Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Jul;16(7):1232-1242.
doi: 10.1111/cts.13526. Epub 2023 May 31.

Translation of the efficacy of antibody-drug conjugates from preclinical to clinical using a semimechanistic PK/PD model: A case study with RC88

Qiaoning Li  1   2 , Ling Wang  1   2 , Jinfeng Zhang  3 , Guorui Zhao  1   2 , Zhihao Liu  1   2 , Xinting Ma  1   2 , Jing Jiang  2   3
Affiliations

Translation of the efficacy of antibody-drug conjugates from preclinical to clinical using a semimechanistic PK/PD model: A case study with RC88

Qiaoning Li et al. Clin Transl Sci. 2023 Jul.

Abstract

Three semimechanistic pharmacokinetic/pharmacodynamic (PK/PD) models, Simeoni, Jumbe, and Hybrid, were used for the efficacy translation of RC88 from preclinical to clinical. RC88 is a mesothelin-targeting antibody-drug conjugate for malignant solid tumor. In the preclinical study, the relationship between PKs and PDs was determined using the xenograft mouse model derived from ovarian cancer and lung cancer cell lines. A secondary parameter representing the efficacy index of the drug, termed as tumor static concentration (TSC), was calculated using the three semimechanistic PK/PD models. A mechanism-based target-mediated drug disposition model was used to predict the human PKs. TSC from mice and predicted human PK were integrated to predict human efficacy dose. Results showed that 2 cell lines were sensitive to drugs, and the predicted efficacy dose was between 0.82 and 1.96 mg/kg q1w.

PubMed Disclaimer

Conflict of interest statement

The authors declared no competing interests for this work.

Figures

FIGURE 1
FIGURE 1
Schematic representation of PK/PD model (a) Two‐compartment linear PK model was linked to (b) a model of tumor growth inhibition; (c) the TMDD PK models. ADC, antibody‐drug conjugated; CL, clearance; PD, pharmacodynamic; PK, pharmacokinetic; TMDD, target‐mediated drug disposition; V max, maximal rate of metabolism.
FIGURE 2
FIGURE 2
Balb/c nude mice were treated with the vehicle, RC88. (a) OVCAR3‐MSLN‐3# cell line on Q1W × 1 schedule; (b) OVCAR3‐MSLN‐3# cell line on Q1W × 3 schedule. RC88 treatment had a significant effect at 1.5 and 3 mg/kg. (c) H292‐MSLN‐9C8 cell line on q1w × 3 schedule. RC88 treatment had significant effect at 1.5 and 3 mg/kg and moderate effect at 0.75 mg/kg.
FIGURE 3
FIGURE 3
Concentration versus time profiles of RC88. (a) Observed and model fitted mouse profiles at 0.7 and 2.1 mg/kg; (b) Observed and model fitted monkey profiles at 0.5, 1.5, and 5 mg/kg. Circles represent observations, curves represent individual predictions.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Hafeez U, Parakh S, Gan HK, Scott AM. Antibody‐drug conjugates for cancer therapy. Molecules. 2020;25:15‐29. doi:10.3390/molecules25204764 - DOI - PMC - PubMed
    1. Sievers EL, Senter PD. Antibody‐drug conjugates in cancer therapy. Annu Rev Med. 2013;64:15‐29. doi:10.1146/annurev-med-050311-201823 - DOI - PubMed
    1. Ducry L, Stump B. Antibody‐drug conjugates: linking cytotoxic payloads to monoclonal antibodies. Bioconjug Chem. 2010;21:5‐13. doi:10.1021/bc9002019 - DOI - PubMed
    1. Chari RV, Miller ML, Widdison WC. Antibody‐drug conjugates: an emerging concept in cancer therapy. Angew Chem Int Ed Engl. 2014;53:3796‐3827. doi:10.1002/anie.201307628 - DOI - PubMed
    1. Doi T, Shitara K, Naito Y, et al. Safety, pharmacokinetics, and antitumour activity of trastuzumab deruxtecan (DS‐8201), a HER2‐targeting antibody‐drug conjugate, in patients with advanced breast and gastric or gastro‐oesophageal tumours: a phase 1 dose‐escalation study. Lancet Oncol. 2017;18:1512‐1522. doi:10.1016/S1470-2045(17)30604-6 - DOI - PubMed

Publication types

Substances

LinkOut - more resources