Immunogenicity Assays for Antibody–Drug Conjugates: Case Study with Ado-Trastuzumab Emtansine

Carrasco‐Triguero, Montserrat; Yi, Joo‐Hee; Dere, Randall C.; Qiu, Zhihua; Lei, Corinna; Li, Yanhong; Mahood, Connie; Wang, Bei; Leipold, Douglas D.; Poon, Kirsten Achilles; Kaur, Surinder

doi:10.4155/bio.13.64

Cited by 49 publications

(53 citation statements)

References 23 publications

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“…22–24 Phosphate-buffered saline + 0.5% bovine serum albumin (Sigma-Aldrich, St. Louis, MO) was used as a buffer control. DCLL9718A or MCLL0517A was spiked into each species matrix to a final concentration of 50 µg/mL and incubated at 37 ºC (in CO 2 incubator) with gentle rotation.…”

Section: Methodsmentioning

confidence: 99%

Preclinical pharmacokinetics and pharmacodynamics of DCLL9718A: An antibody-drug conjugate for the treatment of acute myeloid leukemia

Leipold¹,

Figueroa²,

Masih³

et al. 2018

mAbs

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Few treatment options are available for acute myeloid leukemia (AML) patients. DCLL9718A is an antibody-drug conjugate that targets C-type lectin-like molecule-1 (CLL-1). This receptor is prevalent on monocytes, neutrophils, and AML blast cells, and unlike CD33, is not expressed on hematopoietic stem cells, thus providing possible hematopoietic recovery. DCLL9718A comprises an anti-CLL-1 IgG1 antibody (MCLL0517A) linked to a pyrrolobenzodiazepine (PBD) dimer payload, via a cleavable disulfide-labile linker. Here, we characterize the in vitro and in vivo stability, the pharmacokinetics (PK) and pharmacodynamics (PD) of DCLL9718A and MCLL0517A in rodents and cynomolgus monkeys. Three key PK analytes were measured in these studies: total antibody, antibody-conjugated PBD dimer and unconjugated PBD dimer. In vitro, DCLL9718A, was stable with most (> 80%) of the PBD dimer payload remaining conjugated to the antibody over 96 hours. This was recapitulated in vivo with antibody-conjugated PBD dimer clearance estimates similar to DCLL9718A total antibody clearance. Both DCLL9718A and MCLL0517A showed linear PK in the non-binding rodent species, and non-linear PK in cynomolgus monkeys, a binding species. The PK data indicated minimal impact of conjugation on the disposition of DCLL9718A total antibody. Finally, in cynomolgus monkey, MCLL0517A showed target engagement at all doses tested (0.5 and 20 mg/kg) as measured by receptor occupancy, and DCLL9718A (at doses of 0.05, 0.1 and 0.2 mg/kg) showed strong PD activity as evidenced by notable reduction in monocytes and neutrophils.

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Section: Methodsmentioning

confidence: 99%

Preclinical pharmacokinetics and pharmacodynamics of DCLL9718A: An antibody-drug conjugate for the treatment of acute myeloid leukemia

Leipold¹,

Figueroa²,

Masih³

et al. 2018

mAbs

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“…While the incidence of immunogenicity in a preclinical model is not predictive of clinical immunogenicity, general principles of ADC immunogenicity (e.g., role of linker/small-molecule drug) and study interpretation may both benefit from this support. Carrasco-Triguero and colleagues report that an ADA titer greater than 4 (log scale) resulted in decreased exposure for a model trastuzumab ADC in cynomolgus monkey (41). In contrast, an ADA incidence of 4.2% (eight out of 190) was reported in ado-trastuzumab emtansine (T-DM1)-dosed cynomolgus monkeys across eight preclinical studies, with no impact on pharmacokinetics (PK) (41).…”

Section: Preclinical Monitoring Strategiesmentioning

confidence: 99%

“…An alternative strategy is a direct detection method, whereby specific ADC components are used for capturing and/or detecting ADAs directed against a certain domain (42-44). Use of a single structural component to determine specificity may be inconclusive: a negative result infers but does not test specificity to domains that were not included (41).…”

Section: Ada Domain Specificity Strategymentioning

confidence: 99%

“…Carrasco-Triguero and colleagues report that an ADA titer greater than 4 (log scale) resulted in decreased exposure for a model trastuzumab ADC in cynomolgus monkey (41). In contrast, an ADA incidence of 4.2% (eight out of 190) was reported in ado-trastuzumab emtansine (T-DM1)-dosed cynomolgus monkeys across eight preclinical studies, with no impact on pharmacokinetics (PK) (41). These results (among others (20)) for trastuzumab confirm that the particular linker and small-molecule drug may contribute unique immunogenicity properties.…”

Section: Preclinical Monitoring Strategiesmentioning

confidence: 99%

“…In a competition strategy, samples are incubated with separate ADC domain(s) in the confirmatory portion of the screening assay (41). Ablation of specific signal during competition with unlabeled ADC components (mAb or cytotoxic drug) indicates domain specificity.…”

Section: Ada Domain Specificity Strategymentioning

confidence: 99%

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Immunogenicity of Antibody Drug Conjugates: Bioanalytical Methods and Monitoring Strategy for a Novel Therapeutic Modality

Hock

Thudium

Carrasco‐Triguero³

et al. 2014

AAPS J

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Abstract. Immunogenicity (the development of an adaptive immune response reactive with a therapeutic) is a well-described but unwanted facet of biotherapeutic development. There are commonly applied procedures for immunogenicity risk assessment, testing strategies, and bioanalysis. With some modifications, these can be applied to new biotherapeutic modalities. For novel therapies such as antibody-drug conjugates (ADCs), the unique structural components may contribute additional complexities to both immunologic responses and bioanalytical methods. US product inserts (USPIs) for two commercially available ADCs detail the incidence of immunogenicity; however, the body of literature on immunogenicity of ADCs is limited. We recently participated in a conference session on this topic (Annual meeting of the American Association of Pharmaceutical Scientists, held November 2013 in San Antonio, TX, USA. The meeting featured the Symposium: Immunogenicity Assessment for Novel Antibody Drug Conjugates, Nonclinical to Clinical) which prompted an effort to share our perspectives on how immunogenicity risk assessment, testing strategies, and bioanalytical methods can be adapted to reflect the complexity of ADC therapeutics.

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Application of Pyrrolobenzodiazepines in Antibody Drug Conjugates

Zhang

Han

2022

Contemporary Accounts in Drug Discovery and Development

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Immunogenicity Assays for Antibody–Drug Conjugates: Case Study with Ado-Trastuzumab Emtansine

Cited by 49 publications

References 23 publications

Preclinical pharmacokinetics and pharmacodynamics of DCLL9718A: An antibody-drug conjugate for the treatment of acute myeloid leukemia

Preclinical pharmacokinetics and pharmacodynamics of DCLL9718A: An antibody-drug conjugate for the treatment of acute myeloid leukemia

Immunogenicity of Antibody Drug Conjugates: Bioanalytical Methods and Monitoring Strategy for a Novel Therapeutic Modality

Application of Pyrrolobenzodiazepines in Antibody Drug Conjugates

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