antibodies (mAbs) have exquisite target selectivity and hence less toxicity as a result of binding other targets. The clinical value of both mAbs and ligand traps has been proven. New applications of mAbs are being tested and mAbs have now been designed to target two (bi-specific, eg TNF-α and IL-17) or more targets simultaneously, augmenting their therapeutic potential. Because of space limitations and the wide ranging scope of this review there are regrettably, but inevitably, omissions and missing citations. We have chosen to highlight the first successes in inflammatory diseases and cancer, but a broader overview of approved mAbs and related molecules can be found in Table 1.

Keywords: Biologic therapy; cancer; inflammation; monoclonal antibodies; traps.

Fig 1.

Monoclonal antibodies. A – antibody structure showing light (L) and heavy (H) chains with variable (V_L, V_H) and constant (C_L, C_H) regions, which are connected by inter-chain disulphide bonds. Antigen binding (green symbol) occurs at V_H/V_L domains, while effector functions are mediated via the Fc (C_H) portion. B – increasing the amount of human sequences in a murine antibody decreases immunogenic potential. C – on an antibody-drug conjugate (ADC, cytotoxic drugs (orange, red stars) can be linked stochastically to lysine (Lys) residues or on cysteine residues either through reduction of inter-chain disulphides (Cys) or by engineering in cysteines at select conjugation sites (site-specific).

Fig 2.

Strategy and key steps for development of trastuzumab, from target discovery to in vitro and in vivo proof of concept studies. HER2 = human epidermal growth factor receptor 2; TNF = tumour necrosis factor

Fig 3.

Emerging antibody technologies. A – derivatives of classical mAbs: scFv, Fab, and F-Cab antibody formats; B – engineered bi-specific mAbs: structure and mechanism of a bi-specific T-cell engaging (BiTE) antibody; C – novel mAb frameworks: unique structure of camelid antibodies. mAb = monoclonal antibody