Projecting human pharmacokinetics of therapeutic antibodies from nonclinical data

Deng, Rong; Iyer, Suhasini; Theil, Frank‐Peter; Mortensen, Deborah L.; Fielder, Paul J.; Prabhu, Saileta

doi:10.4161/mabs.3.1.13799

Cited by 250 publications

(302 citation statements)

References 22 publications

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“…At the high dose of 20 mg/kg, MCLL0517A demonstrated bi-phasic disposition and a total clearance that was within the expected range for an IgG1 antibody. 15 It was also in line with a non-binding antibody, anti-gD antibody, suggesting that the target was completely saturated at this dose. The saturation of target at 20 mg/kg was also confirmed by the receptor occupancy data, in which MCLL0517A demonstrated near complete and sustained receptor occupancy.…”

Section: Resultsmentioning

confidence: 68%

“…The total clearance of MCLL0517A at the high dose (20 mg/kg) was similar to that of non-binding anti-gD antibody (3.91 mL/day/kg) and is consistent with the expected clearance range for a human IgG1 antibody in cynomolgus monkeys. 15 These data suggest that the target was saturated at the dose level of 20 mg/kg in cynomolgus monkeys for the duration of the study.…”

Section: Resultsmentioning

confidence: 90%

See 1 more Smart Citation

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: 68%

Section: Resultsmentioning

confidence: 90%

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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“…The optimal exponents were estimated to be 0.85 for soluble antigens and 0.9 for membrane-based antigens 13 . In a similar analysis of 13 mAbs with linear CL, Deng et al showed that simple allometric scaling of CL in cynomolgus monkey with an exponent of 0.85 provided a good estimate of human CL 11 . Dong et al also concluded that single species monkey PK predicted human PK of mAbs with linear CL within 2.3 fold 12 .…”

Section: Discussionmentioning

confidence: 99%

“…Cynomolgus monkey is also the preferred species for predicting the PK of mAbs with linear CL in humans: several groups have reported the successful use of fixed allometric exponents to predict CL and volume of distribution of mAbs in human from data in cynomolgus monkey. 11-14 For mAbs that exhibit non-linear CL due to TMDD, scaling of PK is more challenging. In order to take into account the kinetics of mAb binding to its target, a mechanistic TMDD model is required, with proper exploration of species differences in target expression and binding 5 , 15-17.…”

Section: Introductionmentioning

confidence: 99%

Linear pharmacokinetic parameters for monoclonal antibodies are similar within a species and across different pharmacological targets: A comparison between human, cynomolgus monkey and hFcRn Tg32 transgenic mouse using a population-modeling approach

Betts

Keunecke²,

Steeg³

et al. 2018

mAbs

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The linear pharmacokinetics (PK) of therapeutic monoclonal antibodies (mAbs) can be considered a class property with values that are similar to endogenous IgG. Knowledge of these parameters across species could be used to avoid unnecessary in vivo PK studies and to enable early PK predictions and pharmacokinetic/pharmacodynamic (PK/PD) simulations. In this work, population-pharmacokinetic (popPK) modeling was used to determine a single set of ‘typical’ popPK parameters describing the linear PK of mAbs in human, cynomolgus monkey and transgenic mice expressing the human neonatal Fc receptor (hFcRn Tg32), using a rich dataset of 27 mAbs. Non-linear PK was excluded from the datasets and a 2-compartment model was applied to describe mAb disposition. Typical human popPK estimates compared well with data from comparator mAbs with linear PK in the clinic. Outliers with higher than typical clearance were found to have non-specific interactions in an affinity-capture self-interaction nanoparticle spectroscopy assay, offering a potential tool to screen out these mAbs at an early stage. Translational strategies were investigated for prediction of human linear PK of mAbs, including use of typical human popPK parameters and allometric exponents from cynomolgus monkey and Tg32 mouse. Each method gave good prediction of human PK with parameters predicted within 2-fold. These strategies offer alternative options to the use of cynomolgus monkeys for human PK predictions of linear mAbs, based on in silico methods (typical human popPK parameters) or using a rodent species (Tg32 mouse), and call into question the value of completing extensive in vivo preclinical PK to inform linear mAb PK.

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“…1-6 In the case of antibodies that demonstrate significant target-mediated drug disposition (TMDD), PK characterization in non-human primates requires antibody concentration-time profiles over a wide concentration range to capture saturation of target-mediated clearance that frequently manifests in PK non-linearities. This information can only be obtained if the test article is well tolerated in preclinical in vivo studies over a wide dose range.…”

Section: Introductionmentioning

confidence: 99%

Prediction of non-linear pharmacokinetics in humans of an antibody-drug conjugate (ADC) when evaluation of higher doses in animals is limited by tolerability: Case study with an anti-CD33 ADC

Figueroa

Leipold

Leong

et al. 2018

mAbs

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For antibody-drug conjugates (ADCs) that carry a cytotoxic drug, doses that can be administered in preclinical studies are typically limited by tolerability, leading to a narrow dose range that can be tested. For molecules with non-linear pharmacokinetics (PK), this limited dose range may be insufficient to fully characterize the PK of the ADC and limits translation to humans. Mathematical PK models are frequently used for molecule selection during preclinical drug development and for translational predictions to guide clinical study design. Here, we present a practical approach that uses limited PK and receptor occupancy (RO) data of the corresponding unconjugated antibody to predict ADC PK when conjugation does not alter the non-specific clearance or the antibody-target interaction. We used a 2-compartment model incorporating non-specific and specific (target mediated) clearances, where the latter is a function of RO, to describe the PK of anti-CD33 ADC with dose-limiting neutropenia in cynomolgus monkeys. We tested our model by comparing PK predictions based on the unconjugated antibody to observed ADC PK data that was not utilized for model development. Prospective prediction of human PK was performed by incorporating in vitro binding affinity differences between species for varying levels of CD33 target expression. Additionally, this approach was used to predict human PK of other previously tested anti-CD33 molecules with published clinical data. The findings showed that, for a cytotoxic ADC with non-linear PK and limited preclinical PK data, incorporating RO in the PK model and using data from the corresponding unconjugated antibody at higher doses allowed the identification of parameters to characterize monkey PK and enabled human PK predictions.

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Projecting human pharmacokinetics of therapeutic antibodies from nonclinical data

Cited by 250 publications

References 22 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

Linear pharmacokinetic parameters for monoclonal antibodies are similar within a species and across different pharmacological targets: A comparison between human, cynomolgus monkey and hFcRn Tg32 transgenic mouse using a population-modeling approach

Prediction of non-linear pharmacokinetics in humans of an antibody-drug conjugate (ADC) when evaluation of higher doses in animals is limited by tolerability: Case study with an anti-CD33 ADC

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