Los días 15 y 16 de octubre de 2014, la Fundación Ramón Areces y la Real Academia Nacional de Farmacia, en colaboración con la Fundación de la Innovación Bankinter, reunieron en Madrid a algunos de los mayores expertos mundiales en nuevas terapias contra el cáncer. El Simposio Internacional, coordinado por la profesora y académica María José Alonso, analizó el momento actual de la lucha contra esta enfermedad. También fue un punto de encuentro para científicos de los más innovadores institutos de investigación en oncología, quienes debatieron sobre tres grandes temas: la Medicina Personalizada contra el cáncer, los nanomedicamentos en la terapia del cáncer y las terapias basadas en la inmunomodulación.

1. Biomaterials and biotechnology:
From the discovery of the first
angiogenesis inhibitors to the
development of controlled drug
delivery systems and the foundation
of tissue engineering
Dr. Robert S. Langer
David H. Koch Institute Professor
Massachusetts Institute of Technology

2. “Anti-angiogenesis”
(Dormant Tumor)
New Capillaries
T A F

4. TUMOR
POLYMER
1.5mm
4mm
1mm

5. “The agent to be released is a small
molecule with a molecular weight no larger
than a few hundred. One would not expect
that macromolecules e.g. proteins, could be
released because of their extremely small
permeation rates through polymers.”
Adv. Poly. Sci., 1977

7. 10 20 30 40 50 60 70 80 90 100
Days
% Protein Released
90
80
70
60
50
40
30
20
10
Lysozyme
Soybean Trypsin Inhibitor
Alkaline Phosphatase
Catalase
Langer & Folkman, Nature, 1976

8. 80
60
40
20
0
Cumulative Percent release
0 10 20 30 40 50
Days

12. TUMOR
POLYMER
1.5mm
4mm
1mm

13. Rabbit corneal pocket assay
-CDI
+CDI
Langer et al, Science, 1976

14. Angiogenesis inhibitors approved for clinical use
Date Approved Drug Disease
February 2004 Avastin (Bevacizumab) Colorectal Cancer
November 2004 Tarceva (Erlotinib) Lung Cancer
December 2004 Macugen Macular Degeneration
December 2005 Nexavar (Sorafenib) Kidney Cancer
December 2005 Revlimid Myelodysplastic Syndrome
January 2006 Sutent (Sunitinib) Gastric (GIST), Kidney Cancer
June 2006 Lucentis Macular Degeneration
May 2007 Torisel (CCI-779) Kidney Cancer
November 2007 Nexavar (Sorafenib) Hepatocellular Carcinoma
February 2008 Avastin Breast Cancer
May 2009 Avastin Glioblastoma
November 2010 Afinitor Giant Cell Astrocytoma
April 2011 Zactima (Vandetanib) Medullary Thyroid Cancer
May 2011 Sutent Pancreatic Neuroendocrine Tumors
November 2011 Eylea (Aflibercept) Macular Degeneration
January 2012 Axitinib (AG-013736) Kidney Cancer
July 2012 Afinitor Breast Cancer
September 2012 Eylea (Aflibercept) Central Retinal Vein Occlusion
January 2013 Avastin Metastatic Colorectal Cancer
February 2013 Pomalyst (Pomalidomide) Multiple Myeloma
April 2014 Cyramza Advanced Stomach Cancer
August 2014 Avastin (Bevacizumab) Cervical Cancer

16. Overview of targeted therapies
Technology Example Approved
drugs
Payload
Single
molecules
Humira 20 1 molecule
Nanoparticle
conjugates
0 103 - 105
molecules

17. Coating nanoparticles with
polyethylene glycol (PEG)
PEG chains
Biodegradable core + drugs

18. 1 5 50 500 5000
Diameter
(nm)
Intensity

19. In vitro phagocytosis of surface-modified
polymeric particles
Rat alveolar macrophages - 1hr
Polymeric
particles
without PEG
PEG
(20,000 M.W.
Single chain)
PEG
(5000 M.W.
Single chain)
PEG
(5000 M.W.
Triple chain)

20. Gref, R., Minamitake, Y., Peracchia, M., Trubetshoy, V.
Torchillin, V., Langer, R. Biodegradable long-circulating
polymeric nanospheres, Science, 263: 1600-1603, 1994.

21. Targeting
molecule

23. Manufacture: Pre-clinical, clinical
and commercial scale-up
Scale up for pre-clinical,
clinical and commercial
development
Current manufacturing scales
Laboratory 1-10 g
Tox 500 g
Phase 1 5 kg

24. Human PK Data and clinical efficacy: (A) PK profile of Bind-014 at different
doses (B)PK profile of BIND-014 versus DTXL at same dose. (C) PK Data (D)
MRI of patient after treatment
0 20 40 60
100000
10000
1000
100
10
1
Time (hr)
Total Docetaxel Conc
in Plasma (ng/mL)
BIND-014; 30 mg/m2
Taxotere; 30 mg/m2
0 5 10
Before After Before After
100000
10000
1000
100
Time (hr)
Total Docetaxel Conc
in Plasma (ng/mL)
3.5 mg/m2
7 mg/m2
15 mg/m2
30 mg/m2

25. Accurin targeted nanoparticles are engineered
for optimal targeting by two complementary
mechanisms
EPR only
EPR + binding
Labeled Accurins administered to a mouse with two PC3 prostate xenograft
tumors: PSMA- and PSMA+

26. Accurin targeted nanoparticles increase
tumor drug targeting and improve efficacy
Science Translational Medicine, April 2012,
Hrkach et al
Clinical Cancer Research, June 2012, Zamboni et al
Targeted nanoparticles demonstrate significant increase in tumor drug concentrations over
parent drug (docetaxel)
Targeted nanoparticles result in tumor regression compared to tumor growth for parent drug
and non-targeted nanoparticles

27. Genetic medicine
 DNA – Turn Genes “on”
 siRNA – Turn Genes “off”

28. The gene medicine bottleneck:
Delivery
“There are only three problems in
gene therapy: delivery, delivery, and
delivery.”
—Inder Verma, 1999

29. Previous approaches
 Lipids (no more than 30 were used)
 Our approach – chemical libraries using
novel synthesis approaches – more than
1,000 used

30. 1000’s of new polymers and lipid-like
materials developed
O
O
O
O O
O O
O O
O
O
O
O
O O
O
O
O
O
O
O
O
O
O O
O O
O
O
O
O
O
O O
O O O
O
O O
O
O
O
O
O
O
O O O
O
O O
O O
O
O
O
O
O O
O
O
O
O
O
O O
O O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O O
O
O
O
O O
O O O
O
A
B
C
D
E
F
J
K
L
M
O
P
Q
R
S
T
U
Z
AA
O O
O O
BB
O O
O O
O O
F O
O O
O
O
F
F
F
O O
O
O O
II
JJ
KK
LL
O
O O O O O O O
O
O O
O
O
F O
F
F
F
F
F
F
F
PP
O NH2
O
O
O
O NH2
O NH2
O NH2
O NH2
NH2
O
NH2
O
O NH2
O
NH2
O
NH2
O
O
NH2
O
NH2
O
O
NH2
O
NH2
O
NH2
NH2
O
O
NH2
O
O
O
NH2
O
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
HO
HO NH2
NH2
OH
NH2
OH
NH2
OH
HO
NH2
OH
HO
HO NH2
NH2
HO NH2
HO
HO
HO
NH2
NH2
OH
NH2
HO
OH
NH2
HO
NH2
HO
O
NH2
OH
NH2
NH2
HO
NH2
NH2
OH
HO
NH2
HO
NH2
HO
HO
NH2
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
63
64
65
66
67
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
N
H
H
N
N
H
H
N
N
H
H
60 N
61
62
N
H
HN NH
Si NH2
O
O
Si NH2
O
O
O
N
H
N
H
N
H
N
H
N
H
HN
O
O
H
N
HN
O
N
H
NH
O
O
O
NH
H
N
N
H
N
H
N N
H
S
NH2
68
69
70
71
72
73
74
N NH2
N
NH2
N
N NH2
N NH2
N
NH2
NH2
N NH2
N
HO
NH2
N
HO
NH2
N
NH2
N NH2
N NH2
HO
HO
N NH2
N
NH2
O
N
NH2
O N NH2
O N NH2
87
88
89
90
91
92
93
94
NH2
F
F
F
F
F
F
N NH2
N
HN
N
NH2
75
76
77
78
79
80
81
82
83
84
85
86

31. Formulations induce long duration,
reversible knockdown in mice, rats, guinea
pigs, and primates
1.8
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
0 10 20 30 40 50 60 70 80 90 100 110
Time (d)
Relative FVII Protein
siCont siFVII

32. LP-siCont 2.5 LP-siApoB 2.5 LP-siApoB 6.25
mg/kg mg/kg mg/kg
1.4
0.8
0.0
Lipoprotein Relative to Pre-Dose

33. Fully reversible, specific liver
knockdown
1.8
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
0 10 20 30 40 50 60 70 80 90 100 110
Time (d)
Relative FVII Protein
siCont siFVII
Dose 1 Dose 2 Dose 3
No evidence of reduced activity upon repeat administration

34. Improved lipidoid libraries
H2N NH2
O
+ R
90 oC
Created library of 150 new compounds
R R
OH HO
 10 different commercially available epoxide-terminated
tails
 Selection of amines from original lipidoid library
with bias towards good performing amines from
previous libraries
 Tested FIRST IN VITRO
N N
HO OH
R R

35. 2-3 orders of magnitude more efficient
delivery of siRNA in mice APO E independent
NH
O
N
HN
N
N
NH
O N
H
O
NH
O
O
NH
1.2
1
0.8
0.6
0.4
0.2
0
PBS 1mg/kg
siLuc
0.1
mg/kg
0.03
mg/kg
0.01
mg/kg
0.003
mg/kg
6 mg/kg 3 mg/kg 1.5
mg/kg
C12-200 LNP01
Relative FVII Expression
Dose (Entrapped siRNA Content)

36. Single dose knockdown of TTR in
Primates at <0.03 mg/kg
Relative TTR/GAPDH mRNA Level

37. Ten different siRNAs formulated in one
nanoparticle inhibit ten different hepatic
mRNAs
LNP12-Pool of 10
1.5
1.0
0.5
Pool of 10
Luciferase
Luciferase
Pool of 10
Luciferase
Pool of 10
Luciferase
Pool of 10
Luciferase
Pool of 10
Luciferase
Pool of 10
Luciferase
Pool of 10
Luciferase
Pool of 10
Luciferase
Pool of 10
Luciferase
Pool of 10
0.0
PCSK9
FVII
ApoB
TTR
Xbp1
SORT1
TTC39B
Rab5c
ITG1
ApoC3
Target mRNA
Mice, 0.1mg/kg of each siRNA, 48h post tail vein injection

38. Next generation LNPs: Remarkable
potency improvements with novel
lipids
Novel LNPs set new benchmark for systemic RNAi with ~100 fold improved
potency
 Efficacy in pre-clinical models following single IV injection
 Each LNP comprised of distinct cationic lipid component
 Improvements in potency has resulted in single digit /kg ED50
Dlin-MC3-DMA-b
MIT MIT
DLin-KC2-DMA-b
FVII siRNA Dose (mg/kg)
ED50
DLinDAP
0.1 1 10
120
100
80
60
40
20
0
% Residual Factor VII
DLinDMA
98N12-5(I)
DLin-K-DMA
DLin-KC2-DMA-a
0.01
C12-200
0.001
MD1
0.0001
1st Generation LNPs
 ALN-VSP (Phase I Completed)
 ALN-TTR01 (Phase I)
2nd Generation LNPs
 ALN-PCS (CTA Filed)
 ALN-TTR02 (IND, H2 ’11)
MIT
Yizhou, D et al
PNAS 2014

39. Optimized 7C1 forms small, consistent,
stable particles
siRN
A
7C1
C14PEG2000
35-55 nm
100
nm
Microfluidics
1 10 100 1000
25
20
15
10
5
0
Diameter (nm)
Percent Volume
Batch 1
Batch 2
Batch 3
Batch 4
1 10 100 1000
25
20
15
10
5
0
Diameter (nm)
Percent Volume
0 Days
14 Days
40 Days
Consistent Stable
Dahlman et al, Nature Nanotechnology

40. 7C1 reduces endothelial mRNA at doses
100x lower than other technology
50% Silencing 0.017 mg/kg
1.5
1.0
0.5
0.0
0.001 0.010 0.100 1
siVE-cad Dose (mg/kg)
VE-cad/GapDH mRNA
Heart ECs
Renal ECs
Lung ECs
Dahlman et al, Nature Nanotechnology
0 10 20 30 40
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
Days Following Single 0.6 mg/kg Injection
ICAM-2/GapDH mRNA
Silencing >3 weeks

41. Prototype device
Silicon Nitride
or Dioxide
Cathode
Silicon
Active
Substance Anode

43. Reservoir activation
 SEM of a reservoir –
electrode system
before application of
an electric potential

44. Reservoir activation
 SEMs taken after application of 1.04 volts vs. SCE in PBS

45. Single compound release
40
30
20
10
0
Release Rate
1 2 3 4 5 6 7
Time (days)
Fluorescein (ng/min)

46. Multiple compound release
Time (Hours)
60
40
30
20
10
0
Release Rate
50
Fluorescein (ng/min)
45Ca++ (5xNCi/min)
10 20 30 40 50 60 70

47. Clinical trial
 Chips are communicated with over a special
frequency called the Medical Implant
Communications Service Band, approved by both
the FCC and the FDA.
 A patient or doctor enters a special computer code
to administer or change the dose.
 Bidirectional communications link between the chip
and receiver enables the upload of status
information, including confirmation of dose delivery,
battery life, etc.

48. Clinical trial
 8 patients
 PTH (compliance with injections is 25%)
 Small office procedure to implant
 Some pharmacokinetics (less variability)
and Ca, PINP, CTX measures as daily
injections

51. Gates Foundation grants
Phase I: Feasibility
 Granted in December 2012, term: 13 months
 Purpose: to develop a personal fertility control system
with emphasis for use by women living in Developing
World countries as a means to effectively plan their
families
 Amount: $1,579,750
Phase II: Detail Design
 Granted in January 2014, Term: 13 months
 Purpose: to develop a personal system that enables
women to regulate their fertility
 Amount: $4,614,648