New Technologies Bloom Together for Bettering Cancer Drug Conjugates

Abstract

Drug conjugates, including antibody-drug conjugates, are a step toward realizing Paul Ehrlich's idea from over 100 years ago of a "magic bullet" for cancer treatment. Through balancing selective targeting molecules with highly potent payloads, drug conjugates can target specific tumor microenvironments and kill tumor cells. A drug conjugate consists of three parts: a targeting agent, a linker, and a payload. In some conjugates, monoclonal antibodies act as the targeting agent, but new strategies for targeting include antibody derivatives, peptides, and even small molecules. Linkers are responsible for connecting the payload to the targeting agent. Payloads impact vital cellular processes to kill tumor cells. At present, there are 12 antibody-drug conjugates on the market for different types of cancers. Research on drug conjugates is increasing year by year to solve problems encountered in conjugate design, such as tumor heterogeneity, poor circulation, low drug loading, low tumor uptake, and heterogenous expression of target antigens. This review highlights some important preclinical research on drug conjugates in recent years. We focus on three significant areas: improvement of antibody-drug conjugates, identification of new conjugate targets, and development of new types of drug conjugates, including nanotechnology. We close by highlighting the critical barriers to clinical translation and the open questions going forward. SIGNIFICANCE STATEMENT: The development of anticancer drug conjugates is now focused in three broad areas: improvements to existing antibody drug conjugates, identification of new targets, and development of new conjugate forms. This article focuses on the exciting preclinical studies in these three areas and advances in the technology that improves preclinical development.

Graphical abstract

Fig. 1

History, progress, and research stages of drug conjugates.

Fig. 2

ADC antibody engineering to optimize internalization rate. Classic ADC antibodies have two of the same antigen recognition sites that can recognize and bind to two molecules of the target epitope at the exact location on each molecule. The internalization rate is mainly determined by the properties of the antigen. Bispecific antibodies have two different antigen recognition sites that can recognize and bind to two different target antigens: one is a tumor target antigen with low internalization, and the other is an antigen with high internalization. The biepitope antibodies have two different antigen recognition sites that can recognize and bind to two different epitopes on the same antigen molecule. Antibody binding to different epitopes on one antigen may change the internalization rate and promote internalization and/or penetration of the ADC into tumor cells.

Fig. 3

Schematic diagram and features of some new linker technologies tested in ADC design.

Fig. 4

The chemical structures and characteristics of new linker technologies mentioned in this section.

Fig. 5

The chemical structures of payloads mentioned in this section.

Fig. 6

Schematic diagram and features of some novel drug conjugates tested in preclinical studies.

Fig. 7

Schematic diagram of the mechanism of pHLIP-drug conjugate (pHDC). In a neutral environment (normal-cell extracellular matrix), pHDCs can circulate on the extracellular matrix or cling to the cell membrane and finally achieve a dynamic balance. However, in an acidic environment (tumor-cell extracellular matrix), pHDCs penetrate the cell membrane. The section conjugated with the payload is exposed to the intracellular cytoplasm. The linker can sense the environment difference and break to release the payload. Such linkers include disulfide linkers, which can be cleaved by intracellular reduced glutathione.

Fig. 8

Diagram of ADCNs. These conjugates can self-assemble into nanoparticles via hydrophobicity and hydrophilicity interactions of the payload, linker, and antibody. ADCNs can carry plenty of payloads inside the nanoparticle (very high DAR) and display antibodies on their surface for targeted delivery.