The Analysis of Key Factors Related to ADCs Structural Design

Abstract

Antibody–drug conjugates (ADCs) have developed rapidly in recent decades. However, it is complicated to map out a perfect ADC that requires optimization of multiple parameters including antigens, antibodies, linkers, payloads, and the payload-linker linkage. The therapeutic targets of the ADCs are expected to express only on the surface of the corresponding target tumor cells. On the contrary, many antigens usually express on normal tissues to some extent, which could disturb the specificity of ADCs and limit their clinical application, not to mention the antibody is also difficult to choose. It requires to not only target and have affinity with the corresponding antigen, but it also needs to have a linkage site with the linker to load the payloads. In addition, the linker and payload are indispensable in the efficacy of ADCs. The linker is required to stabilize the ADC in the circulatory system and is brittle to release free payload while the antibody combines with antigen. Also, it is a premise that the dose of ADCs will not kill normal tissues and the released payloads are able to fulfill the killing potency in tumor cells at the same time. In this review, we mainly focus on the latest development of key factors affecting ADCs progress, including the selection of antibodies and antigens, the optimization of payload, the modification of linker, payload-linker linkage, and some other relevant parameters of ADCs.

Targeting Vesicular LGALS3BP by an Antibody-Drug Conjugate as Novel Therapeutic Strategy for Neuroblastoma

“…Classically, monoclonal antibodies (mAb) with high internalization capacity have been used in ADC development, as they mediate efficient delivery of the conjugated toxins inside target tumor cells. However, recent studies have revealed that ADCs can also be generated using non-internalizing antibodies [ 26 ], targeting the tumor or its stroma [ 27 , 28 , 29 ]. In the present study, we investigated the therapeutic potential of an ADC targeting exosomal LGALS3BP, consisting of 1959-sss, an engineered humanized anti-LGALS3BP antibody, where the residual cysteines of the light chains was directly coupled to the maytansinoid SH-DM3, through formation of a disulfide bridge [ 30 ].…”

Rapid conjugation of antibodies to toxins to select candidates for the development of anticancer Antibody-Drug Conjugates (ADCs)

“…When choosing a target for ADC development, it is important to differentiate between antigens that do not internalize upon antibody binding, antigens that internalize with the antibody but rapidly recycle to the cell membrane and antigens that get internalized without rapid recycling of the antibody (Fig. 5a) 23 . Only the latter option is a valuable target for ADC development so the antibody can act as a vehicle to specifically deliver payloads to cells expressing the target of interest 24 .…”

Advances in Antibody–Drug Conjugate Design: Current Clinical Landscape and Future Innovations

“…These latter properties can be tailored through the use of different IgG isotypes and mutations in the Fc portion of the antibody. 142,143 More recently, innovations related to the site of conjugation of the payload on the antibody have been addressed.…”