Improving the developability of an anti-EphA2 single-chain variable fragment for nanoparticle targeting

Geddie, Melissa L.; Kohli, Neeraj; Kirpotin, Dmitri B.; Razlog, Maja; Jiao, Yang; Kornaga, Tad; Rennard, Rachel; Xu, Lihui; Schoerberl, Birgit; Marks, James D.; Drummond, Daryl C.; Lugovskoy, Alexey A.

doi:10.1080/19420862.2016.1259047

Cited by 24 publications

(12 citation statements)

References 46 publications

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“…Such a delivery approach markedly reduces the amounts of circulating free TMB, consequently minimizing undesirable effects. Likewise, MM-310 (EphA2-ILs-DTXp) are immunoliposomes encapsulating the readily hydrolysable docetaxel prodrug (DTXp) with conjugation to the high-affinity signal-chain variable fragment (scFv-3) targeting EphA2 [ 76 , 113 ]. Administration of MM-310 was shown to remarkably enhance anticancer activity in multiple mouse tumor xenografts (from breast, prostate, gastric, and esophageal cancer cells), in comparison with the free docetaxel and non-targeted nanotherapeutic control groups [ 76 ].…”

Section: Targeting Epha2 In Cancermentioning

confidence: 99%

Targeting EphA2 in cancer

et al. 2020

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Eph receptors and the corresponding Eph receptor-interacting (ephrin) ligands jointly constitute a critical cell signaling network that has multiple functions. The tyrosine kinase EphA2, which belongs to the family of Eph receptors, is highly produced in tumor tissues, while found at relatively low levels in most normal adult tissues, indicating its potential application in cancer treatment. After 30 years of investigation, a large amount of data regarding EphA2 functions have been compiled. Meanwhile, several compounds targeting EphA2 have been evaluated and tested in clinical studies, albeit with limited clinical success. The present review briefly describes the contribution of EphA2-ephrin A1 signaling axis to carcinogenesis. In addition, the roles of EphA2 in resistance to molecular-targeted agents were examined. In particular, we focused on EphA2's potential as a target for cancer treatment to provide insights into the application of EphA2 targeting in anticancer strategies. Overall, EphA2 represents a potential target for treating malignant tumors.

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Section: Targeting Epha2 In Cancermentioning

confidence: 99%

Targeting EphA2 in cancer

et al. 2020

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“…Briefly, the anti-EphA2 scFv protein 310-24 scFv was expressed in mammalian cell culture, purified by protein-A affinity chromatography, and conjugated through an engineered C-terminal cysteine residue to the maleimide-terminated lipopolymer, mal-PEG-DSPE. The 310-24 scFv was previously described as scFv-3 by Geddie and has a T m of 71.7 °C and a monovalent K D of 4.1 nM [ 32 ]. EphA2-ILs-DTXp was then prepared as previously described [ 30 ].…”

Section: Methodsmentioning

confidence: 99%

Targeting EphA2 in Bladder Cancer Using a Novel Antibody-Directed Nanotherapeutic

et al. 2020

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Ephrin receptor A2 (EphA2) is a member of the Ephrin/Eph receptor cell-to-cell signaling family of molecules, and it plays a key role in cell proliferation, differentiation, and migration. EphA2 is overexpressed in a broad range of cancers, and its expression is in many cases associated with poor prognosis. We recently developed a novel EphA2-targeting antibody-directed nanotherapeutic encapsulating a labile prodrug of docetaxel (EphA2-ILs-DTXp) for the treatment of EphA2-expressing malignancies. Here, we characterized the expression of EphA2 in bladder cancer using immunohistochemistry in 177 human bladder cancer samples and determined the preclinical efficacy of EphA2-ILs-DTXp in four EphA2-positive patient-derived xenograft (PDX) models of the disease, either as a monotherapy, or in combination with gemcitabine. EphA2 expression was detected in 80–100% of bladder cancer samples and correlated with shorter patient survival. EphA2 was found to be expressed in tumor cells and/or tumor-associated blood vessels in both primary and metastatic lesions with a concordance rate of approximately 90%. The EphA2-targeted antibody-directed nanotherapeutic EphA2-ILs-DTXp controlled tumor growth, mediated greater regression, and was more active than free docetaxel at equitoxic dosing in all four EphA2-positive bladder cancer PDX models. Combination of EphA2-ILs-DTXp and gemcitabine in one PDX model led to improved tumor growth control compared to monotherapies or the combination of free docetaxel and gemcitabine. These data demonstrating the prevalence of EphA2 in bladder cancers and efficacy of EphA2-ILs-DTXp in PDX models support the clinical exploration of EphA2 targeting in bladder cancer.

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“…Despite the success of these and other approaches [ 47 , 49 , 50 , 51 , 52 ], stabilizing mutations in the CDRs or frameworks would be highly valuable. Fortunately, computational approaches for the design of antibodies with high affinity and thermostability have made significant recent advances [ 53 , 54 , 55 , 56 , 57 , 58 ].…”

Section: Physical and Chemical Stabilitymentioning

confidence: 99%

Toward Drug-Like Multispecific Antibodies by Design

Sawant

Streu

et al. 2020

IJMS

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The success of antibody therapeutics is strongly influenced by their multifunctional nature that couples antigen recognition mediated by their variable regions with effector functions and half-life extension mediated by a subset of their constant regions. Nevertheless, the monospecific IgG format is not optimal for many therapeutic applications, and this has led to the design of a vast number of unique multispecific antibody formats that enable targeting of multiple antigens or multiple epitopes on the same antigen. Despite the diversity of these formats, a common challenge in generating multispecific antibodies is that they display suboptimal physical and chemical properties relative to conventional IgGs and are more difficult to develop into therapeutics. Here we review advances in the design and engineering of multispecific antibodies with drug-like properties, including favorable stability, solubility, viscosity, specificity and pharmacokinetic properties. We also highlight emerging experimental and computational methods for improving the next generation of multispecific antibodies, as well as their constituent antibody fragments, with natural IgG-like properties. Finally, we identify several outstanding challenges that need to be addressed to increase the success of multispecific antibodies in the clinic.

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Improving the developability of an anti-EphA2 single-chain variable fragment for nanoparticle targeting

Cited by 24 publications

References 46 publications

Targeting EphA2 in cancer

Targeting EphA2 in cancer

Targeting EphA2 in Bladder Cancer Using a Novel Antibody-Directed Nanotherapeutic

Toward Drug-Like Multispecific Antibodies by Design

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