Antibody-drug conjugates: recent advances in conjugation and linker chemistries

Tsuchikama, Kyoji; An, Zhiqiang

doi:10.1007/s13238-016-0323-0

Cited by 516 publications

(492 citation statements)

References 65 publications

(75 reference statements)

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“…The pharmaceutical payload must contain reactive group(s) for covalent conjugation. There are a variety of conjugation strategies available, including the formation of ester bond, amide bond, thiol‐ene reaction, azide‐alkyne click reaction, bioreducible disulfide, and many others . The conjugation can form amphiphilic drugs with cleavable or noncleavable linkage.…”

Section: The Design Principles Of Self‐delivery Amphiphilic Drugsmentioning

confidence: 99%

Recent Advances in the Design of Self‐Delivery Amphiphilic Drugs and Vaccines

Liu

2019

Advanced Therapeutics

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Amphiphilic drugs are molecular drugs or drug conjugates possessing both hydrophilic and lipophilic properties. Representative amphiphilic drugs are composed of a pharmaceutical payload, a linker, and an appropriate amphiphilic modification. The physicochemical properties of amphiphilic drugs can be tailored by structure‐based engineering, which ultimately determine the drug molecules’ self‐assemble ability, bioavailability, protein binding, membrane anchoring, organ and intracellular distributions, side effects, and biological efficacy. Unlike the traditional carrier‐assistant drug delivery system, many of the amphiphilic drugs are carrier‐free and can self‐deliver to target sites/cells and access intracellular organelles without an external delivery carrier. This is achieved by molecular designs that control the delivery pathways of amphiphilic drugs at organ/tissue, cellular, and intracellular levels. In this review the recent advances in self‐delivery amphiphilic drugs and vaccines are highlighted, with emphasis on the underlying design principles and emerging applications.

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Section: The Design Principles Of Self‐delivery Amphiphilic Drugsmentioning

confidence: 99%

Recent Advances in the Design of Self‐Delivery Amphiphilic Drugs and Vaccines

Liu

2019

Advanced Therapeutics

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“…5 In addition, most major biopharmaceutical companies are currently active in antibody drug conjugate (ADC) research and development, particularly in the eld of oncology, and various new hybrids of small and large molecules are being actively examined that defy traditional categorization of molecular size. 6 Much of the motivation for this push into new molecular modalities is due to the untapped pool of potential PPI drug targets, an interest likely to continue given the current intense industry focus on immuno oncology, for which a wealth of PPI drug targets are anticipated. It is hoped that a new generation of medium sized molecules could be used to address some challenging drug targets traditionally considered only for antibodies, while retaining many of the desirable properties of smaller molecules.…”

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confidence: 99%

Constrained Peptides in Drug Discovery and Development

Cary¹,

Ohuchi²,

Reid³

et al. 2017

J. Synth. Org. Chem. Jpn.

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Constrained peptides represent a new class of peptide molecules whose supramolecular structure is controlled via intramolecular covalent bonds, generally to confer upon them biochemical and/or physicochemical properties superior to those of ordinary peptides. Both academia and industry are showing increasing interest in constrained peptides, due to their promise as medicines and tools for drug discovery. The major categories of constrained peptides are macrocyclic peptides 1 and stapled peptides, 2 as illustrated in Figure 1. The related eld of foldamers, which can be thought of as conformationally constrained peptides, has been recently reviewed and will not be discussed here.3 This paper will present an overview of ongoing research and development efforts in this eld, with particular focus on our approach toward constrained peptide research and development. Why Study Constrained Peptides? PPI Drug TargetsMost investigational and approved drugs to date fall into the broad categories of small molecules or macromolecular biologics, with antibodies, proteins and vaccines representing the predominant forms of approved biologic therapies. Until recently, aside from a small number of natural products, there has been much less progress in designing drugs for the intervening space of medium sized molecules, de ned here as molecules with molecular weights ranging from 500 to 6000 Daltons.From the perspective of small molecule drug discovery, the FDA approval of Bcl 2 inhibitor venetoclax (Figure 2) in 2016, after nearly 30 years of research and development, dem- Abstract: Constrained peptides, namely macrocyclic and stapled peptides, are receiving increasing attention as a promising class of compounds for the inhibition of protein protein interactions (PPI). The current state of peptide therapeutics is discussed, including their merits and challenges, as well as recent technological developments that have enabled a new era in peptide research and development. The technology behind PeptiDream s Peptide Discovery Platform System (PDPS) is described, showing how it can be used to rapidly generate libraries of constrained peptides and obtain detailed SAR information. This technology can provide, with a high rate of success, potent peptide ligands that may be developed as drug candidates themselves, utilized in peptide drug conjugates (PDC), or converted into small molecule drug leads. The outlook for the eld of constrained peptides and their use in the clinic is also described.

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“…A wide range of chemical and enzymatic methods, based on site‐specific conjugation approaches can be applied, such as lysine and thiol modifications, native chemical ligation, unnatural amino acid incorporation, enzymatic production of formylglycine residues, and incorporation of modified sugar residues . They all present advantages and disadvantages . Nevertheless, the most promising strategies rely on copper‐free chemistry, sortase‐mediated protein ligation (SMPL), and SEPL …”

Section: Peptibodiesmentioning

confidence: 99%

Peptibodies: An elegant solution for a long‐standing problem

2017

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Chimeric proteins composed of a biologically active peptide and a fragment crystallizable (Fc) domain of immunoglobulin G (IgG) are known as peptibodies. They present an extended half-life due to neonatal Fc receptor (FcRn) salvage pathway, a decreased renal clearance rate owing to its increased size (70 kDa) and, depending on the peptide used in the design of the peptibody, an active-targeting moiety. Also, the peptides therapeutic activity is boosted by the number of peptides in the fusion protein (at least two peptides) and to some peptides' alterations. Peptibodies are mainly obtained through recombinant DNA technology. However, to improve peptide properties, "unnatural" changes have been introduced to the original peptides' sequence, for instance, the incorporation of D-or non-natural amino acid residues or even cyclization thus, limiting the application of genetic engineering in the production of peptibodies, since these peptides must be obtained via chemical synthesis. This constrains prompted the development of new methods for conjugation of peptides to Fc domains. Another challenge, subject of intense research, relates to the large-scale production of such peptibodies using these new techniques, which can be minimized by their proved value. To date, two peptibodies, romiplostim and dulaglutide, have been approved and stay as the standard of care in their areas of action. Furthermore, a considerable number of peptibodies are currently in preclinical and clinical development. K E Y W O R D Scopper-free click chemistry, peptibody, peptide-Fc fusion protein, sortase-mediated protein ligation, streamlined-expressed protein ligation

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Antibody-drug conjugates: recent advances in conjugation and linker chemistries

Cited by 516 publications

References 65 publications

Recent Advances in the Design of Self‐Delivery Amphiphilic Drugs and Vaccines

Recent Advances in the Design of Self‐Delivery Amphiphilic Drugs and Vaccines

Constrained Peptides in Drug Discovery and Development

Peptibodies: An elegant solution for a long‐standing problem

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