#DRUGS
Fragmented antibody for covid 19 treatmentThe antibody molecule is modular and
separate domains can be extracted through biochemical or genetic means.It is clear from review of the literaturethat a wave of novel, antigen-specific molecular forms may soon enter clinical evaluation. This report examines the developmental histories of therapeutics
derived from antigen-specific fragments of antibodies produced by recombinant
processes. Three general types of fragments were observed, antigen-binding
fragments (Fab), single chain variable fragments (scFv) and “third generation”
(3G), each representing a successive wave of antibody fragment technology. In
parallel, drug developers have explored multi-specificity and conjugation with exogenous functional moieties in all three fragment types. Despite high hopes and an active pipeline, enthusiasm for differentiating performance of fragments should, perhaps, be tempered as there are yet few data that suggest these molecules have distinct clinical properties due only
to their size. Introduction Antibody drug designers have long hypothesized that the modular nature of immunoglobulins could be exploited to engineer “customized” therapeutics, with
pharmacologic properties optimized for specific applications. Thus, half-life and distribution, valency, affinity and avidity, tissue penetration and bioactivities could each be controlled by selection of
appropriate molecular domains or defined
genetic features, thereby theoretically
allowing developers control over both
safety and efficacy of antibody products.
It is tempting to further speculate that the
properties of designed antibodies could
confer additional benefits for biomanufacturing, such as improved purity, quality
and quantity of goods, and homogeneity of molecular species produced. This
is a remarkable vision, and one might be
tempted to see the beginnings of this revolution in antibody fragment products such
as the marketed therapeutic certolizumab
pegol (Cimzia).
This report focuses on therapeutics
derived from antigen-specific fragments
of antibodies produced by recombinant
processes of any derivation and discusses
54 of these molecules that entered clinical
study sponsored by a commercial firm, as
well as candidates in preclinical development. Fusion proteins such as etanercept
(Enbrel), which is composed of the ligand
binding portion of TNFα receptor fused
to an antibody Fc domain, were therefore
excluded. Due to the extensive literature
describing the technologies and specific
antibody drug candidates, only selected
references are provided.
Three technologies—antigen-binding
fragments (Fab), single chain variable fragments (scFv), and “third generation” (3G)
molecules—represent successive waves
of antibody fragment technologies (Fig.
1). Fabs are clearly the most thoroughly
explored; knowledge and experience was
generated during the development of three
US Food and Drug Administration (FDA)
approved therapeutics (Table 1), six agents
in active clinical development, and 20 discontinued programs, which collectively
account for 49% of 54 identified antibody
fragments that entered the commercial
Antibody fragments
Hope and hype
Aaron L. Nelson
Tufts University School of Medicine; Boston, MA USA
78 mAbs Volume 2 Issue 1
bispecific and multimeric molecules will
expand, creating additional opportunities
for clinical benefit. Given the coming diversification of fragment types, it is possible
that antibody fragments, or modular therapeutics incorporating antibody domains,
with efficacy and safety profiles superior
to full-sized mAbs will be approved in the
coming decade. Alternatively, fragments,
as a class, may never empirically out-perform full-sized mAbs generally, but drug
developers and clinicians might identify
select applications for which fragmentderived molecules have unique utility.
Pros and Cons
Fragmentation of antibodies results in
altered physiochemical features of these
therapeutic molecules. For instance, the
smaller size of fragments permits penetration into tissues inaccessible to full-size
mAbs.3,4 As previously noted, antibody
fragments may prove easier and less costly
to manufacture due to the lack of glycosylation and relatively small size, which permits use of prokaryotic expression systems.
However, fragments lack the Fc domain
that serves to both stabilize full-size antibodies and allow FcR-mediated recycling.
As a consequence, fragments are rapidly
degraded in humans and have short circulating half-lives.5
Several strategies have
been developed to extend the half-life of
fragments, including conjugation to proteins such as albumin6
and PEGylation,7
which was applied to the FDA approved
anti-TNFα Fab, certolizumab pegol.
However, biomanufacturing advantages
of fragment production may be lost if
PEGylation is required because the process can prove expensive and technically
challenging.