Biomedical Engineering Reference
In-Depth Information
TABLE 6.1 GLP-1 Versions with Extended Half-Life
DPP IV
Resistant
Name
Company
Technology
t
1/2
(h)
Organism
Phase
Liraglutide (Victoza
1
)
Novo Nordisk
Yes
Albumin binding
12
Human
Market
Albugon
HGSI
No
Albumin fusion
120
Human
III
Dulaglutide
Eli Lilly
Yes
Fc-IgG4 fusion
48
Cynomolgus
III
Albiglutide (Syncria
1
)
HGSI
Yes
2xGLP-1 albumin fusion
120
Human
III
Taspoglutide
Ipsen
Yes
Bulky side chain
10
Rat in vitro
III term
CJC-1131
ConjuChem
Yes
Albumin conjugate
240
Human
II
Semaglutide
Novo Nordisk
No
Bulky side chain
n.a.
n.a.
II
Glymera
PhaseBio
n.a.
ELP fusion
148
Human
IIa
CVX-096
CovX
No
IgG1
96
Rodents
I
CNTO736
Centocor
No
Fc fusion
30
Mouse
Preclin.
n.a.
BioRexis
Yes
Transferrin fusion
44
Cynomolgus
Preclin.
GLP-1 t
1/2
in human: 7 min.
molecules a ssociate with the membrane-bound receptor,
and are transported back to the cell membrane, where they
di ssociate in a pH-dependent m anner f rom the receptor.
Th us, both albumin and immune gl obulins a re pr otected
from proteolytic degradation that would happen i n the
more acidic lysosome. If the r eceptors are saturated, excess
unbound albumin or antibody are catabolized in the lyso-
some. Even a transcytosis where album in or antibody
crosses t he cell from the a pical to the basolateral s ide is
possible [9] (Figure 6.3).
Th e phenom enon that albumi n accumul ates in tumors can
be utilize d for therapeutic appro aches in combina tion to the
intrinsic ability to enhanc e the half-life of protei ns fuse d or
attached to it [10]. Another advanta ge is the tend ency of
albumin to sta bilize prot eins despi te its own conform ational
instability. With a G-CSF fusion to HSA it was dem onstrated
that HSA overco mes the aggregation tendency of G-CSF
[11]. However, it has to be taken int o accou nt that the
presence of multipl e doma ins wi th different aggregation
susceptibi lity formul ation has to be careful ly asse ssed for
the whole mol ecule.
A further advanta ge is the possi bility to attac h the fusion
partner either at the N- or C-term inus of HSA [12] . Th is
gives suffic ient flexibility for the design of novel chimer ic
molecu les. During the man ufacture of Albuferon, a combi-
nation of interfer on-
a
2b (IFN-
a
2b) with albumi n, it was
observed that becau se of incomplet e d isulfide bridge forma-
tion, aggregates wer e formed , which dras tically reduc ed the
recovery. This phenom enon coul d be reversed by positi on-
ing the IFN -
a
2b on the N- terminus instea d [13] . The half-
life extension was sufficient to prepare administration inter-
vals of 2-4 weeks [14]. However, in 2010 the development
of the HSA-IFN-
a
fusion protein was stopped at Phase III
because of concerns about the risk benefits of this drug
(http://www.novartis.com/newsroom/media-releases/en/2010/
1449 020. shtml).
Currently, a number of therapeutic proteins have been
fused to albumin. For instance, an insulin-HSA variant
showed normal activity and drastically prolonged half-life
[15]. To the evaluated proteins belong the blood clotting
factors FVIIa and FIX with very short half-lives that require
frequent dosing. In the case of FVIIa, the albumin fusion had
a six- to sevenfold extended half-life [16]. For FIX, not only
the circulation time could be improved, but introducing
a cleavable linker between albumin and FIX increased
specific clotting activity 10- to 30-fold as well. This linker
was designed to be cleaved in parallel to FIX activation, thus
releasing the small blood factor from its bulky fusion partner
TABLE 6.2 Exenedin-4 Versions with Extended Half-Life
Name
Company
Fusion
t
1/2
(h)
Organism
Phase
Lixisenatide (Lyxumia
1
)
Sanofi
Amino acid extension
4
Human
III
Exenatide/NexP
TM
Alteogen
Alpha 1 antitrypsin
13
Rat
Preclin.
VRS 859
Versatis
XTEN fusion
60
Cynomolgus
II
CJC-1134 PC
ConjuChem
Albumin conjugate
192
Human
II
LAPS-Exenedin
Hanmi
Fc fusion
n.a.
n.a.
II
PF-04603629
Pfizer
Transferrin fusion
n.a.
n.a.
I term
Exenedin-4 t
1/2
in human: 2 h.
Search WWH ::
Custom Search