Model-Informed Drug Development of the Masked Anti-PD-L1 Antibody CX-072

Abstract

CX‑072 is an anti‑PD‑L1 (programmed death ligand 1) Probody therapeutic (Pb‐Tx) designed to be preferentially activated by proteases in the tumor microenvironment and not in healthy tissue. Here, we report the model‐informed drug development of CX‐072. A quantitative systems pharmacology (QSP) model that captured known mechanisms of Pb‐Tx activation, biodistribution, elimination, and target engagement was used to inform clinical translation.

Mechanistic PKPD Models of Protein Therapeutics for Early Clinical Development

Abstract

Mechanistic PKPD models support FIH trial design, development of targeted immunotherapies, and understanding complex PK properties and covariates. 

Mechanistic Quantitative Pharmacology Strategies for the Early Clinical Development of Bispecific Antibodies in Oncology

Abstract

Bispecific antibodies (bsAbs) have become an integral component of the therapeutic research strategy to treat cancer. In addition to clinically validated immune cell re‐targeting, bsAbs are being designed for tumor targeting and as dual immune modulators. Explorative preclinical and emerging clinical data indicate potential for enhanced efficacy and reduced systemic toxicity.

Fibrinolytic Therapy for Refractory COVID‐19 Acute Respiratory Distress Syndrome: Scientific Rationale and Review

Abstract

The coronavirus disease 2019 (COVID‐19) pandemic has caused respiratory failure and associated mortality in numbers that have overwhelmed global health systems. Thrombotic coagulopathy is present in nearly three quarters of patients with COVID‐19 admitted to the intensive care unit, and both the clinical picture and pathologic findings are consistent with microvascular occlusive phenomena being a major contributor to their unique form of respiratory failure.

QSP Model of Colonic Motility

Abstract

In this collaboration with Takeda, we developed a mathematical model of colon physiology driven by serotonin signaling in the enteric nervous system. No such models are currently available to assist drug discovery and development for GI motility disorders. Model parameterization was informed by published preclinical and clinical data. Our simulations provide clinically relevant readouts of bowel movement frequency and stool consistency.

QSP Model of a Masked, Tumor-Activated Antibody

Abstract

PROBODY therapeutics (Pb‐Tx) are protease‐activatable prodrugs of monoclonal antibodies (mA bs) designed to target tumors where protease activity is elevated while avoiding normal tissue. They are composed of a parental mA b, a mask that inhibits antibody binding to target, and a protease‐cleavable substrate between the mask and the mA b. We report a quantitative systems pharmacology model for the rational design and clinical translation of Pb‐Tx.

Model Firsts: How QSP can Pick the Right Dose for First-in-Human Trials

Abstract

By combining disparate data into coherent mechanistic models, quantitative systems pharmacology is becoming a key tool for picking the right dose for first-in-human trials and other early make-or-break decisions. Advocates see it as part of an expanding toolbox of models that can yield better safety and efficacy predictions from preclinical data, and want regulators to include it in their guidances.

QSP Model of modRNA to Treat Crigler-Najjar Syndrome Type 1

Abstract

Crigler‐Najjar syndrome type 1 (CN1) is an autosomal recessive disease caused by a marked decrease in uridine‐diphosphate‐glucuronosyltransferase (UGT1A1) enzyme activity. Delivery of hUGT1A1‐modRNA (a modified messenger RNA encoding for UGT1A1) as a lipid nanoparticle is anticipated to restore hepatic expression of UGT1A1, allowing normal glucuronidation and clearance of bilirubin in patients. To support translation from preclinical to clinical studies, and first‐in‐human studies, a quantitative systems pharmacology (QSP) model was developed.