Immunotoxins and Anticancer Drug Conjugate Assemblies: The Role of the Linkage between Components

Abstract

Immunotoxins and antibody-drug conjugates are protein-based drugs combining a target-specific binding domain with a cytotoxic domain. Such compounds are potentially therapeutic against diseases including cancer, and several clinical trials have shown encouraging results. Although the targeted elimination of malignant cells is an elegant concept, there are numerous practical challenges that limit conjugates’ therapeutic use, including inefficient cellular uptake, low cytotoxicity, and off-target effects. During the preparation of immunoconjugates by chemical synthesis, the choice of the hinge component joining the two building blocks is of paramount importance: the conjugate must remain stable in vivo but must afford efficient release of the toxic moiety when the target is reached. Vast efforts have been made, and the present article reviews strategies employed in developing immunoconjugates, focusing on the evolution of chemical linkers.

Antibody-Based Immunotoxins for the Treatment of Cancer

“…Although the abnormality of angiogenesis in cancer tumors increase their leakiness and cause accumulation of high molar weight molecules in the tumor area [8], the permeability of solid tumors is size-limited. Therefore, the potency of immunotoxins may be increased by lowering its molar weight.…”

“…Chimerization and humanization of MAbs have enhanced the clinical efficiency of murine MAbs and accelerated the rate of approvals for MAbs and classic monovalent antibody fragment (Fab) molecules for the treatment of cancer, and promoted the use of other small MAb fragments in the development of new treatments [6,7]. Despite the clinical success of therapeutic MAbs, naked antibodies, targeting cell surface tumor antigens expressed on carcinomas, are rarely potent enough by themselves, and thus are usually administered in combination with chemotherapy [8]. Several approaches were developed to solve this problem.…”

Brentuximab Vedotin: New Possibilities for Treatment of Relapses and Refractory Hodgkin’s Lymphomas

“…Противоопухолевая активность ММАЕ в доклинических исследованиях, проведенных на широкой панели клеточных линий опухолей человека, оказалась в 200 раз выше эффективности винбластина, одного из базовых препаратов для лечения ЛХ с анало-гичным механизмом воздействия на опухолевую клетку. Однако токсичность ММАЕ была столь же высокой, как и его эффективность, что стало препятствием для его непосредственного клинического применения [8]. Возможность использовать ММАЕ в клинической практике появилась только тогда, когда удалось создать конъюгат -соединить ММАЕ с моноклональным анти-CD30-антителом SGN-30 посредством линкера (рис.…”

Cytotoxic effect of the immunotoxin constructed of the ribosome-inactivating protein curcin and the monoclonal antibody against Her2 receptor on tumor cells

“…Thus, the characteristics of the targeting agent, the biodegradability of the linkage, and the potency of the bioactive anticancer agent are essential in the immunotoxins. 12,13) Immunotoxins have evolved with time and technology and can be divided into three generations. Firstgeneration immunotoxins were prepared by chemically coupling the whole toxins to antibodies; second-generation immunotoxins were produced by chemical conjugation but with modified toxins where the cell-binding domains were removed; and third-generation immunotoxins were made by recombinant DNA techniques and as a group are called recombinant immunotoxins.…”