Evaluating the Use of Antibody Variable Region (Fv) Charge as a Risk Assessment Tool for Predicting Typical Cynomolgus Monkey Pharmacokinetics.
The pharmacokinetic (PK) behavior of monoclonal antibodies in cynomolgus monkeys (cynos) is generally translatable to that in humans. Unfortunately, about 39% of the antibodies evaluated for PKs in cynos have fast nonspecific (or non-target-mediated) clearance (in-house data). An empirical model relating variable region (Fv) charge and hydrophobicity to cyno nonspecific clearance was developed to gauge the risk an antibody would have for fast nonspecific clearance in the monkey. The purpose of this study was to evaluate the predictability of this empirical model on cyno nonspecific clearance with antibodies specifically engineered to have either high or low Fv charge. These amino acid changes were made in the Fv region of two test antibodies, humAb4D5-8 and anti-lymphotoxin α. The humAb4D5-8 has a typical nonspecific clearance in cynos, and by making it more positively charged, the antibody acquires fast nonspecific clearance, and making it less positively charged did not impact its clearance. Anti-lymphotoxin α has fast nonspecific clearance in cynos, and making it more positively charged caused it to clear even faster, whereas making it less positively charged caused it to clear slower and within the typical range. These trends in clearance were also observed in two other preclinical species, mice and rats. The effect of modifying Fv charge on subcutaneous bioavailability was also examined, and in general bioavailability was inversely related to the direction of the Fv charge change. Thus, modifying Fv charge appears to impact antibody PKs, and the changes tended to correlate with those predicted by the empirical model.
From the Departments of Preclinical and Translational Pharmacokinetics.
Daniela
D
Bumbaca Yadav
Late Stage Pharmaceutical Development.
Vikas K
VK
Sharma
From the Departments of Preclinical and Translational Pharmacokinetics.
Charles Andrew
CA
Boswell
Antibody Engineering.
Isidro
I
Hotzel
Drug Delivery, Genentech Inc., South San Francisco, California 94080.
Devin
D
Tesar
Antibody Engineering.
Yonglei
Y
Shang
BioAnalytical Sciences.
Yong
Y
Ying
BioAnalytical Sciences.
Saloumeh K
SK
Fischer
Research.
Jane L
JL
Grogan
Research.
Eugene Y
EY
Chiang
Nonclinical Operations, and.
Konnie
K
Urban
Nonclinical Operations, and.
Sheila
S
Ulufatu
From the Departments of Preclinical and Translational Pharmacokinetics.
Leslie A
LA
Khawli
From the Departments of Preclinical and Translational Pharmacokinetics.
Saileta
S
Prabhu
From the Departments of Preclinical and Translational Pharmacokinetics.
Sean
S
Joseph
Drug Delivery, Genentech Inc., South San Francisco, California 94080 kelley.bob@gene.com.
Robert F
RF
Kelley
D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D007135:Immunoglobulin Variable Region / Q000737:chemistry / Q000276:immunology*; D008252:Macaca fascicularis; D010599:Pharmacokinetics; D018570:Risk Assessment
D007135:Immunoglobulin Variable Region
antibody; antibody engineering; charge; clearance; homology modeling; mutant; pharmacokinetics