The development of immunoconjugates for targeted cancer therapy

Abstract

Immunoconjugates are specific, highly effective, minimally toxic anticancer therapies that are beginning to show promise in the clinic. Immunoconjugates consist of three separate components: an antibody that binds to a cancer cell antigen with high specificity, an effector molecule that has a high capacity to kill the cancer cell, and a linker that will ensure the effector does not separate from the antibody during transit and will reliably release the effector to the cancer cell or tumour stroma. The high affinity antibody-antigen interaction allows specific and selective delivery of a range of effectors, including pharmacologic agents, radioisotopes, and toxins, to cancer cells. Some anticancer molecules are not well tolerated when administered systemically owing to unacceptable toxicity to the host. However, this limitation can be overcome through the linking of such cytotoxins to specific antibodies, which mask the toxic effects of the drug until it reaches its target. Conversely, many unconjugated antibodies are highly specific for a cancer target, but have low therapeutic potential and can be repurposed as delivery vehicles for highly potent effectors. In this Review, we summarize the successes and shortcomings of immunoconjugates, and discuss the future potential for the development of these therapies.

Figure 1

Immunoconjugate modules. Immunoconjugates are composed of three different components: a monoclonal antibody, a therapeutic entity, and a linker that joins the antibody and the therapeutic agent. Using this basic immunoconjugate model, different therapeutic entities, including pharmacologics, radioactive agents, and toxins, can be delivered to the cancer cells.

Figure 2

Immunoconjugates structure. a | IgG is the typical antibody component of the immunoconjugate. The Fa domain of the antibody is responsible for the antigen binding. Through the use of various display technologies, the Fv molecules, composed of variable-heavy (V_H) and variable-light (V_L) chains, can be designed to achieve high antigen affinity. The Fc-region glycan, through point mutation or glycan modification, can be modified in immunoconjugate synthesis to link a therapeutic molecule for delivery to a cancer cell. b | Enzymatically cleaved antibody fragments such as Fab' or F(ab')₂ and their recombinantly designed counterparts are smaller than typical IgG, and thus are cleared more rapidly. c | Genetically engineered antibody-based molecules based on a single chain Fv (scFv) composed of the variable domains (V_H and V_L) of an antibody, combined or altered to construct a wide array of recombinant molecules including (scFV)₂, minibody, diabody, triabody and tetrabody. Many of these constructs are small enough to achieve highly selective tumour targeting, with potentials for both therapy and imaging applications.

Figure 3

Internalization process. a | Immunoconjugates with non-cleavable linkers are internalized once the antibody binds to the antigen on the cell surface. Release of the therapeutic entity requires complete digestion of the antibody inside the lysosome. A thioether bond (see inset) is an example of a non-cleavable linker. b | Immunoconjugates with cleavable linkers are internalized once the antibody binds to the antigen on the cell surface. Release of the therapeutic is achieved by cleavage of the linker. Hydrazone bonds and disulfide bonds (see inset) are examples of commonly employed cleavable linkers. c | Immunoconjugates with cleavable linkers in some cases will undergo cleavage extracellularly, once bound to the cancer cell antigen, with the therapeutic entity undergoing internalization after being released.