Biomedical Engineering Reference
In-Depth Information
Abs with two addi tional binding sites engi neered into the
CH3 doma ins. Non-A b bispecifi c const ructs have also been
developed. Am gen acquired Avidia in 2006, g aining Avimer
technology, formed of two or more linked peptide sequences
generated from extrace llular receptor domains that convey
binding or inhi bitory prope rties . As with other FP segments,
the performanc e of different com peting technolog ies is
likely to depend on factor s such as the nature of specific
targets interact ed with and their loca tion. There are thoug h
key themes exhibited and smaller structure s can be advan-
taged by greater tissue penetra tion, but conversely, suffer
from shorter h alf-lives com pared to larger alternatives. The
importanc e of these difference s will vary from product to
product. In terms of in-ma rket pricin g and profitabili ty, a
number of structure s such as Avimer s can benefit from
the possi bility of bein g produc ed in bacterial expression
systems [28].
3.1.7.3 Other Ab Fr agment Struc tures Other Ab fra g-
ment structure s are not FPs themse lves, but can be fuse d to
other protei n compon ents. These scaffolds are o ften devel-
oped as a sta ndalone techn ology first, before being expanded
into FP designs. Early-s tage FP developers shoul d theref ore
consider how technol ogies that do n ot compet e at pres ent,
might later do so. Indeed, an under standing of innovative
protein designs can aid FP developers to sta ke initial p atent
claims for FP-based extensi ons of n ovel protei n scaffolds.
Acquired through Domant is, GlaxoSm ithKline's Domain
Antibodie s (dAbs) are 11-15 kDa str uctures that consist of
either an antibody heavy (VH) or light (VL) doma in.
Bispecific dAbs can be create d by fusing one dAb to anot her.
Similar ly, Ablynx' s Nanobodi es
1
are sing le-domai n struc-
tures (sdAb) consisting of a sing le VH doma in. In keeping
with the technol ogy overlaps, the two compani es have b een
involved in a numb er of pate nt challenges, disp utes and
settlement s. Affibody' s Affibodi es
1
are triple helix struc-
tures based on the Z doma in (th e IgG G-binding do main) of
protein A. Non- Ab technol ogies include Archemi x's
aptamers, which are peptide or nucl eotide seque nces gener-
ated from an in vitro selection process that bind to target
molecu les.
Unlike more com plete Ab-base d struct ures, these sma ller
binding molecu les do not exhibit CDC or ADCC activity due
to the absence of an Fc region. Their sma ll size facilitat es
tissue penet ration but also leads to a short half-life. Strate -
gies to increas e the half-lif e have been developed, including
linking dAbs to ABD s in AlbudAbs (discussed earlier) .
3.1.7.2 Mini aturized Abs: Ab-B inding Domain Fused to
Fc Effec tor (7b) One FP uses an scFv fragment for
targeting attac hed to an Fc moiety, giving what is in effect,
a scaled down mAb struct ure. Such fusions benefit from the
high specificity targeting capab ilitie s of the Ab- binding
domain compon ents, alon gside the natu ral Fc effector func-
tion, whi ch is partic ularly usef ul for cel l-killing activity.
Emergent BioSol utions' SBI-087 (PF-05 230895) is a Smal l
Modular Immun o Pharm aceutical (SMIP
TM
), part nered with
Pfizer and in Phase II trials for rheumatoi d arthriti s. The
product act s by directing an immu ne resp onse to cells
expressing CD20, in a mec hanism similar to that of mar-
keted mAb Rituxan
1
(rituximab) . Th is results in a number
of actions including B- cell reduc tion through ADC C and
CDC driven by the Fc component . SBI-087 was found to
achieve surpris ing levels of Fc -mediated cel lular toxicity
compared to Ritu xan. This is thoug ht to be due to it binding
primarily to CD20 in solu ble regions of the plas ma mem-
brane, whereas Rituxan can intera ct with, or relocat e CD20
into inso luble regions [29].
SMIPs consi st of scFvs that do not cont ain the CH1 and
CL domains pres ent in conventional mAbs. Like several
non-Ab delivery options, the smaller SMIP structure s poten-
tially allow improved tissue penetra tion and biodistri bution
compared to protei ns attac hed to mAbs [30]. Furthermor e,
with a shorter distanc e betwee n binding doma ins (60-80 A
)
compared to Abs (95-14 0 A
), the differing geometry of
SMIPs can result in uniqu e interact ions and can be engi-
neered to deliver signaling responses .
8
Both mAbs and
SMIPs are produced in mammal ian cell expression syst ems.
F-star's Fcabs relate to a further miniaturiz ed Ab tec hnol-
ogy, with an Ab Fc domain linked to two identi cal antigen
binding sites engi neered into the CH3 doma ins.
3.1.8 Ab- and no n-Ab-Targe ting Decisions
As shown in Figure 3.2, the direct ion of FPs to target sites
can be driven either by the strai ght affinity of the active
component with its targets (as in simpl e therape utic proteins,
or FP decoy rece ptors and ligand half-life produc ts) or by a
fused targeting moiety. We have divided targeting partners
into thos e that are Ab-base d and those that are not, although
in simple terms, the rol e of these partners is just to bind to
target sites in such a way as to alter the distribution of the
product's activity in the body. Targeted or localized delivery
of a cytotoxic agent, for example, may be desirable to reduce
activity in nondiseased tissues and therefore, the side effect
profile. Alternatively, targeting may be employed to deliver
antigens to the immune system machinery, or in the case of
bispecifics, to bring two targets into close proximity.
While half-life extension is a primary purpose of almost
half of all FPs in Phase II development or more advanced,
the remaining 24 are designed around the concept of more
specific (targeted) delivery. These are split equally between
Ab targeting and non-Ab targeting. Since non-Ab
approaches include various ligand, receptor and enzyme
targeting, this highlights the disproportionately high contri-
bution from Ab fusions, which all relate to scFv-type
8
http://www.truemergent.com/wp-content/uploads/SMIPS-vs-Mabs-Data-
Sheet-11-2010.pdf
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