Abstract
Antibody drug conjugates (ADCs), consisting of a cancer-specific antibody and cytotoxic payload, are shown to be a potent class of anticancer therapeutics, with enhanced therapeutic efficacy and reduced “off-target” side effects. However, the therapeutic window of ADCs is narrowed by problems such as difficulty in site-specific conjugation of payload, changes in antibody stability due to payload conjugation, and difficulty in tissue penetration. In this respect, aptamers have advantages in drug-delivery, as they can be easily and stably conjugated with cytotoxic drugs. We previously reported that oligobody, an aptamer-antibody complex, is a novel delivery method for aptamer-based therapeutics. In the current study, we describe DOligobody, a drug-conjugated oligobody comprising an aptamer-drug conjugate and an antibody. A cotinine-conjugated anti-HER2 aptamer (cot-HER2apt) was specifically bound to HER2-positive NCI-N87 cells, and underwent receptor-mediated endocytosis. Further, HER2-DOligobody, a cot-HER2apt-conjugated monomethyl auristatin E (cot-HER2apt-MMAE) oligobody, inhibited the growth of HER2-positive NCI-N87 cells. Finally, systemic administration of HER2-DOligobody significantly reduced tumor growth in a xenograft mouse model. Taken together, these results suggest that our DOligobody strategy may be a powerful platform for rapid, low-cost and effective cancer therapy.
Highlights
Cytotoxic chemotherapies inhibit cell division and are being widely used for various types of cancer [1]
We developed DOligobody, a drug-conjugated oligobody composed of an aptamer—drug conjugate and antibody
We demonstrated that the conjugate takes advantage of beneficial aspects of both the aptamers and Antibody drug conjugates (ADCs)
Summary
Cytotoxic chemotherapies inhibit cell division and are being widely used for various types of cancer [1]. ADCs are recognized as one of the most promising tools for the selective ablation of cancer cells, several critical issues must be addressed and investigated regarding the development of ADCs, including optimization of the linker, conjugation site, payload and drug loading [32] Many macromolecules, such as antibodies, tend to be prone to conformational changes that may lead to the loss of their unique tertiary structures. Too few of the drug molecules being attached to the antibody results in low efficacy, whereas too many of the payload molecules causes the ADC to have unstable properties, increased plasma clearance, reduced half-life, and increased toxicity [17] Another advantage of aptamers is that they are easy to chemically synthesize, and the number of payloads conjugated at any desired site of aptamer can be precisely controlled [35]. We expect that the administration of higher doses of DOligobody will further reduce tumor growth in vivo
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