Current strategies for the discovery and bioconjugation of smaller, targetable drug conjugates tailored for solid tumor therapy.

Published on Jan 11, 2021in Expert Opinion on Drug Discovery4.887
· DOI :10.1080/17460441.2021.1858050
Mahendra Deonarain19
Estimated H-index: 19
(Imperial College London),
Gokhan Yahioglu24
Estimated H-index: 24
(Imperial College London)
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Abstract
Introduction: Antibody-Drug Conjugates (ADCs) have undergone a recent resurgence with 5 product approvals over the last 2 years but for those close to the field, it’s been repeated cycles of setbac...
References84
Newest
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Abstract Despite some approvals of antibody-drug conjugates, their clinical success rate is unsatisfactory because of very small therapeutic windows, influenced by on-target and off-target toxicities of conjugate and liberated toxin. Additional formats with systematically investigated molecular parameters must therefore be explored to increase the therapeutic window. Here we focused on the effective molecular weight. To generate conjugates with exactly defined drug loads and tunable pharmacokine...
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Antibody Drug Conjugates (ADCs) are failing due to 3 critical limitations: Low potency, ineffective solid-tumour penetration and poor tolerability. The industry is full of approaches where full-length Immunoglobulins have been engineered to carry defined numbers of payloads with higher-loadings of less potent payloads appearing to be well-tolerated. However, antibody fragments (e.g. single-chain Fcs-scFvs), which have many advantages including rapid tumour penetration, faster clearance, inexpens...
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A highly efficient disulfide rebridging strategy for the modification of monoclonal antibodies with substituted divinyltriazine linkers is reported. The reaction proceeds efficiently under mild conditions with near stoichiometric quantities of linker. This method of conjugation yields serum stable antibody conjugates with a controlled payload loading of 4.
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The EphA2 receptor is found at high levels in tumors and low levels in normal tissue and high EphA2 expression in biopsies is a predictor of poor outcome in patients. Drug discovery groups have therefore sought to develop EphA2 based therapies using small molecule, peptide and nanoparticle-based approaches. However, until now only EphA2 targeting antibody drug conjugates (ADCs) have entered clinical development. For example, MEDI-547, is an EphA2 targeting ADC that displayed encouraging antitumo...
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In spite of significant progress in the field of targeted anticancer therapy, the FDA has approved only five ADC-based drugs. Hence the search for new targeted anticancer agents is an unfulfilled n...
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Antibody-coupled photosensitive molecules can achieve ideal tumor-specific photodynamic therapy (PDT) and show strong clinical application potential. However, some inherent disadvantages, such as long circulation half-life, poor permeation into solid tumors and difficulty in obtaining uniform coupling products, present potential problems to clinical application. In this study, we propose a novel design of targeting photosensitizers, based on a very small targeting protein (an affibody molecule) ...
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Affibody molecules hold great promise as carriers of cytotoxic drugs for cancer therapy due to their typically high affinity, easy production, and inherent control of the drug molecules' loading and spatial arrangement. Here, the impact of increasing the drug load from one to three on the properties of an affibody drug conjugate targeting the human epidermal growth factor receptor 2 (HER2) was investigated. The affibody carrier was recombinantly expressed as a fusion to an albumin-binding domain...
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The fibronectin type III (FN3) monobody domain is a promising non-antibody scaffold which features a less complex architecture than an antibody while maintaining analogous binding loops. We previously developed FN3Con, a hyper-stable monobody derivative with diagnostic and therapeutic potential. Pre-stabilization of the scaffold mitigates the stability-function trade-off commonly associated with evolving a protein domain towards biological activity. Here, we aimed to examine if the FN3Con monobo...
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