Related Experiment Video

Updated: May 10, 2026

Potentiation of Anticancer Antibody Efficacy by Antineoplastic Drugs: Detection of Antibody-drug Synergism Using the Combination Index Equation
15:04

Potentiation of Anticancer Antibody Efficacy by Antineoplastic Drugs: Detection of Antibody-drug Synergism Using the Combination Index Equation

Published on: January 19, 2019

Death receptor 5 agonistic antibody PRO95780: preclinical pharmacokinetics and concentration-effect relationship

Hong Xiang1, Arthur E Reyes, Steve Eppler

  • 1Department of Pharmacokinetic and Pharmacodynamic Sciences, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. hxc@gene.com

Cancer Chemotherapy and Pharmacology
|June 18, 2013
PubMed
Abstract

Insights

PRO95780, a monoclonal antibody targeting death receptor 5, exhibits linear pharmacokinetics across species. A dose of 10 mg/kg every two weeks is predicted to achieve target serum concentrations in 95% of patients for cancer treatment.

Area of Science:

  • Pharmacology
  • Immunology
  • Oncology

Background:

  • PRO95780 is a human monoclonal antibody (mAb) targeting death receptor 5 (DR5).
  • It was developed as a potential cancer therapeutic agent.
  • Understanding its pharmacokinetic and concentration-effect relationships is crucial for clinical trial design.

Purpose of the Study:

  • Characterize the pharmacokinetics (PK) of PRO95780 in mice, rats, and cynomolgus monkeys.
  • Determine concentration-effect relationships in human cancer xenograft models.
  • Guide the selection of optimal dose and regimen for clinical trials.

Main Methods:

  • PK profiles were assessed in mice, rats, and cynomolgus monkeys.
  • Efficacy studies were conducted in three human cancer xenograft models.
  • PK/pharmacodynamic (PD) modeling was used to determine tumor-istatic serum concentrations (TSCs).
  • Species-invariant time PK scaling estimated human disposition.

Main Results:

  • Linear PK was observed across all tested species.
  • A target TSC of 22 μg/mL was identified in mice.
  • A dose of 10 mg/kg administered every two weeks (Q2W) is predicted to achieve TSC in 95% of patients.

Conclusions:

  • PRO95780 demonstrates linear PK in preclinical species.
  • Estimated TSCs varied across different xenograft models.
  • The projected human dose and Q2W regimen are achievable within the range of existing mAbs.

More Related Videos

Initial Evaluation of Antibody-conjugates Modified with Viral-derived Peptides for Increasing Cellular Accumulation and Improving Tumor Targeting11:58

Initial Evaluation of Antibody-conjugates Modified with Viral-derived Peptides for Increasing Cellular Accumulation and Improving Tumor Targeting

Published on: March 8, 2018

In Vitro Methods for Comparing Target Binding and CDC Induction Between Therapeutic Antibodies: Applications in Biosimilarity Analysis07:25

In Vitro Methods for Comparing Target Binding and CDC Induction Between Therapeutic Antibodies: Applications in Biosimilarity Analysis

Published on: May 4, 2017

Related Concept Videos

Pharmacokinetic–Pharmacodynamic Relationship: Intensity of Dose-Effect Relationship01:23

Pharmacokinetic–Pharmacodynamic Relationship: Intensity of Dose-Effect Relationship

Pharmacodynamics explores the relationship between drug concentration and its effect. In a quantal response drug, the duration of action better correlates with drug concentration, while for graded effect drugs, the intensity of response is more relevant. This intensity depends on the dose, drug removal rate, and the region of the concentration–response curve.The concentration–response curve can be divided into three regions. Region 3 (80–100% maximum response) demonstrates that even as drug...
Pharmacokinetic–Pharmacodynamic Relationship: Dose to Pharmacological Effect01:28

Pharmacokinetic–Pharmacodynamic Relationship: Dose to Pharmacological Effect

A drug’s dosage and pharmacokinetic properties determine how quickly it acts, how intense its effects are, and how long it lasts. Higher doses increase drug concentration at receptor sites, producing a hyperbolic curve when pharmacologic response is plotted against drug dose. Converting this scale to a log-linear format results in a sigmoidal curve, better representing dose–response relationships.For drugs following a one-compartment model, the pharmacologic response is directly proportional to...
Pharmacokinetic–Pharmacodynamic Relationship: Exposure, Response and Effect01:26

Pharmacokinetic–Pharmacodynamic Relationship: Exposure, Response and Effect

The pharmacokinetic-pharmacodynamic (PK-PD) relationship describes the intricate link between drug exposure, efficacy, and toxicity, forming the foundation for optimal dosing regimens. This relationship uses mathematical modeling to characterize drug concentration-effect dynamics, ensuring precise therapeutic outcomes.Exposure represents the pharmacokinetic aspect of the PK-PD relationship, denoting the drug amount that elicits a biological response. It is typically quantified by administered...
Pharmacokinetic–Pharmacodynamic Relationship: Duration of Dose-Effect Relationship01:14

Pharmacokinetic–Pharmacodynamic Relationship: Duration of Dose-Effect Relationship

For drugs producing a quantal response, onset occurs when plasma concentration reaches a minimum effective level (Cmin). The drug's action duration depends on how long the plasma concentration remains above Cmin.Two primary factors influence this duration: dose size and the rate of drug removal from the action site. Both depend on the drug's redistribution to poorly perfused tissues and elimination processes. A larger dose promotes rapid onset and prolongs the effect's duration.Consider a...