A mechanistic PK/PD model of AZD0171 (anti‐LIF) to support Phase II dose selection

AZD0171 (INN: Falbikitug) is being developed as a humanized monoclonal antibody (mAb), immunoglobulin G subclass 1 (IgG1), which binds specifically to the immunosuppressive human cytokine leukemia inhibitory factor (LIF) and inhibits downstream signaling by blocking recruitment of glycoprotein 130 (...

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Published in:CPT: pharmacometrics and systems pharmacology 2024-10, Vol.13 (10), p.1670-1681
Main Authors: Shahraz, Azar, Penney, Mark, Candido, Juliana, Opoku‐Ansah, Grace, Neubauer, Melanie, Eyles, Jim, Ojo, Oluwaseun, Liu, Nelson, Luheshi, Nadia M., Phipps, Alex, Vishwanathan, Karthick
Format: Article
Language:English
Subjects:
Antibodies
Antibodies, Monoclonal, Humanized - administration & dosage
Antibodies, Monoclonal, Humanized - pharmacokinetics
Antibodies, Monoclonal, Humanized - pharmacology
Cancer therapies
Chemotherapy
Clinical Trials, Phase II as Topic
Dose-Response Relationship, Drug
Drug dosages
Glycoproteins
Humans
International organizations
Leukemia
Leukemia Inhibitory Factor - metabolism
Lung cancer
Medical prognosis
Models, Biological
Neoplasms - drug therapy
Pancreatic cancer
Patients
Pharmacodynamics
Pharmacokinetics
Signal Transduction - drug effects
Tumors
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Summary:AZD0171 (INN: Falbikitug) is being developed as a humanized monoclonal antibody (mAb), immunoglobulin G subclass 1 (IgG1), which binds specifically to the immunosuppressive human cytokine leukemia inhibitory factor (LIF) and inhibits downstream signaling by blocking recruitment of glycoprotein 130 (gp130) to the LIF receptor (LIFR) subunit (gp190) and the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and is intended to treat adult participants with advanced solid tumors. LIF is a pleiotropic cytokine (and a member of the IL‐6 family of cytokines) involved in many physiological and pathological processes and is highly expressed in a subset of solid tumors, including non‐small cell lung cancer (NSCLC), colon, ovarian, prostate, and pancreatic cancer. The aim of this work was to develop a mechanistic PK/PD model to investigate the effect of AZD0171 on tumor LIF levels, predict the level of downstream signaling complex (LIF:LIFR:gp130) inhibition, and examine the dose–response relationship to support dose selection for a Phase II clinical study. Modeling results show that tumor LIF is inhibited in a dose‐dependent manner with >90% inhibition for 95% of patients at the Phase II clinical dose of 1500 mg Q2W.
ISSN:2163-8306
2163-8306
DOI:10.1002/psp4.13204