Biomedical Engineering Reference
In-Depth Information
TABLE 24.2
5T4 Reactivity in a Variety of Tumor Types
Cancer
Stage/Type
Reactivity
Reference
Conclusions
Breast
Mixed
5/5
51/58
[50]
Active Biotech unpublished data
85-95% of patients express the 5T4
antigen
Cervix
Mixed
5/5
[50]
85-90% of patients express the 5T4
antigen
I
22/25
[56]
II
22/26
[56]
III
9/10
[56]
IV
5/6
[56]
Colorectal
Mixed
4/13
7/9
[50]
Active Biotech unpublished data
40-50% of patients express the 5T4
antigen. In Dukes stage D patients, more
than 70% overexpress the antigen
A
2/8
[53]
B
7/34
[53]
C
13/21
[53]
D
7/9
[53]
Gastric
Mixed
6/7
35/86
[50]
[54]
Approximately 50% of patients express the
5T4 antigen on tumor cells. Most
samples with 5T4 negative tumor cells
have 5T4 positive tumor stroma [54]
I
1/2
[53]
II
1/4
[53]
III
1/1
[53]
IV
12/20
[53]
NSCLC
Mixed
10/10
249/251
[50]
Active Biotech unpublished data
99% of patients express the 5T4 antigen
Ovarian
Mixed
4/7
[50]
More than 70% of patients express the 5T4
antigen. For stage IV patients, 90-95%
of the patients are 5T4 positive
I
2/10
[55]
II
4/57
[55]
III
21/29
[55]
IV
24/26
[55]
Pancreatic
Mixed
3/3
20/20
[50]
Active Biotech unpublished data
100% of patients express the 5T4 antigen
Prostate
Mixed
26/26
Active Biotech unpublished data
100% of patients express the 5T4 antigen
Renal
Clear cell
1/1
214/221
18/18
16/17
20/20
[50]
Active Biotech unpublished data
Active Biotech unpublished data
Active Biotech unpublished data
[57]
>
95% of patients express the 5T4 antigen
Papillary
Mixed
characterized by the use of the murine IgG1 mAb 5T4
[46,47]. 5T4 antigen expression has been shown to influence
adhesion, cytoskeletal organization, and motility, properties
that might account for its association with poorer clinical
outcome in some cancers. Recently it was shown that the
5T4 glycoprotein is associated with functional cell surface
expression of the chemokine receptor CXCR4- and
CXCL12-mediated chemotaxis [48]. A general screen by
immunohistochemistry on frozen sections showed that many
different carcinomas express the 5T4 antigen [49-56]
(Table 24.2). Studies have shown tumor reactivity, which
in most cases is moderate to strong, in more than 95% of
nonsmall cell lung cancer (NSCLC), pancreatic cancer (PC),
and renal cell cancer (RCC). In many cases, tumor stromal
reactivity has been observed in addition to the tumor cell
reactivity. Outside the placenta, 5T4 normal tissue reactivity
is considered to be most limited, and there is no evidence of
circulating 5T4 antigen.
The TTS therapeutic proteins are applicable in all malig-
nant diseases where tumor selective mAbs can be produced.
The 5T4 mAb, selected for clinical development primarily in
the indications of NSCLC and RCC, targets the TTS fusion
proteins to a tumor antigen broadly expressed on tumor cells,
with very low expression on normal tissue and without
interference by soluble antigen.
24.4 INCREASING THE THERAPEUTIC WINDOW
AND EXPOSURE BY THE CREATION OF A NOVEL
TTS FUSION PROTEIN WITH MINIMAL MHC
CLASS II AFFINITY; NAPTUMOMAB
ESTAFENATOX
The early clinical trials with TTS fusion proteins were
performed using wild-type SEA as the T-cell activator
[32,33]. However, this fusion protein (nacolomab tafenatox)
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