Antibody fragments: hope and hype

Abstract

The antibody molecule is modular and separate domains can be extracted through biochemical or genetic means. It is clear from review of the literature that a wave of novel, antigen-specific molecular forms may soon enter clinical evaluation. This report examines the developmental histories of therapeutics derived from antigen-specific fragments of antibodies produced by recombinant processes. Three general types of fragments were observed, antigen-binding fragments (Fab), single chain variable fragments (scFv) and "third generation" (3G), each representing a successive wave of antibody fragment technology. In parallel, drug developers have explored multi-specificity and conjugation with exogenous functional moieties in all three fragment types. Despite high hopes and an active pipeline, enthusiasm for differentiating performance of fragments should, perhaps, be tempered as there are yet few data that suggest these molecules have distinct clinical properties due only to their size.

Figure 1

Antibody fragment types. Depiction of a full size antibody and various antibody fragment types. CH, constant heavy chain; CL, constant light chain; IgG, immunoglobulin; Fab, antigen binding fragment; scFv, single chain variable fragment, V_H, variable heavy chain; V_L, variable light chain. Source: Michael Hust, Technical University of Braunschweig. Figure used with permission.

Figure 2

Antibody probabilities of success. ‘Known fate’ is the percentage of candidates that were either FDA-approved or discontinued of those in a given cohort. Clinical phase transition probabilities were calculated as follows: the number of products that completed a given phase and entered the next was divided by the difference between the number of products that entered the phase and those that were still in the phase at the time of the calculation. Transitions occurring between phases of clinical studies conducted world-wide were included. The ‘cumulative rate’ is the percentage of FDA approved products of the total candidates with a known fate (FDA approved or discontinued).