Anti-CD22-MCC-DM1 and MC-MMAF Conjugates: Impact of Assay Format on Pharmacokinetic Parameters Determination

Stéphan, Jean-Philippe; Chan, Pamela; Lee, Chien; Nelson, Christopher G.; Elliott, J. Michael; Bechtel, Charity; Raab, Helga; Xie, David; Akutagawa, Jon; Baudys, Jakub; Saad, Ola M.; Prabhu, Saileta; Wong, Wai Lee; Vandlen, Richard; Jacobson, Fred; Ebens, Allen

doi:10.1021/bc800059t

Cited by 75 publications

(52 citation statements)

References 26 publications

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“…The effect is small, however, and the difference in clearance between total trastuzumab and T-DM1 was barely differentiated with a 7-day observation period (18). The results are not unique to T-DM1 as other Ab-SMCC-DM1 conjugates have similarly shown slightly faster clearance of conjugate versus total antibody in preclinical studies (11,21). The preclinical observations with T-DM1 appear to translate to the clinic: analysis of data from four clinical studies of single agent T-DM1 administered at 3.6 mg/kg every 3 weeks have shown that the clearance rate of T-DM1 and total trastuzumab in patients ranged from 7 to 13 and 3 to 6 mL/kg/day, respectively, with half-lives of about 4 and 9-11 days for T-DM1 and for total trastuzumab, respectively (13).…”

Section: Pharmacokineticsmentioning

confidence: 97%

“…The superior thioether stability of the Ab-SMCC-DM1 ADCs as compared to the cysteine linked ADCs may stem from inherent differences in the Michael donor reactivity of the sulfhydryl group of DM1 vs. the sulfhydryl group of cysteine side chains (25). Additional work is necessary to understand the mechanism(s) that underlie these pharmacokinetic observations (11,13,21). One might speculate that such maytansinoid loss may be accounted for by a low rate of cleavage of the amide bond of the linker-DM1 species from the antibody and/or by a slightly faster rate of clearance from circulation of species with more than the median load of DM1 molecules per antibody versus those species with less than the median number of DM1 molecules per antibody.…”

Section: Pharmacokineticsmentioning

confidence: 99%

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ADME of Antibody–Maytansinoid Conjugates

Erickson

Lambert

2012

AAPS J

115

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Abstract. The concept of treating cancer with antibody-drug conjugates (ADCs) has gained momentum with the favorable activity and safety of trastuzumab emtansine (T-DM1), SAR3419, and lorvotuzumab mertansine (IMGN901). All three ADCs utilize maytansinoid cell-killing agents which target tubulin and suppress microtubule dynamics. Each ADC utilizes a different optimized chemical linker to attach the maytansinoid to the antibody. Characterizing the absorption, distribution, metabolism, and excretion (ADME) of these ADCs in preclinical animal models is important to understanding their efficacy and safety profiles. The ADME properties of these ADCs in rodents were inferred from studies with radiolabeled ADCs prepared with nonbinding antibodies since T-DM1, SAR3419, IMGN901 all lack crossreactivity with rodent antigens. For studies exploring tumor localization and activation in tumor-bearing mice, tritium-labeled T-DM1, SAR3419, and IMGN901 were utilized. The chemical nature of the linker was found to have a significant impact on the ADME properties of these ADCs-particularly on the plasma pharmacokinetics and observed catabolites in tumor and liver tissues. Despite these differences, T-DM1, SAR3419, and IMGN901 were all found to facilitate efficient deliveries of active maytansinoid catabolites to the tumor tissue in mouse xenograft models. In addition, all three ADCs were effectively detoxified during hepatobiliary elimination in rodents.

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Section: Pharmacokineticsmentioning

confidence: 97%

Section: Pharmacokineticsmentioning

confidence: 99%

ADME of Antibody–Maytansinoid Conjugates

Erickson

Lambert

2012

AAPS J

115

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“…In addition to the discussion in the review articles [1][2][3] one well-accepted opinion is that the assay format, using different combination of capture and detection reagents, could affect the DAR characteristics of total-antibody and conjugated-antibody assays and hence the PK parameters [18,19]. Ideally, a DAR insensitive ADC conjugated-antibody assay is preferred [1][2][3]20].…”

Section: Ligand-binding Assays (Lba) For Adc Pkmentioning

confidence: 99%

Current status of antibody-drug conjugate bioanalysis

Wang¹

2017

J Appl Bioanal

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Keywords: antibody-drug conjugate bioanalysis, ligand-binding assay, hybrid ligand-binding/LC-MS assay, drug-toantibody ratio Antibody-drug conjugate (ADC) consists of a cytotoxic drug covalently bound to a monoclonal antibody via a linker. Because of the complexity of ADC structure unique bioanalytical strategies are needed to identify, characterize and quantify the ADC species most relevant to safety and efficacy. ADC bioanalysis need an integrated bioanalytical approach including ligand-binding assay (LBA) and LC-MS based assays to provide comprehensive characterization of the exposure/response relationship. This mini-review will summarize recent publications on ADC bioanalytical strategies and will focus on the publications within last three years on the advancement of hybrid ligand-binding/LC-MS methods for ADC PK and stability evaluation and for intact ADC-DAR distribution measurement to profile ADC biotransformation and catabolism. Special attention is paid to the publications on selection of ADC analytes, assay platforms and DAR characteristics of LBA as well as on the transition of the bioanalytical testing strategy at different phases of clinical development.

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“…Total anti-CD22 (hu10F4), anti-CD22 (hu10F4)-MCC-DM1 and free DM1 were analyzed as previously described. 16 All animals were euthanized and necropsied on either day 25 or 43 and tissues were thoroughly evaluated by gross and microscopic examination. Urinalysis was performed on urine collected by cystocentesis at necropsy.…”

Section: Cynomolgus Monkey Safety Studymentioning

confidence: 99%

Anti-CD22-MCC-DM1: an antibody-drug conjugate with a stable linker for the treatment of non-Hodgkin's lymphoma

Polson¹,

Williams²,

Gray³

et al. 2010

Leukemia

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Antibody-drug conjugates (ADCs) are potent cytotoxic drugs linked to antibodies through chemical linkers, and allow specific targeting of drugs to neoplastic cells. The expression of CD22 is limited to B-cells, and we show that CD22 is expressed on the vast majority of non-Hodgkin's lymphomas (NHLs). An ideal target for an ADC for the treatment of NHL would have limited expression outside the B-cell compartment and be highly effective against NHL. We generated an ADC consisting of a humanized anti-CD22 antibody conjugated to the anti-mitotic agent maytansine with a stable linker (anti-CD22-MCC-DM1). Anti-CD22-MCC-DM1 was broadly effective in in vitro killing assays on NHL B-cell lines. We did not find a strong correlation between in vitro potency and CD22 surface expression, internalization of ADC or sensitivity to free drug. We show that anti-CD22-MCC-DM1 was capable of inducing complete tumor regression in NHL xenograft mouse models. Further, anti-CD22-MCC-DM1 was well tolerated in cynomolgus monkeys and substantially decreased circulating B-cells as well as follicle size and germinal center formation in lymphoid organs. These results suggest that anti-CD22-MCC-DM1 has an efficacy, safety and pharmacodynamic profile that support its use as a treatment for NHL.

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Anti-CD22-MCC-DM1 and MC-MMAF Conjugates: Impact of Assay Format on Pharmacokinetic Parameters Determination

Cited by 75 publications

References 26 publications

ADME of Antibody–Maytansinoid Conjugates

ADME of Antibody–Maytansinoid Conjugates

Current status of antibody-drug conjugate bioanalysis

Anti-CD22-MCC-DM1: an antibody-drug conjugate with a stable linker for the treatment of non-Hodgkin's lymphoma

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