Design and Pharmacokinetic Characterization of Novel Antibody Formats for Ocular Therapeutics.
OBJECTIVE
To design and select the next generation of ocular therapeutics, we performed a comprehensive ocular and systemic pharmacokinetic (PK) analysis of a variety of antibodies and antibody fragments, including a novel-designed bispecific antibody.


METHODS
Molecules were administrated via intravitreal (IVT) or intravenous (IV) injections in rabbits, and antibody concentrations in each tissue were determined by ELISA. A novel mathematical model was developed to quantitate the structure-PK relationship.


RESULTS
After IVT injection, differences in vitreal half-life observed across all molecules ranged between 3.2 and 5.2 days. Modification or elimination of the fragment crystallizable (Fc) region reduced serum half-life from 9 days for the IgG to 5 days for the neonatal Fc receptor (FcRn) null mAb, to 3.1 to 3.4 days for the other formats. The F(ab')2 was the optimal format for ocular therapeutics with comparable vitreal half-life to full-length antibodies, but with minimized systemic exposure. Concomitantly, the consistency among mathematical model predictions and observed data validated the model for future PK predictions. In addition, we showed a novel design to develop bispecific antibodies, here with activity targeting multiple angiogenesis pathways.


CONCLUSIONS
We demonstrated that protein molecular weight and Fc region do not play a critical role in ocular PK, as they do systemically. Moreover, the mathematical model supports the selection of the "ideal therapeutic" by predicting ocular and systemic PK of any antibody format for any dose regimen. These findings have important implications for the design and selection of ocular therapeutics according to treatment needs, such as maximizing ocular half-life and minimizing systemic exposure.
Department of Preclinical and Translational Pharmacokinetics Genentech, Inc., South San Francisco, California, United States.
Kapil
K
Gadkar
Department of Preclinical and Translational Pharmacokinetics Genentech, Inc., South San Francisco, California, United States.
Cinthia V
CV
Pastuskovas
Department of Molecular Oncology, Genentech, Inc., South San Francisco, California, United States.
Jennifer E
JE
Le Couter
Department of Protein Chemistry, Genentech, Inc., South San Francisco, California, United States.
J Michael
JM
Elliott
Department of Biochemical and Cellular Pharmacology, Genentech, Inc., South San Francisco, California, United States.
Jianhuan
J
Zhang
Department of Antibody Engineering, Genentech, Inc., South San Francisco, California, United States.
Chingwei V
CV
Lee
Department of Antibody Engineering, Genentech, Inc., South San Francisco, California, United States.
Sarah
S
Sanowar
Department of Antibody Engineering, Genentech, Inc., South San Francisco, California, United States.
Germaine
G
Fuh
Department of Antibody Engineering, Genentech, Inc., South San Francisco, California, United States.
Hok Seon
HS
Kim
Department of Antibody Engineering, Genentech, Inc., South San Francisco, California, United States.
T Noelle
TN
Lombana
Department of Antibody Engineering, Genentech, Inc., South San Francisco, California, United States.
Christoph
C
Spiess
Department of Protein Chemistry, Genentech, Inc., South San Francisco, California, United States.
Makia
M
Nakamura
Department of Protein Chemistry, Genentech, Inc., South San Francisco, California, United States.
Phil
P
Hass
Department of Protein Chemistry, Genentech, Inc., South San Francisco, California, United States.
Whitney
W
Shatz
Department of Biochemical and Cellular Pharmacology, Genentech, Inc., South San Francisco, California, United States.
Y Gloria
YG
Meng
Department of Protein Chemistry, Genentech, Inc., South San Francisco, California, United States.
Justin M
JM
Scheer
D000818:Animals; D000906:Antibodies / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000915:Antibody Affinity; D015195:Drug Design; D005123:Eye / Q000378:metabolism*; D005128:Eye Diseases / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D058449:Intravitreal Injections; D008297:Male; D011485:Protein Binding; D011817:Rabbits
D000906:Antibodies; D000911:Antibodies, Monoclonal