Biotransformation and stability of antibody-drug conjugates: payload metabolism and linker cleavage delineation.

Published on Jun 25, 2015in Bioanalysis2.371
路 DOI :10.4155/BIO.15.50
Vangipuram S. Rangan12
Estimated H-index: 12
,
Heather Myler19
Estimated H-index: 19
+ 3 AuthorsShrikant Deshpande9
Estimated H-index: 9
(BMS: Bristol-Myers Squibb)
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Abstract
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References6
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#1Boris Gorovits (Pfizer)H-Index: 24
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Last. Patricia SiguenzaH-Index: 7
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Antibody鈥揹rug conjugates (ADCs) typically consist of a cytotoxic drug covalently bound to an antibody by a linker. These conjugates have the potential to substantially improve efficacy and reduce toxicity compared with cytotoxic small-molecule drugs. Since ADCs are generally complex heterogeneous mixtures of multiple species, these novel therapeutic products present unique bioanalytical challenges. The growing number of ADCs being developed across the industry suggests the need for alignment of ...
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#1Keyang Xu (Genentech)H-Index: 21
#2Luna LiuH-Index: 12
Last. Surinder KaurH-Index: 23
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Background: Antibody鈥揹rug conjugates (ADCs) are a new class of cancer therapeutics that deliver potent cytotoxins specifically to tumors to minimize systemic toxicity. However, undesirable release of covalently linked drugs in circulation can affect safety and efficacy. The objective of this manuscript was to propose and assess the assays that allow for the characterization of the drug deconjugation in plasma/serum. Results: ADCs of three main drug conjugation platforms, linked via lysine, site-...
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#1Surinder Kaur (Genentech)H-Index: 23
#2Keyang XuH-Index: 21
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Antibody鈥揹rug conjugates (ADCs) are monoclonal antibodies with covalently bound cytotoxic drugs. They are designed to target tumor antigens selectively and offer the hope of cancer treatment without the debilitating side-effects of conventional therapies. The concept of ADCs is not new; however, development of these therapeutics is challenging and only recently are promising clinical data emerging. These challenges include ADC bioanalysis, such as quantifying in serum/plasma for PK studies and s...
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Antibody-drug conjugates (ADCs), which combine the specificity, favorable pharmacokinetics, and biodistribution of a monoclonal antibody (mAb) with the cytotoxic potency of a drug, are promising new therapies for cancer. Along with the development of monoclonal antibodies (mAbs) and cytotoxic drugs, the design of the linker is of essential importance, because it impacts the efficacy and tolerability of ADCs. The linker needs to provide sufficient stability during systemic circulation but allow f...
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#1Stephen C. Alley (Seattle Genetics)H-Index: 30
#2Dennis BenjaminH-Index: 17
Last. Peter D. SenterH-Index: 72
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The linker component of antibody鈭抎rug conjugates (ADC) is a key feature in developing optimized therapeutic agents that are highly active at well tolerated doses. For maximal intratumoral drug delivery, linkers are required that are highly stable in the systemic circulation, yet allow for efficient drug release at the target site. In this respect, amide bond-based technologies constitute a technological advancement, since the linker half-lives in circulation (t1/2 鈭 7 days) are much longer than ...
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The therapeutic activity of most anticancer drugs in clinical use is limited by their general toxicity to proliferating cells, including some normal cells. Although, chemists continue to develop novel cytotoxic agents with unique mechanisms of action, many of these compounds still lack tumor selectivity and have not been therapeutically useful. Monoclonal antibodies that bind to specific markers on the surface of tumor cells offer an alternative therapy that is tumor specific and thus less toxic...
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Cited By7
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#1Srikanth Kotapati (BMS: Bristol-Myers Squibb)H-Index: 9
#2Madhura Deshpande (BMS: Bristol-Myers Squibb)H-Index: 2
Last. Gavin Dollinger (BMS: Bristol-Myers Squibb)H-Index: 8
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Ligand-binding assay (LBA) and LC鈥揗S have been the preferred bioanalytical techniques for the quantitation and biotransformation assessment of various therapeutic modalities. This review provides a...
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#1Aarti Jashnani (BMS: Bristol-Myers Squibb)H-Index: 1
#2Srikanth Kotapati (BMS: Bristol-Myers Squibb)H-Index: 9
Last. Gavin Dollinger (BMS: Bristol-Myers Squibb)H-Index: 8
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Traditionally the biotransformation of antibody drug conjugates (ADCs) has been evaluated by affinity capture on streptavidin magnetic beads coated with a biotinylated capture reagent. To reduce th...
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#1Srikanth KotapatiH-Index: 9
#2David PassmoreH-Index: 8
Last. Arvind RajpalH-Index: 32
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Antibody drug conjugates (ADCs) can undergo in vivo biotransformation (e.g., payload metabolism, deconjugation) leading to reduced or complete loss of activity. The location/site of conjugation of payload-linker can have an effect on ADC stability and hence needs to be carefully optimized. Affinity capture LC-MS of intact ADCs or ADC subfragments has been extensively used to evaluate ADC biotransformation. However, the current methods have certain limitations such as the requirement of specific ...
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#1Leanne Grafmuller (Pfizer)H-Index: 1
#2Cong Wei (Pfizer)H-Index: 19
Last. Joseph A Tweed (Pfizer)H-Index: 6
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Aim: The application of high-resolution MS to antibody鈥揹rug conjugate (ADC) drug development may provide insight into their safety and efficacy. Quantification of unconjugated cytotoxic drug (payload) and characterization of drug-to-antibody ratio distribution were determined in plasma using orthogonal acceleration quadrupole-time-of-flight MS. Results: Unconjugated payload quantification determined by quadrupole-time-of-flight-based MRMhighresolution and triple quadrupole-based multiple reactio...
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#1Jian Wang (BMS: Bristol-Myers Squibb)H-Index: 14
#2Huidong Gu (BMS: Bristol-Myers Squibb)H-Index: 17
Last. Binodh DeSilva (BMS: Bristol-Myers Squibb)H-Index: 20
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Background: Antibody鈥揹rug conjugates (ADCs) are complex drug constructs with multiple species in the heterogeneous mixture that contribute to their efficacy and toxicity. The bioanalysis of ADCs involves multiple assays and analytical platforms. Methods: A series of ligand binding and LC鈥揗S/MS (LB-LC鈥揗S/MS) hybrid assays, through different combinations of anti-idiotype (anti-Id), anti-payload, or generic capture reagents, and cathepsin-B or trypsin enzyme digestion, were developed and evaluated ...
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#1Russell J. Sanderson (Seattle Genetics)H-Index: 9
#2Nicole D Nicholas (Seattle Genetics)H-Index: 4
Last. Stephen C. Alley (Seattle Genetics)H-Index: 30
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Background: Antibody鈥揹rug conjugates (ADCs) require multiple assays to characterize their PK. These assays can separately evaluate the ADC by quantifying the antibody or the conjugated drug and may give different answers due to assay measurement differences, heterogeneous nature of ADCs and potential biotransformations that occur in vivo. Results: We present a new version of the antibody-conjugated drug assay for valine-citrulline-linked monomethylauristatin E (vcMMAE) ADCs. A stable isotope-lab...
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#1Theingi M. ThwayH-Index: 10
#2Binodh DeSilva (BMS: Bristol-Myers Squibb)H-Index: 20
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