Lecture 24 Spring 2006 1

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Lecture 24 Spring 2006 1

Biomaterials as Adjuvants

ANNOUNCEMENTS:

Last Time: drug targeting

Today: Delivering activation signals to dendritic cells in vaccines Reading:

Supplementary Reading:

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Targeting vaccines to dendritic cells

Targets on DCs:

DEC-205 CD11c TLR3

…particles, in general

Images removed due to copyright restrictions.

Please see: Kwon, et al.PNAS102 (2005): 18264-18268.

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Lecture 24 Spring 2006 3

Figure removed due to copyright restrictions.

Please see: Figure 4 in Kwon, et al. PNAS 102 (2005): 18264-18268.

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‘REVERSE TARGETING’, CONTINUED

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Lecture 24 Spring 2006 5 Lecture 24 Spring 2006

4) Activation of naïve T cells in the lymph nodes Infection site

1) Attraction to sites of infection

2) Antigen loading and

activation

3) Trafficking to lymph

nodes Infected cells

1) Chemotaxis:

Migration ‘up’ concentration gradients of chemoattractant

Targeting dendritic cells to

vaccines: ‘Reverse targeting’ to

mimic infection site recruitment

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3 mm

~1 mm

1.2 mm

collagen gel

‘Vaccination site’ source well

CH C O

O CH

C O

O

CH₂ CH₃

CH₃

C O

H₂ C

C O

O O

x y

PLGA

Please see: Zhao, X., et al. Biomaterials 26 (2005): 5048.

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Lecture 24 Spring 2006 7

Dendritic cell attraction, antigen loading, and activation

Antigen-delivery nanoparticles

chemokine

Alginate microsphere

DCs

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Iso-octane

CaCl

₂

solution

Wash alginate

How to encapsulate multiple factors under mild conditions for ‘reverse targeting’?

Image removed due to copyright restrictions.

Please see: http://www.lsbu.ac.uk/water/hyalg.html COOH

O

OH OH

H

H H

H

H H

COOH

OH OH

H

H H

H

COOH

OH OH

H

H H

H

COOH

OH OH

H

H H

H

H O

O O O

Mannuronic acid block Guluronic acid block

ALGINATE

Figure by MIT OCW.

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Lecture 24 Spring 2006 9

Fluorescent nanoparticles Fluorescent chemokine

0 20 40 60 80 100

0 1 2 3 4 5 6 7

Time (Days)

% MIP-3α Released

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-200 -100 0 100 200

x- distance from bead

y- distance from bead

-200 -100 0 100 200

x- distance from bead

y- distance from bead

Migration Histogram N=100

0 5 10 15 20 25

25 75 125

175 225

275 325

375 425

Distance (μm)

# Cells

collagen gel

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Lecture 24 Spring 2006 11 Amount of DQ-ovalbumin internalized

Alginate microspheres loaded with:

# cells

Antigen nanoparticles Antigen nanoparticles + MIP-3α

3.9% 17.9%

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Issues in targeted delivery

• Where is the target molecule expressed?

• Is it expressed by normal tissues?

• Is it stably expressed?

• Can select out evasive tumor cells/viruses

• What is the affinity of binding?

• immune response to targeting agent

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Lecture 24 Spring 2006 13

ADJUVANTING VACCINES WITH SYNTHETIC MATERIALS

MIMICKING PATHOGEN-HOST INTERACTIONS TO STIMULATE

IMMUNITY

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ADJUVANTING FUNCTIONS OF BIOMATERIALS

• Sustain delivery of antigen

– Extracellular or intracellular

• Mimic pathogen delivery of activation signals to dendritic cells and B cells

– Mimic multivalent surface structure of pathogens

• Limit dose, but enhance response

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Lecture 24 Spring 2006 15

SUSTAINING ANTIGEN DELIVERY TO DENDRITIC CELLS EXTRACELLULAR DEPOTS INTRACELLULAR DEPOTS

Please see: Shen, et al. Immunology 117 (2005): 78-88.

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pathogens as biomaterials: how the structure of pathogens relates to immune responses

Please see: http://www.kripafoundation.org/ Rehabilitation%20Programs/faqhiv.html

Please see: http://textbookofbacteriology.net/BSRP.html

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Lecture 24 Spring 2006 17

pathogens as biomaterials: how the structure of pathogens relates

to immune responses

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Dose sparing of adjuvants by co-delivery in particles

T cell proliferation measured ex vivo 10d after 2 injections:

Many immunostimulatory factors that activate DCs are also potent inflammatory stimuli:

Please see: Heikenwalder, et al. Nat Med10 (2004): 187-192.

Please see: Diwan, et al. Current Drug Deliv 1, no. 4 (2004): 405-412.

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Lecture 24 Spring 2006 19 +

+ + +

+ +

+ + + +

+ +

- -

-

- - - - -

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- -

-

+ + - -

- - -

-

- - -

CpG oligos

Nanoparticles that mimic pathogen structural features

500 nm

(2) surface display of repeated native

Ag epitopes

Poly(L-arginine)

(3) surface display of ‘pathogen

associated molecular patterns’

(1) Particulate

antigen delivery

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Please see: Jain, S., et al. Biomacromolecules6 (2005): 2590.

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Lecture 24 Spring 2006 21

Please see: Jain, S., et al. Biomacromolecules6 (2005): 2590.

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Proposed mechanism for antigen delivery to dendritic cells

1.

2.

3. Soluble Ova + CatD

Graphs removed due to copyright restrictions.

Please see: Jain, S. et al. Biomacromolecules6 (2005): 2590.

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Lecture 24 Spring 2006 23

0

40 80 120 160

0.001 0.01 0.1 1

CpG concentration (PM)

IL-12p70 (pg/ml)

CpG particles particle-CpG

0 3000 6000 9000 12000 15000 18000

0.001 0.01 0.1 1

CpG concentration (PM)

IL-6 (pg/ml)

soluble CpG particles particle-CpG

Cytokine Secretion by Activated DCs

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pathogens as biomaterials: how the structure of pathogens relates to immune responses

Please see: http://www.kripafoundation.org/ Rehabilitation%20Programs/faqhiv.html

Please see: http://textbookofbacteriology.net/BSRP.html

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Lecture 24 Spring 2006 25

0

10000 20000 30000 40000 50000 60000 70000

ova ova + CpG particles particles + CpG

PpR60-CpG ova + CFA

Samples

A n ti -o v a I g G t it e rs

week 1 week 3 week 5 week 7

B Cell Activation In Vivo

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Synthetic pathogens?

I II III

mobile ligand particles

biotin-ova

SAv

biotinylated phagocytosis ligand

Image removed due to copyright restrictions.

Please see: Troutier, et al. Langmuir 21 (2005): 1305-1313.

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Lecture 24 Spring 2006 27

Synthetic pathogens?

Figures removed due to copyright restrictions.

Please see: Figures 3 and 5 in Yu, et al. Adv Mater17 (2005): 1477-1480.