Transcript Document

nab-Paclitaxel
Mechanism of Action
Selected slides
Mechanism of Action of nab-Paclitaxel
.
SPARC, secreted protein acidic and rich in cysteine.
Investigation of the functional importance of SPARC
with respect to nab-paclitaxel is ongoing.
A novel approach
Leveraging nanotechnology &
natural transport properties of
albumin
Nanotechnology in medicine:
A new therapeutic strategy to face a historical challenge
• Deal with developing drugs within 1-100 nano meters
dimension(s)1
• Improve drug performance and overcome limitations
of classical chemotherapeutics agents2
• Penetrate tissues more efficiently3
–
Targeting a drug to the tumour site, thereby enhancing tumoural
drug levels, through passive and active targeting2
–
Directing the drug away from body sites particularly sensitive to
its toxic effects, aiming for reduced damage to healthy tissues2
1) Wikipedia
2) Lammers T , Hennink WE, Storm G. Tumour-targeted nanomedicines: principles and practice. British Journal of Cancer. 2008;(99):392-397.
3) Minchinton AI, Tannock IF. Drug penetration in solid tumours. Nat Rev Cancer. 2006;6(8):583-92.
A Novel Approach:
Leveraging the natural transport properties of albumin
• Albumin is involved in specific
endogenous molecular
pathways1,2
• Albumin is a natural carrier for
several molecules in the body 3,4
(fatty acids, hormones, vitamins etc)
3D molecular structure
of albumin
1)
2)
3)
4)
• A single albumin molecule can
bind and transport more than 6
molecules of paclitaxel4
Ibrahim NK, Samuels B, Page R, et al. Multicenter phase II trial of ABI-007, an albumin-bound paclitaxel, in women with metastatic breast cancer. J Clin Oncol. 2005;23(25):6019-6026.
Scheff RJ. Breast cancer and the new taxanes: focus on nab-paclitaxel Commun Oncol 2008;5(suppl 8):7–13.
Chuang VTG, Kragh-Hansen U, Otagiri M. Pharmaceutical strategies utilizing recombinant human serum albumin. Pharmaceut Res. 2002; 19: 569-577.
Paal et al. High affinity binding of paclitaxel to human serum albumin. Eur J Biochem. 2001; 268(7):2187-91.
Tumors have high metabolic uptake of Albumin
0 hr
1,2
24 hr
Gadolinium-labelled albumin, experiment in mouse models
1) Chuang VTG, Kragh-Hansen U, Otagiri M. Pharmaceutical strategies utilizing recombinant human serum albumin. Pharmaceut Res. 2002; 19: 569-577.
2) Kiessling F, Fink C, Hansen M, et al. Magnetic resonance imaging of nude mice with heterotransplanted high-grade squamous cell carcinomas: use of a low loaded, covalently bound
gd-hsa conjugate as contrast agent with high tumor affi nity. Invest Radiol 2002;37:193-198.
nab-Paclitaxel is the first tumour-targeted
chemotherapy approved in mBC leveraging
nanotechnology & natural transport properties of
albumin
nab-Paclitaxel
individual molecule
nab-Paclitaxel
complex
6-7 nm sized 1,2
Albumin
Paclitaxel
130 nm sized 1,2
1. Desai et al. SABCS. 2004 [abstract 1071].
2. Kratz et al. J Control Release. 2008;132(3):171-183.
nab-Paclitaxel Accumulates in Tumors
More Efficiently Than
Cremophor EL Paclitaxel
Paclitaxel Administered as nab-Paclitaxel Accumulates
in Human Tumor Xenografts More Efficiently Than
CrEL Paclitaxel at Equal Dosesa
140
Paclitaxel (nCi/g)
nab-Paclitaxel
120
CrEL Paclitaxel
100
80
Tumor AUC nab-Paclitaxel =
1.33 × CrEL Paclitaxel
P < .0001 ANOVA
60
40
0.01
0.1
1
10
100
Hours
a
Dose of both nab-paclitaxel and Cremophor® EL paclitaxel = 20-mg/kg dose of paclitaxel; experiments in
human breast tumor xenografts in nude mice.
ANOVA, analysis of variance; AUC, area under the curve.
Desai et al. Clin Cancer Res. 2006;12:1317-1324.
nab-Paclitaxel Targets the Tumour
Relative Concentration
(Abraxane®/Conventional paclitaxel)
• nab-Paclitaxel demonstrates greater selectivity in tumour vs. normal
tissue compared to CrEL paclitaxel in some preclinical models1,2
1.5
1.0
Tumour: nab-Paclitaxel
>
CrEL paclitaxel
nab-Paclitaxel
=
CrEL paclitaxel
Healthy tissues: nab®-Paclitaxel
<
CrEL paclitaxel
0.5
0.0
Comparative tissue distribution (ratio) of radiolabeled drug in mice bearing
human breast tumor xenografts 1 hour after dose1,2.
1)Hawkins M, et al. AACR. 2003. Poster 1189.
2)Desai N, et al. SPARC Expression Correlates with Tumor Response to Albumin-Bound Paclitaxel in Head and Neck Cancer Patients. Translational Oncology. 2009;2:59-64.7.
Potential link between
nab-Paclitaxel Mechanism of
Action & Clinical outcome
nab-Paclitaxel Achieves Higher Efficacy Through the
Unique Properties of Albumin
nab-Paclitaxel
demonstrated
a tumors
higher ORR
(27%
vs ®
• 33%
higher concentration
vs Cremophor
The
combination
of a higher in
recommended
dose (260
13%)
,2 longer
(21
vs. 16
weeks)
&doses
OS
(13.2 Vs
2)injected
EL paclitaxel
when
at equal
mg/m
vs 175TTP
mg/m
and
greater
tumor
selectivity
®in
10.9
months)
compared
with
paclitaxel
• Higher
recommended
doseCrEL
vs Cremophor
EL2nd+ to
allows
a higher
dose of nab-paclitaxel
to be delivered
2 vs 175 mg/m2)
line
MBC
patients
paclitaxel
(260 mg/m
tumors
compared
with CrEL
paclitaxel
In a phase III trial vs CrEL paclitaxel, nab-paclitaxel led
When delivered at equal doses, nab-paclitaxel 2
Higher
paclitaxel
clearance (21.1
14.8 L/h/m
)
to
less grade
4 neutropenia,
equalvsfebrile
neutropenia,
demonstrates lower accumulation in normal tissues
compared
with CrEL
paclitaxel
and
more grade
3 SN,
although the SN improved to
compared with CrEL paclitaxel
grade ≤ 2 at a median of 22 days
Clinical Benefit
Implications
MoA
See notes for references.