Emerging formats for next-generation antibody drug conjugates

Deonarain, Mahendra P.; Yahioglu, Gökhan; Stamati, Ioanna; Marklew, Jared S.

doi:10.1517/17460441.2015.1025049

Cited by 63 publications

(52 citation statements)

References 104 publications

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“…Similar to tumor-targeting antibodies, both tumor-targeting antibody fragments and non-Ig scaffolds can be conjugated with cytotoxic drugs. 156,157 Protein backbones that have been used to target anticancer drugs include diabodies, Fab fragments, and designed ankyrin repeat proteins. 157 The effect of drug conjugation has been described for an anti-CD30 diabody that was engineered with two cysteine mutations for site-specific drug conjugation.…”

Section: Drug Conjugationmentioning

confidence: 99%

Influence of protein properties and protein modification on biodistribution and tumor uptake of anticancer antibodies, antibody derivatives, and non‐Ig scaffolds

Warnders

Hooge

Vries

et al. 2018

Medicinal Research Reviews

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Newly developed protein drugs that target tumor-associated antigens are often modified in order to increase their therapeutic effect, tumor exposure, and safety profile. During the development of protein drugs, molecular imaging is increasingly used to provide additional information on their in vivo behavior. As a result, there are increasing numbers of studies that demonstrate the effect of protein modification on whole body distribution and tumor uptake of protein drugs. However, much still remains unclear about how to interpret obtained biodistribution data correctly. Consequently, there is a need for more insight in the correct way of interpreting preclinical and clinical imaging data. Summarizing the knowledge gained to date may facilitate this interpretation. This review therefore provides an overview of specific protein properties and modifications that can affect biodistribution and tumor uptake of anticancer antibodies, antibody fragments, and nonimmunoglobulin scaffolds. Protein properties that are discussed in this review are molecular size, target interaction, FcRn binding, and charge. Protein modifications that are discussed are radiolabeling, fluorescent labeling drug conjugation, glycosylation, humanization, albumin binding, and polyethylene glycolation.

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Section: Drug Conjugationmentioning

confidence: 99%

Influence of protein properties and protein modification on biodistribution and tumor uptake of anticancer antibodies, antibody derivatives, and non‐Ig scaffolds

Warnders

Hooge

Vries

et al. 2018

Medicinal Research Reviews

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“…Covalent tethering of antibodies to supports typically utilizes one of three functionalities in the antibody molecule: lysine amino acids, of which approximately 40-50 are accessible for modification, 12 cysteine residues, and 2-5 carbohydrate moieties in the Fc stem. [64] Amine conjugation involves the conjugation of native or recombinant proteins to biomaterials via an amine functionality present on the surface of either the protein or the biomaterial. [15,65] The coupling of primary amines is usually carried out using the corrosive carbodiimide (EDC or DCC)/N-hydroxysuccinimide (NHS) to link carboxyl groups in the biomaterial to primary amines in the protein via an NHS-ester intermediate.…”

Section: Covalent Modification Techniquesmentioning

confidence: 99%

Adding Functions to Biomaterial Surfaces through Protein Incorporation

et al. 2016

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The concept of biomaterials has evolved from one of inert mechanical supports with a long-term, biologically inactive role in the body into complex matrices that exhibit selective cell binding, promote proliferation and matrix production, and may ultimately become replaced by newly generated tissues in vivo. Functionalization of material surfaces with biomolecules is critical to their ability to evade immunorecognition, interact productively with surrounding tissues and extracellular matrix, and avoid bacterial colonization. Antibody molecules and their derived fragments are commonly immobilized on materials to mediate coating with specific cell types in fields such as stent endothelialization and drug delivery. The incorporation of growth factors into biomaterials has found application in promoting and accelerating bone formation in osteogenerative and related applications. Peptides and extracellular matrix proteins can impart biomolecule- and cell-specificities to materials while antimicrobial peptides have found roles in preventing biofilm formation on devices and implants. In this progress report, we detail developments in the use of diverse proteins and peptides to modify the surfaces of hard biomaterials in vivo and in vitro. Chemical approaches to immobilizing active biomolecules are presented, as well as platform technologies for isolation or generation of natural or synthetic molecules suitable for biomaterial functionalization.

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“…Furthermore, sitespecific coupling will facilitate production of linking other novel payloads (Behrens and Liu 2014;Deonarain et al 2015).…”

Section: Linker Designmentioning

confidence: 99%

Antibody drug conjugates

Bakhtiar

2016

Biotechnol Lett

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Antibody drug conjugates (ADCs) have emerged as a viable option in targeted delivery of highly potent cytotoxic drugs in treatment of solid tumors. At the time of writing, only two ADCs have received regulatory approval with >40 others in clinical development. The first generation ADCs suffered from a lack of specificity in amino acid site-conjugations, yielding statistically heterogeneous stoichiometric ratios of drug molecules per antibody molecule. For the second generation ADCs, however, site-specific amino acid conjugation using enzymatic ligation, introduction of unnatural amino acids, and site-specific protein engineering hold promise to alleviate some of the current technical limitations. The rapid progress in technology platforms and antibody engineering has introduced novel linkers, site-specific conjugation chemistry, and new payload candidates that could possibly be exploited in the context of ADCs. A search using the Clinical Trial Database registry ( www.clinicaltrials.gov ), using the keyword 'antibody drug conjugate', yielded ~270 hits. The main focus of this article is to present a brief overview of the recent developments and current challenges related to ADC development.

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Emerging formats for next-generation antibody drug conjugates

Cited by 63 publications

References 104 publications

Influence of protein properties and protein modification on biodistribution and tumor uptake of anticancer antibodies, antibody derivatives, and non‐Ig scaffolds

Influence of protein properties and protein modification on biodistribution and tumor uptake of anticancer antibodies, antibody derivatives, and non‐Ig scaffolds

Adding Functions to Biomaterial Surfaces through Protein Incorporation

Antibody drug conjugates

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