Immunogenicity of biologically-derived therapeutics: Assessment and interpretation of nonclinical safety studies

Ponce, Rafael; Abad, Leslie W.; Amaravadi, Lakshmi; Gelzleichter, Thomas; Gore, Elizabeth R.; Green, James; Gupta, Shalini; Herzyk, Danuta J.; Hurst, Christopher; Ivens, Inge A.; Kawabata, Thomas T.; Maier, Curtis C.; Mounho, Barbara; Rup, Bonita; Shankar, Gopi; Smith, Holly W.; Thomas, Peter T.; Wierda, Daniel

doi:10.1016/j.yrtph.2009.03.012

Cited by 227 publications

(165 citation statements)

References 108 publications

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“…Although the presence of ADAs had an effect on PK and PD following the second dose, and high incidence of ADAs was observed pre-clinically, ADAs in animals are generally not considered predictive in the clinic. 20 …”

Section: Resultsmentioning

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: Resultsmentioning

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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“…Robust immunoassays are critical for evaluation of antibody immunogenicity (IM) during both preclinical and clinical phases (40)(41)(42)(43)(44). Various methodologies have been used for IM testing; however, these methodologies differ with respect to sensitivity for measuring both low-and high-affinity antibody responses (45,46).…”

Section: Introductionmentioning

confidence: 99%

Application of Quantitative Pharmacology in Development of Therapeutic Monoclonal Antibodies

Tabrizi

Funelas

Suria

2010

AAPS J

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Abstract. The advancement of therapeutic monoclonal antibodies during various stages of the drug development process can be effectively streamlined when appropriate translational strategies are applied. Design of successful translational strategies for development of monoclonal antibodies should allow for understanding of the dose-and concentration-response relationships with respect to both beneficial and toxic effects from early phases of drug development. Evaluation of relevant biomarkers during early stages of drug development should facilitate the successful design of safe and effective dosing strategies. Moreover, application of quantitative pharmacology is critical for translation of exposure-response relationships early on.

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“…Interpretation of ADA data should be made in the context of pharmaco kinetics/optical density (OD) readout and observed adverse toxicity effects. In presented case studies, the approach published by Ponce et al was applied for both nonclinical and clinical immunogenicity evaluations [6]. The presenter suggested that ADA testing could be suspended if no immunogenicity development is observed in the study.…”

Section: News and Analysis | Conference Reportmentioning

confidence: 99%

Conference Report: Immunogenicity: Prediction, Detection and Effective Assay Development

Gorovits

2010

Bioanalysis

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The Immunogenicity: Prediction, Detection and Effective Assay Development conference, organized by the Pharma iQ, a division of IQPC, was held in Munich, Germany, 21–23 June of 2010. The meeting covered a broad range of topics related to the unwanted immunogenicity of biotherapeutics. Perspectives from the US FDA and EMA were presented along with discussions focusing on analytical method development and validation, methodologies allowing for prediction of potential immunogenicity, risk-based assessment and mitigation of immunogenic potential of biologics, and other topics. The conference consisted of a preconference workshop and 2 days of plenary sessions, which included presentations as well as group discussions. Particular attention was drawn to the review of the FDA guidance and Committee for Medicinal Products for Human Use guidelines on immunogenicity evaluation. Presenters and meeting participants engaged in an active and productive discussion around scientific aspects involved in immunogenicity evaluation and methodologies involved during routine sample testing. Discussions also centered around challenges and opportunities related to detection and characterization of immunogenicity, as well as analysis of the latest technologies to enable accurate and meaningful interpretation of the results. The meeting attracted a broad range of participants from various sized companies, backgrounds and interests.

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Immunogenicity of biologically-derived therapeutics: Assessment and interpretation of nonclinical safety studies

Cited by 227 publications

References 108 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

Application of Quantitative Pharmacology in Development of Therapeutic Monoclonal Antibodies

Conference Report: Immunogenicity: Prediction, Detection and Effective Assay Development

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