Quantitative Pharmacology and Individualized Therapy Strategies in Development of Therapeutic Proteins for Immune-Mediated Inflammatory Diseases
by Honghui Zhou, Diane R. Mould
4 Application of Minimal Anticipated Biological Effect Level (MABEL) in Human Starting Dose Selection for Immunomodulatory Protein Therapeutics – Principles and Case Studies
Haiqing Wang1, Zheng Yang1 and Rong Shi2
1Bristol‐Myers Squibb Co., Department of Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization, 3551 Lawrenceville Princeton, Lawrence Township, NJ, 08648, USA
2Bristol‐Myers Squibb Co., Department of Clinical Pharmacology and Pharmacometrics, 3551 Lawrenceville Princeton, Lawrence Township, NJ, 08648, USA
4.1 Introduction
Immunomodulatory protein therapeutics (IMPTs) are designed to interact with one or more components of the immune system to either enhance or suppress immune responses. These protein therapeutics have revolutionized the treatment of cancer and immune‐related diseases in the past two decades. One of the most notable examples is the immune checkpoint inhibitors, such as anti‐cytotoxic T‐lymphocyte‐associated protein 4 (CTLA‐4, Yervoy®) and anti‐programmed cell death protein 1 (PD‐1) (Opdivo® and Keytruda®) monoclonal antibodies (mAbs), which have demonstrated remarkable anti‐tumor efficacy by effectively enhancing patient immune responses against cancer cells [1]. Likewise, immune suppressive therapeutic proteins such as anti‐tumor necrosis factor α (TNFα) antibody (e.g. Humira®) and CTLA‐4 Fc fusion protein (Oriencia®) have also improved the treatment of various inflammatory and autoimmune diseases [2].
A key challenge in ...