1. nab-Paclitaxel Mechanism of Action Selected slides

2. Mechanism of Action of nab-Paclitaxel
Summary of the mechanism of action (MoA) of nab®-paclitaxel
Upon administration, particles of nab-paclitaxel rapidly dissolve.
Moving through the bloodstream, paclitaxel exists in 2 main forms: free paclitaxel and albumin-bound paclitaxel. Free paclitaxel is small enough to pass through cells via a passive form of transport. In this way, paclitaxel can be delivered to tumor cells, where it can disrupt microtubule dynamics to induce tumor cell death.
Circulating albumin binds to receptors on endothelial cells. This leads to endocytosis of vesicles, which then pass through endothelial cells and are emptied into the subendothelial space. Albumin-bound paclitaxel can pass through endothelial cells in this manner to be delivered to tumors.
It is proposed that extracellular matrix albumin-binding proteins, such as secreted protein acidic and rich in cysteine (SPARC), may draw albumin-bound paclitaxel to tumor cells, thus enriching tumoral uptake of the drug. Once inside tumor cells, paclitaxel dissociates from albumin and acts on microtubule dynamics to induce cell death. .
SPARC, secreted protein acidic and rich in cysteine.
Investigation of the functional importance of SPARC with respect to nab-paclitaxel is ongoing.

3. A novel approach Leveraging nanotechnology & natural transport properties of albumin

4. Deal with developing drugs within 1-100 nano meters dimension(s)1
Nanotechnology in medicine: A new therapeutic strategy to face a historical challenge
Deal with developing drugs within 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
Wikipedia
Lammers T , Hennink WE, Storm G. Tumour-targeted nanomedicines: principles and practice. British Journal of Cancer. 2008;(99):
Minchinton AI, Tannock IF. Drug penetration in solid tumours. Nat Rev Cancer. 2006;6(8):

5. Albumin is involved in specific endogenous molecular pathways1,2
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)
A single albumin molecule can bind and transport more than 6 molecules of paclitaxel4
3D molecular structure
of albumin
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):
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:
Paal et al. High affinity binding of paclitaxel to human serum albumin. Eur J Biochem. 2001; 268(7):

6. Tumors have high metabolic uptake of Albumin1,2
0 hr
24 hr
Gadolinium-labelled albumin, experiment in mouse models
Chuang VTG, Kragh-Hansen U, Otagiri M. Pharmaceutical strategies utilizing recombinant human serum albumin. Pharmaceut Res. 2002; 19:
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:

7. nab-Paclitaxel individual molecule nab-Paclitaxel complex
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
This slide is a brief introduction to nab-paclitaxel. The important points are the size of the nab-paclitaxel particle (130 nm) and the linear pharmacokinetics (PK). The linearity point is developed further in more specific PK slides in the MoA master slide deck.
Paclitaxel
130 nm sized 1,2
1. Desai et al. SABCS [abstract 1071].
2. Kratz et al. J Control Release. 2008;132(3):

8. nab-Paclitaxel Accumulates in Tumors More Efficiently Than Cremophor EL Paclitaxel

9. Tumor AUC nab-Paclitaxel = 1.33 × CrEL Paclitaxel P < .0001 ANOVA
Paclitaxel Administered as nab-Paclitaxel Accumulates in Human Tumor Xenografts More Efficiently Than CrEL Paclitaxel at Equal Dosesa
Hours
Paclitaxel (nCi/g)
140 80 60 40
0.1 1 10
100
0.01
120
Tumor AUC nab-Paclitaxel = 1.33 × CrEL Paclitaxel P < ANOVA
nab-Paclitaxel
CrEL Paclitaxel
The graph on this slide represents a time course of accumulation of a radioactively labeled form of paclitaxel in MX-1 human breast cancer xenograft tumors in nude mice. A 20- mg/kg dose of either nab-paclitaxel or CrEL paclitaxel was administered, and tumors were dissected at the indicated time points for quantification of radioactivity. For each treatment group, 9 mice were evaluated at each time point. The radioactivity over time was then plotted, and AUCs were determined for each group. The nab-paclitaxel group demonstrated a 33% higher AUC compared with the CrEL paclitaxel group.
Possible explanation: that nab-paclitaxel is taken up by tumors to a greater degree relative to CrEL paclitaxel implies that something specific about the physiology or biology of the tumor allows more uptake of the nab-paclitaxel formulation. The reason for this is not entirely clear. Hypothetical explanations center on 3 main ideas.
A higher fraction of paclitaxel may be bound to albumin in the nab-paclitaxel formulation. Tumors, including surrounding stromal cells, secrete albumin-binding proteins that would lead to enrichment of albumin-bound drug in tumors. Indeed, tumors are known to take up large quantities of albumin for energy (Kratz F. J Control Release. 2008;132[3]: ).
The second explanation centers on increased vascularization and a tumor-specific leakiness of blood vessels (Kratz). The nab-paclitaxel formulation leads to a significantly higher free paclitaxel fraction vs CrEL paclitaxel (Gardner ER et al. Clin Cancer Res. 2008;14[13]: ) that could enter the tumors through this vasculature.
Thirdly, Desai et al (Clin Cancer Res. 2006;12[4]: ) showed that the nab- paclitaxel formulation allows for higher transport across endothelial cells compared with CrEL paclitaxel. This, combined with increased vasculature of tumors, would also explain the greater tumor selectivity of nab-paclitaxel.
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:

10. nab-Paclitaxel Targets the Tumour
nab-Paclitaxel demonstrates greater selectivity in tumour vs. normal tissue compared to CrEL paclitaxel in some preclinical models1,2
1.5
Tumour: nab-Paclitaxel
>
CrEL paclitaxel
nab-Paclitaxel =
CrEL paclitaxel
1.0
Relative Concentration (Abraxane®/Conventional paclitaxel)
Healthy tissues: nab®-Paclitaxel
<
CrEL paclitaxel
0.5
0.0
Tumour
Muscle
Heart
Kidney
Lung
Spleen
Blood
Comparative tissue distribution (ratio) of radiolabeled drug in mice bearing human breast tumor xenografts 1 hour after dose1,2.
Hawkins M, et al. AACR Poster 1189.
Desai N, et al. SPARC Expression Correlates with Tumor Response to Albumin-Bound Paclitaxel in Head and Neck Cancer Patients. Translational Oncology. 2009;2:

11. Potential link between nab-Paclitaxel Mechanism of Action & Clinical outcome

12. Less drug exposure to healthy tissue4 Higher administered dose 5,6
nab-Paclitaxel Achieves Higher Efficacy Through the Unique Properties of Albumin
33% higher concentration in tumors vs Cremophor® EL paclitaxel when injected at equal doses
Higher recommended dose vs Cremophor® EL paclitaxel (260 mg/m2 vs 175 mg/m2)
In a phase III trial vs CrEL paclitaxel, nab-paclitaxel led to less grade 4 neutropenia, equal febrile neutropenia, and more grade 3 SN, although the SN improved to grade ≤ 2 at a median of 22 days
When delivered at equal doses, nab-paclitaxel demonstrates lower accumulation in normal tissues compared with CrEL paclitaxel
Higher paclitaxel clearance (21.1 vs 14.8 L/h/m2) compared with CrEL paclitaxel
nab-Paclitaxel demonstrated a higher ORR (27% vs 13%) , longer TTP (21 vs. 16 weeks) & OS (13.2 Vs 10.9 months) compared with CrEL paclitaxel in 2nd+ line MBC patients
The combination of a higher recommended dose (260 mg/m2 vs 175 mg/m2) and greater tumor selectivity allows a higher dose of nab-paclitaxel to be delivered to tumors compared with CrEL paclitaxel
Clinical Benefit
Greater Efficacy7
Well tolerated7
Implications
Less drug exposure to healthy tissue4
Higher drug to tumor3,5,6
Gardner ER et al. Clin Cancer Res. 2008;14(13):
Schnitzer JE et al. J Biol Chem. 1994;269(8):
Desai N et al. Clin Cancer Res. 2006;12(4):
Hawkins M et al. AACR Poster 1189.
Abraxane [package insert]. Summit, NJ: Celgene Corporation; 2011.
Taxol [package insert]. Princeton, NJ: Bristol-Meyers Squibb; 2010.
Gradishar WJ et al. J Clin Oncol. 2005;23(31):
Sparreboom A et al. Clin Cancer Res. 2005;11(11):
Cmax, maximum concentration; FDA, Food and Drug Administration; MBC, metastatic breast cancer; MoA, mechanism of action; ORR, overall response rate; SN, sensory neuropathy; TTP, time to tumor progression.
Speaker Notes
The pyramid shown consists of 3 layers (MoA, MoA implications, and clinical benefit) and 2 sides (one focused on efficacy and the other on tolerability). Each statement in the pyramid is supported by the references listed. Clicking on the individual statements causes a text pop-up to appear that expands on each point with data. To make the pop-up disappear again, simply click on the same statement.
The effort here was to show in a single slide the key aspects of the MoA of nab-paclitaxel. All comparative statements on nab-paclitaxel are made in reference to CrEL paclitaxel. This representation may allow for a progression of logic that would lead from the MoA to clinical efficacy, providing a reason for the viewer to become engaged and understand the importance of the MoA.
MoA
Tumor selectivity2-4
Higher administered dose 5,6
Tumor selectivity 2-4
Rapid clearance8
See notes for references.