CovX-BODIES - Fusion Protein Technologies for Biopharmaceuticals: Applications and Challenges - page 546

38

CovX-BODIES

A BHIJIT B HAT ,O LIVIER L AURENT , AND R ODNEY L APPE

CovX Research, Pfizer Worldwide R & D, San Diego, CA, USA

38.1 The CovX-body concept
38.2 Technological aspects
38.3 Applications of the CovX-body technology
References

improve the stability, metabolic liabilities, and pharmaco-
kinetic profiles of the lead molecules. Often, medicinal
chemistry programs are predominantly focused on improv-
ing the safety and pharmacokinetic properties of small
molecules. This is often complicated by the fact that the
chemical and structural modifications that result in increased
potency or selectivity in small molecules also often result in
poor pharmaceutical properties. Peptides have proven to be
even more challenging for drug development as they suffer
from rapid clearance, poor metabolic stability, and lack of
oral bioavailability. Therapeutic antibodies, on the other
hand, are enjoying growing success as biotherapeutic agents
as they generally offer high selectivity and potency against
their molecular targets along with prolonged circulating half
lives [1]. The CovX-Body technology offers a way to confer
antibody-like properties on small molecules and peptides
and enables clinical development of molecules that may
otherwise be compromised by their poor pharmaceutical
properties. CovX-Bodies, like antibodies, work best against
extracellular targets and are currently administered via
intravenous or subcutaneous injections.

38.1 THE CovX-BODY CONCEPT

CovX-Body TM represents a new class of biotherapeutic
agent created by the fusion of a relatively small molecular
weight payload with an antibody, which serves as a carrier
protein scaffold. The fused payload determines the targeting
properties of the CovX-Body, whereas the antibody scaffold
provides bivalency and long circulating half-life for the
payload. The antibody scaffold prevents rapid renal clear-
ance and also slows down the proteolytic and metabolic
degradation of the fused pharmacophore and thereby pro-
vides an elegant solution to overcome the PK-PD problems
of some peptides, small proteins, and traditional small
molecules (Figure 38.1). The fusion reaction in a CovX-
Body is mediated by a linker that is designed to react
exclusively with a specific Lysine residue in the Fab region
the carrier antibody. CovX-Bodies are one of the first
examples of a class of site-specific antibody drug conjugates
wherein the stoichiometry and the site of the drug attach-
ment are precisely defined. CovX-Bodies are also unique in
the respect that the scaffold antibody has no known targets in
vivo and can be used across multiple therapeutic programs
by changing the nature of the fused pharmacophore.
During the course of preclinical development of low
molecular weight therapeutics such as peptides or small
molecules, significant time and resources are devoted to

38.2 TECHNOLOGICAL ASPECTS

38.2.1 Scaffold Antibody

The origins of the scaffold antibody used to generate CovX-
Bodies can be traced to the catalytic antibody work done at the
Scripps Research Institute (La Jolla, CA) in the 1990s, where
researchers pioneered a new process termed “reactive
immunization” to generate antibody catalysts [2]. In general,
thehaptens used togenerate catalytic antibodies up to that point
were designed to mimic the geometric and electronic features
of the proposed transition state of the reaction of interest.