Biomedical Engineering Reference
In-Depth Information
structure s. FP developers must choose which approache s to
use for the targeted delivery of fuse d act ive partner s and the
factors directing thi s choice are discusse d.
Where othe r compani es hold IP that restricts freedom to
operate , choi ce of targeting mechani sm may be limited.
Similar ly, a com pany built on a partic ular targeting platfo rm
is likely to focus development efforts on this rather than
alternat ives. In both cases, drug developers mus t emp loy the
most effective soluti ons if they are to raise their chanc es of
success. A produc t payi ng royalt ies on sign ificant sales still
offers superior retu rns to o ne that fails in clinical trials o r
cannot compet e in the market. However, the best targeting
approach for an active part ner may only becom e appar ent
once several steps alon g the developme nt pathwa y have
already been undertak en.
Rega rdle ss of IP re st ric ti ons, c hoi ce of a n Ab o r n on- Ab
t a rg e t i n g p a r t n e r c a n b e d r iven b y t h e avai l a b i l i t y o f k n own
binding components w ith suitable specificity. There will
not a lways be a n e ndogenous protein that s electivel y
targets a particular antigen, in which case, Abs or alterna-
tive targeting moieties must be e ngi neered. Non-A b FP
targeting a pproaches include AdNexus' fibronectin-based
Adnectins
1
,Altor'sSTAR
TM
(sol uble T-cell antigen
receptor) platform, Mol ecular Part ners' DARPins (ankyrin
repeat proteins), Pieris' Anticalin
1
engineered lipocalins
and transferrin for delivery a cross the blood-brain barrier
[31]. Ful l mAbs are naturally bi functional and c an there-
f o r e o ffe r a d van t a g e s w h e r e t h e e ffe c t o r f u n c t i o n s o f t h e F c
domain are w anted. Fusion or conjugation to f ull Abs can
therefore be desirable for therapies aimed at bringing about
cell death, such as those developed f or oncology indica-
tions. Full mAbs offe r a well-known safety pr ofile, s tan-
dardized manufacturing processes, and a long half-life
(manufacturing consider ations of all FPs are discussed
i n t h e f o l l owi n g s e c t i o n ) . H owever, t h e i r l a rg e s i z e c a n
dampen activity of the part ner or restrict tissue penetration,
potentially i mpacting the prod u c t 's e f fi c a cy. A t a rg e t m a y
be accessible to FPs base d on a ligand or receptor frag-
ment , but not larger full mAbs. Structures based on Ab
fragments can potentially circumvent the issue. In both the
case of FPs and non-FP Ab f ragments, the bene fits of
smaller t argeting component s must be w eighed up against
disa dvant age s s uc h a s m or e r apid pl as ma cle a ra n ce , w hi ch
can reduce half-life. In each case, the pharmacokinetic
properties w ill de pend on further f actors such as the tissue
type and ar ea of t he body t arg et ed, o r c an be diffic u lt to
predict. For example, the clearance rate of Ab-G-C SF FPs
from plasma is highly increa sed compared with t he paren-
tal A b [32]. Simil arly, the a ct iv it y o f T NF-
a
or IL-12 FPs
can be m arke dly l owe r than for the s imple recombinant
cytokines, although targ eting m oieties e mployed i n FPs
h ave a l s o b e e n s h own t o a l s o exe r t d i r e c t a c t i o n , s u c h a s t h e
t u m o r vas c u l a r- t a rg e t i n g N G R s e q u e n c e u s e d t o d e l iver
TNF i n M ol Med's NGF-hTNF [ 33].
3.1.9 Tar geted Enz ymes (2a)
Three targeted enzyme FPs are in development (all Phase II) .
Two related to structure s that locali ze enzymes . As with
targeted toxins, for example, this pote ntially allows greater
potency at the desired site of act ion while reducing side
effects. NexBio's Fluda se
1
consist s of the sia lidase cata-
lytic domain fuse d to a respir atory epitheli um cell surface -
anchor ing seque nce. It is designed to wor k by inactivating
sialic aci d recepto rs on cells li ning the respir atory tract that
are othe rwise used by influe nza vir uses to gain entry into
cells. The anchorin g seque nce increas es retention time at the
sites whe re the enzym e act ion is require d. Fluda se is the only
FP in Phase II or above adm inistered by inha lation. En obia's
ENB-0 040 (asfotase alfa) also u ses a ligand- targeting moi-
ety to loca lize enzyme activity. A deca-asp artat e peptide
derived from the bon e remodeli ng protei n osteopont in
delivers the fuse d enzyme, tissue non specific alkaline phos-
phatase (TNSALP) , to bone.
Localiz ed or targeted enzymes can also be u sed for
activation of an adm inistered prodr ug at only desired sites.
This appro ach is emp loyed with mAbs in ADEPT and has
been tested wi th FPs, albe it not any that are currently in
Phase II or above [34] . Smal ler Ab fragme nts have also been
fused to enzyme domains in FPs to improve the targeting
efficiency over that of conj ugated ADEPT mAb s, dem on-
strating very high distri bution different ials betwee n tumor
cells and normal tissue [35,36 ]. A key advanta ge of loca lized
enzymes over nonenz ymatic targeted toxins is that as cata-
lysts, they are able to turn over multipl e copi es of active drug
at the target sites. Lo calized enzymes can resu lt in greater
bystander effects on surrounding cells compared to inter-
nalized proteins. This wider action on cells can be advanta-
geous for tumor killing for example, paticularly where not
all cells exhibit the target toxin, but can also cause side
effects in healthy tissue.
A further FP, Menarini's amediplase consists of an
enzyme fragment fused to another enzyme fragment. We
have classified it within the enzyme localization group since
the fusion is inherently designed such that the second
enzyme's activity is located near that of the other enzyme
component; however, the product is not strictly a targeted
enzyme. Amediplase combines a fragment of tissue plas-
minogen activator (tPA) with a urokinase fragment. Both are
human profibrinolytic factors that help to breakdown clots.
The fusion is designed to offer the high specificity of one
enzyme with the high catalytic activity and resistance to
inhibitors of another, as well as increasing half-life.
Although amediplase is described as “ready to enter Phase
III trials,” it is unclear when or if this will occur.
9
Fused or
bifunctional enzymes have been shown to hold pharmaco-
kinetic advantages over
the separate enzymes [36,37].
9
http://www.menarini.com/r_d/therapeutic_areas/R_D/amediplase
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