Recent Advances in Drug–Antibody Ratio Determination of Antibody–Drug Conjugates

Matsuda, Yutaka; Mendelsohn, Brian A.

doi:10.1248/cpb.c21-00258

Cited by 46 publications

(41 citation statements)

References 75 publications

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“…Over the last two decades, antibody–drug conjugates (ADCs) have become a potential embodiment of Ehrlich’s notion. ADCs are promising cancer therapeutics consisting of recombinant monoclonal antibodies. − Although this concept may seem simple, there is a critical issue with the synthesis of traditional ADCs. Non-specific drug conjugation on naturally available amino acid residues, such as lysine and reduced interchain cysteine residues, is used to construct the chemical links between the antibodies and payloads.…”

Section: Introductionmentioning

confidence: 99%

Chemical Site-Specific Conjugation Platform to Improve the Pharmacokinetics and Therapeutic Index of Antibody–Drug Conjugates

et al. 2021

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To overcome a lack of selectivity during the chemical modification of native non-engineered antibodies, we have developed a technology platform termed “AJICAP” for the site-specific chemical conjugation of antibodies through the use of a class of IgG Fc-affinity reagents. To date, a limited number of antibody–drug conjugates (ADCs) have been synthesized via this approach, and no toxicological study was reported. Herein, we describe the compatibility and robustness of AJICAP technology, which enabled the synthesis of a wide variety of ADCs. A stability assessment of a thiol-modified antibody synthesized by AJICAP technology indicated no appreciable increase in aggregation or decomposition upon prolonged storage, indicating that the unexpectedly stable thiol intermediate has a great potential intermediate for payload or linker screening or large-scale manufacturing. Payload conjugation with this stable thiol intermediate generated several AJICAP-ADCs. In vivo xenograft studies indicated that the AJICAP-ADCs displayed significant tumor inhibition comparable to benchmark ADC Kadcyla. Furthermore, a rat pharmacokinetic analysis and toxicology study indicated an increase in the maximum tolerated dose, demonstrating an expansion of the AJICAP-ADC therapeutic index, compared with stochastic conjugation technology. This is the first report of the therapeutic index estimation of site-specific ADCs produced by utilizing Fc affinity reagent conjugation. The described site-specific conjugation technology is a powerful platform to enable next-generation ADCs through reduced heterogeneity and enhanced therapeutic index.

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Section: Introductionmentioning

confidence: 99%

Chemical Site-Specific Conjugation Platform to Improve the Pharmacokinetics and Therapeutic Index of Antibody–Drug Conjugates

et al. 2021

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“…Consistent DAR of the final product is of importance for reproducibility during manufacturing and safety for the patient. A variety of methods have therefore been described to evaluate DAR values to ensure batch-to-batch consistency, which are discussed elsewhere [156,157]. Studies suggest a DAR of roughly 3-4 to hit the sweet spot between efficacy and clearance for current small molecule toxin ADCs [158][159][160] and thereby maximizing the therapeutic index.…”

Section: Arming the Arsenal: Adc Payloadsmentioning

confidence: 99%

More than Toxins—Current Prospects in Designing the Next Generation of Antibody Drug Conjugates

Schwach¹,

Abdellatif²,

Stengl³

2022

Front. Biosci. (Landmark Ed)

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Antibody drug conjugates (ADCs) are rapidly becoming a cornerstone in targeted therapies, especially for the treatment of cancer. Currently, there are 12 FDA-approved ADCs, eight of which have been approved within the last five years, with numerous candidates in clinical trials. The promising clinical perspective of ADCs has led to the development of not only novel conjugation techniques, but also antibody formats, linkers, and payloads. While the majority of currently approved ADCs relies on cytotoxic small molecule warheads, alternative modes of action imparted by novel payloads and non-classical antibody formats are gaining attention. In this review, we summarize the current state of the art of ADC technologies, as well as comprehensively examine alternative payloads, such as toxic proteins, cytokines, PROTACs and oligonucleotides, and highlight the potential of multi-specific antibody formats for the next generation of therapeutic antibody conjugates.

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“…Promising conjugation technologies are required for efficacious/safe ADC production and the establishment of robust and streamline ADC manufacturing processes. Currently, the development of scalable ADC processes is still a highly challenging task for not only pharmaceutical companies but also for CDMOs [28,29]. From a straightforward CMC perspective, chemical conjugation is advantageous because this method requires only small molecular compounds such as cross-linkers and/or reductants besides the drug-linkers.…”

Section: F I G U R E 2 Typical Manufacturing Approaches To Produce Adcsmentioning

confidence: 99%

Current approaches for the purification of antibody–drug conjugates

Matsuda

2021

J of Separation Science

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In the past two decades, antibody-drug conjugates have gained increasing attention because they expand the therapeutic index when compared with that of traditional chemotherapies. Antibody-drug conjugates are highly complex structures consisting of antibodies covalently conjugated with small-molecule cytotoxic drugs. The complex structure of antibody-drug conjugates makes chemistry, manufacturing, and control difficult. In contrast to antibody production, distinct purification methods following conjugation of antibodies with druglinkers are required for the manufacturing. For process development of antibody drug conjugates, the drug-to-antibody ratio, free drug-linkers, and aggregates are critical quality attributes that must be strictly controlled and removed by appropriate purification techniques. In this review, features of various purification methods used to purify antibody drug conjugates are described and evaluated. The future landscape of the antibody-conjugates field is also discussed briefly.

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Recent Advances in Drug–Antibody Ratio Determination of Antibody–Drug Conjugates

Cited by 46 publications

References 75 publications

Chemical Site-Specific Conjugation Platform to Improve the Pharmacokinetics and Therapeutic Index of Antibody–Drug Conjugates

Chemical Site-Specific Conjugation Platform to Improve the Pharmacokinetics and Therapeutic Index of Antibody–Drug Conjugates

More than Toxins—Current Prospects in Designing the Next Generation of Antibody Drug Conjugates

Current approaches for the purification of antibody–drug conjugates

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