Antibody Fragments

A full-length mAb consists of the constant Fc (crystallizable fragment) domain and an antigen-binding domain, comprising the Fv (variable fragment) and the Fab region (antibody binding fragment). Nevertheless, a full-length antibody with a glycosylated Fc domain is not necessary for antigen recognition. Therefore, some antibody drugs are developed as antibody fragments, where all or some parts of constant regions are eliminated while the essential antigen-binding region is preserved. In addition, fragment antibodies are emerging as great tools in imaging and diagnostics. There are many formats of antibody fragments. Among them, antigen-binding fragments (Fab) and single-chain variable fragments (scFV) are common antibody fragments that have been investigated.

Fig.1 Structure of a typical full-size IgG antibody molecule showing its various domains. (Rodrigo, 2015)

Types of Antibody Fragments

• Fab, Fab₂, and Fab₃

The Fab fragments are consisting of one constant and one inconstant domain of heavy and light chains, linked by an intramolecular disulfide bond. Genetic methods are also used to create bispecific Fab dimers (Fab₂) and trispecific Fab trimers (Fab₃).

• scFv, Diabody, Triabody, Tetrabody, Bis-scFv, Minibody

scFV fragments are recombinant molecules with the fusion of the varying areas of heavy and light chains through a short polypeptide linker. Except for fundamental scFv molecules, paired scFvs bind to one another through complementary regions to form bivalent molecules (diabodies), triabodies, or tetrabodies. Complementary scFvs themselves produce as a single chain (tandem scFvs or tascFvs), and bispecific tandem scFvs (bis-scFvs), among others. Minibodies are scFv-CH3 fusion proteins that assemble into bivalent dimers.

• Camelid/Shark Antibodies and sdAb

Single-domain antibodies, also known as sdAb, are small antigen-binding fragments that are derived from heavy chain only antibodies (HcAb) present in camelids (V_HH, from camels and llamas), and cartilaginous fishes (Ig_NAR, from sharks).

Fig.2 Schematic representation of different antibody formats. (Holliger, 2005)

Advantages of Antibody Fragments

The majority of antibody fragments currently being developed in the clinic are for oncological applications. Because of their smaller size as functional components of the whole molecule, antibody fragments have several advantages as therapeutics compared with full-size mAb therapeutics.

• Easier and less costly expression in microbial expression systems
• Penetrating tissues and tumors more rapidly and deeply than mAbs
• Short circulating half-lives
• Reducing the immunogenicity potential of antibody fragment-based drugs
• Availability of various in vitro display technologies to improve several characteristics of antibodies.

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References

1. Rodrigo, G.; et al. Antibody fragments and their purification by protein L affinity chromatography. Antibodies. 2015, 4(3): 259-277.
2. Holliger, P.; Hudson, P.J. Engineered antibody fragments and the rise of single domains. Nature biotechnology. 2005, 23(9): 1126-1136.