Abstract
Antibody drug conjugates (ADCs) have become an important modality of clinical cancer treatment. However, traditional ADCs have some limitations, such as reduced permeability in solid tumors due to the high molecular weight of monoclonal antibodies, difficulty in preparation and heterogeneity of products due to the high drug/antibody ratio (4–8 small molecules per antibody). Miniaturized ADCs may be a potential solution, although their short circulation half-life may lead to new problems. In this study, we propose a novel design strategy for miniaturized ADCs in which drug molecules and small ligand proteins are site-specifically coupled via a bifunctional poly(ethylene glycol) (PEG) chain. The results showed that the inserted PEG chains significantly prolonged the circulation half-life but also obviously reduced the cytotoxicity of the conjugates. Compared with the conjugate ZHER2-SMCC-MMAE (HM), which has no PEG insertion, ZHER2-PEG4K-MMAE (HP4KM) and ZHER2-PEG10K-MMAE (HP10KM) with 4 or 10 kDa PEG insertions have 2.5- and 11.2-fold half-life extensions and 4.5- and 22-fold in vitro cytotoxicity reductions, respectively. The combined effect leads to HP10KM having the most ideal tumor therapeutic ability at the same dosages in the animal model, and its off-target toxicity was also reduced by more than 4 times compared with that of HM. These results may indicate that prolonging the half-life is very helpful in improving the therapeutic capacity of miniaturized ADCs. In the future, the design of better strategies that can prolong half-life without affecting cytotoxicity may be useful for further improving the therapeutic potential of these molecules.
Highlights
Human epidermal growth factor receptor 2 (HER2), known as erbB-2, is a receptor tyrosine-protein kinase that belongs to the epidermal growth factor receptor family [1,2]
ZHER2:2891 and monomethyl auristatin E (MMAE) are located at the ends and connected by succinimidyl-trans-4-(N-maleimidylmethyl)cyclohexane-1-carboxylate (SMCC) or poly(ethylene glycol) (PEG) chains with bifunctional groups, i.e., maleimide and activated ester, which can react and efficiently with sulfhydryl and amine groups
A cysteine residue was introduced at the C-terminus of ZHER2:2891 for site-specific coupling based on the reaction between the sulfhydryl group and maleimide group
Summary
Human epidermal growth factor receptor 2 (HER2), known as erbB-2, is a receptor tyrosine-protein kinase that belongs to the epidermal growth factor receptor family [1,2] It is expressed at low levels in normal tissues but is expressed highly in many tumor tissues, such as breast, ovarian, prostate, and several gastric cancers [3], which makes it an effective target for tumor therapy [4]. The synthesized product molecules are often complex mixtures of multiple positional isomers with varied numbers of small molecules [12,13], which makes purification and quality control difficult To circumvent these limitations, new strategies for ADC drug design need to be developed
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