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)
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...
#1Fabian Brandl (University of Bern)H-Index: 5
#2Sarah Busslinger (UZH: University of Zurich)H-Index: 1
Last. Andreas Plückthun (UZH: University of Zurich)H-Index: 127
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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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#1Anish ThomasH-Index: 36
Last. Mark T. BilodeauH-Index: 31
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Background: Heat Shock Protein 90 (HSP90) is a molecular chaperone that aids in folding and trafficking of proteins and is upregulated in cells under stress. HSP90 is overexpressed in cancer cells and exists in the activated configuration within the tumor microenvironment. PEN-866 is a novel small molecule drug conjugate containing a HSP90 targeting moiety that accumulates in tumors and releases its payload SN-38 through a cleavable linker within the tumor cells. The first in human phase 1/2a PE...
2 CitationsSource
#1Mahendra DeonarainH-Index: 19
#2Gokhan YahiogluH-Index: 24
Last. Quinn XueH-Index: 1
view all 12 authors...
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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7 CitationsSource
#1Andrew J. Counsell (University of Cambridge)H-Index: 2
#1Andrew J. Counsell (University of Cambridge)H-Index: 4
Last. David R. Spring (University of Cambridge)H-Index: 62
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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.
4 CitationsSource
#1Gavin BennettH-Index: 3
Last. Nicholas KeenH-Index: 14
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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...
12 CitationsSource
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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#1Johanna C. Bendell (Sarah Cannon Research Institute)H-Index: 69
#2Judy Sing-Zan Wang (Sarah Cannon Research Institute)H-Index: 17
Last. Geoffrey I. Shapiro (Harvard University)H-Index: 102
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TPS3655Background: BT5528 is a Bicycle Toxin Conjugate (BTC), comprising a bicyclic peptide targeting the tumor antigen EphA2, linked to a cytotoxin (monomethyl auristatin E [MMAE]) via a tumor mic...
2 CitationsSource
#1Shuang Li (NKU: Nankai University)H-Index: 4
#2Yingying JinH-Index: 2
Last. Zhangyong Hong (NKU: Nankai University)H-Index: 16
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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) ...
4 CitationsSource
#1Derek Y KunimotoH-Index: 14
#2Young Hee Yoon (Asan Medical Center)H-Index: 30
Last. Sequoia Study GroupsH-Index: 2
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Abstract Objective To compare the efficacy and safety of abicipar every 8 weeks and quarterly (after initial doses) versus ranibizumab every 4 weeks in treatment-naive patients with neovascular age-related macular degeneration (AMD). Design Two randomized, multicenter, double-masked, parallel-group, active-controlled, phase 3 clinical trials (CEDAR, SEQUOIA) with identical protocols were conducted. Data from both trials were pooled for analysis. Participants Patients with active choroidal neovas...
21 CitationsSource
Cited By3
#1Haozhong DingH-Index: 3
#2Tianqi XuH-Index: 2
Last. Anzhelika VorobyevaH-Index: 10
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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...
#1Peter G. Chandler (Monash University, Clayton campus)H-Index: 3
#2Li Lynn Tan (ANU: Australian National University)
Last. Ashley M. Buckle (Monash University, Clayton campus)H-Index: 46
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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...