Biomedical Engineering Reference
In-Depth Information
binding. Furthermore, once-internalized, additional factors
include whether the target receptor is recycled or degraded,
as well as how the conditions experienced will affect toxin
release or its activity [23]. Levels of active toxin release
from target cells can cause bystander effects on surrounding
cells. This can aid efficacy, but also increase associated
toxicity side effects.
Not all highly specific disease-associated targets will
drive internalization of an attached toxin. Once Active
Biotech's Phase II/III candidate Anyara (ABR-217620,
naptumomab estafenatox) has bound to target cancer cells,
the fused toxin recruits T cells that initiate cell death. In a
lower specificity approach, Protox's PRX-302 is an FP
containing a cleavage site that allows the toxic prodrug to
be activated by the enzyme PSA. PSA is produced at high
levels in the prostates of patients with prostate cancer but
less so in other areas of the body. This mechanism of action
is similar to that of antibody-directed enzyme prodrug
therapy (ADEPT). Localization of activity can also be
achieved by tethering radionucleotides to target cells
(non-FP). Spectrum/Bayer's Zevalin
1
(ibritumomab tiux-
etan) launched in 2002, followed by Corixa/Glaxo
SmithKline's Bexxar
1
(tositumomab) in 2003.
The stability of the linker between the toxin and delivery
components of an FP or conjugate can have a major impact
on its efficacy and safety. The structural chemistry and
amino acid sequence of the linker will determine its sus-
ceptibility to be broken down in any particular location.
Toxin release away from intended sites increases the risk of
side effects. Various different linker structures are in devel-
opment, with an aim of ensuring that toxins remain attached
in serum but are appropriately released and active in target
cells. Conjugated immunotoxins can potentially employ a
wider range of linker designs compared to FPs, since they
can utilize synthetic linkers or chemistry not possible with
FP protein expression processes. In March 2011, Abbott
agreed to license Seattle Genetics' antibody-drug conjugate
technology, based on a stable linker and potent cytotoxic
agent. As with several other FP classes, conjugation may
represent a comparable alternative and the sum of overall
advantages and disadvantages of conjugated toxins will vary
on a case-by-case basis.
It is notable that the non-Ab delivered toxins do not
involve any component specifically added to increase half-
life. While this may be due to the targeting partner already
conveying sufficient half-life properties to the toxin, a
shorter half-life may be desirable for targeted toxins to
avoid sensitivity reactions [24]. It can also allow higher
maximum tolerated doses, since where off-target release
can occur, it is preferable for toxins to be delivered to
target cells in a minimal timeframe, or within the window
of a short half-life. This is in contrast to several products in
other FP groups that require a long or sustained duration of
actiontobeefficacious.
3.1.6.2 Targeted Ligands (4a and 4b) As described
earlier, a number of FPs consist of a ligand attached to a
half-life moiety to achieve long-acting blockade or activa-
tion of signaling. While these products are directed simply
by the affinity of the ligand to certain targets, further FP
groups involve fused components that provide active deliv-
ery. All six cases in Phase II or above are in development for
cancer indications, delivering highly potent cytokines, TNF
or IL-2, to drive cell death. The majority of these are Ab-
delivered “immunocytokines.” Targeted cytokines primarily
bring about cell death by directing the immune system to
target cells. In contrast to most targeted toxins, the targeted
ligands typically bind to targets that allow the cytokine to
tether and elicit receptor-mediated death-signaling, rather
than undergo internalization.
Novartis markets Proleukin
1
, a recombinant IL-2 for the
treatment of various cancers. High-dose IL-2 induces tumor
response rates of
15% in patients with metastatic mela-
noma, with nearly half of these responses being extremely
durable [25]. IL-2 acts by raising the immune system's
awareness of cancerous cells. High concentrations of IL-2
through systemic administration are associated with severe
side effects. Direct injection can improve the treatment of
some solid tumors, but most are not localized or accessible.
As such, a number of candidates are in development to
provide more targeted delivery of IL-2. Attachment to a
partner protein typically also serves to increase half-life—
which is less than an hour for IL-2 alone. Against competi-
tion from Proleukin and upcoming biosimilars, IL-2-based
FPs developed for overlapping indications must offer suffi-
cient increases in efficacy, or reduction in side effects to
warrant market share capture.
Of the six targeted ligands, four use Ab delivery. Philogen
is developing three of the products. Two are based on the
L19 antibody that binds to tumor-associated fibronectin,
which is a marker of angiogenesis. Bayer Schering initially
licensed rights to three such products in 1999—Darleukin
(L19-IL2), L19-TNF, and a non-FP radiolabel radretumab
(L19-131I). A further unpartnered FP is in Phase II that
consists of IL-2 fused to an alternative antibody. Darleukin is
the most advanced, with a Phase III trial for malignant
melanoma planned. Bayer had ended its agreement for
the product by mid-2009, but in February 2011 also returned
rights to L19-TNF and radretumab, citing a change of
strategy. As a result, Philogen had to cancel its planned
IPO. Philogen has several different products based on the
same antibody, allowing some comparison of the approaches
to be made. However, head-to-head or same indication trials
have not yet been undertaken, which may relate to different
approaches being better suited to certain cancers than others.
Merck KGaA is developing a further immunocytokine FP,
huKS-IL2 (tucotuzumab celmoleukin, EMD 273066)
although a Phase II trial for ovarian cancer was terminated
by April 2009 due to poor recruitment and a study design
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