Mechanistic Projection of First-in-Human Dose for Bispecific Immunomodulatory P-Cadherin LP-DART: An Integrated PK/PD Modeling Approach

被引：34

作者：

Chen, X. ^{[1
]}

Haddish-Berhane, N. ^{[2
,3
]}

Moore, P. ^{[4
]}

Clark, T. ^{[2
]}

Yang, Y. ^{[4
]}

Li, H. ^{[4
]}

Xuan, D. ^{[5
]}

Barton, H. A. ^{[2
]}

Betts, A. M. ^{[2
]}

Barletta, F. ^{[6
]}

机构：

[1] Pfizer, Pharmacokinet Dynam & Metab, Cambridge, MA USA

[2] Pfizer, Pharmacokinet Dynam & Metab, Groton, CT USA

[3] Janssen Pharmaceut, Clin Pharmacol & Pharmacometr, Quantitat Sci, Spring House, PA USA

[4] MacroGenics, Rockville, MD USA

[5] Pfizer, Clin Pharmacol, San Diego, CA USA

[6] Pfizer, Pharmacokinet Dynam & Metab, Pearl River, NY USA

来源：

CLINICAL PHARMACOLOGY & THERAPEUTICS | 2016年 / 100卷 / 03期

关键词：

THERAPEUTIC ANTIBODIES; BREAST-CANCER; FRAGMENT; TRIALS;

D O I：

10.1002/cpt.393

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

A bispecific immunomodulatory biotherapeutic molecule (P-cadherin LP-DART) based on the Dual Affinity Re-Targeting (DART) scaffold has been developed as a potential antitumor treatment showing efficacy in preclinical testing. A minimal anticipated biological effect level (MABEL) approach was applied to project the first-in-human (FIH) dose, because of its immune agonistic properties following target engagement. The pharmacological activity of P-cadherin LP-DART is driven by binding to both P-cadherin on the tumor cells and CD3 on T cells. Therefore, the concentration of the tri-molecular synapse formed between drug, T cell, and tumor cell, rather than drug concentration, is responsible for efficacy. A mechanistic pharmacokinetic/pharmacodynamic (PK/PD)-driven approach was explored to understand the exposure-response relationship based on the synapse concentration to project the MABEL dose. Orthogonal approaches including PK-driven and receptor occupancy calculations were also investigated. This study showcases the application of PK/PD modeling in immune-oncology, and could potentially be implemented for other bispecific biotherapeutics.

引用

页码：232 / 241

页数：10

共 27 条

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