Download Presentation

Survey
yes no Was this document useful for you?
   Thank you for your participation!

* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project

Document related concepts

Human microbiota wikipedia , lookup

Molecular mimicry wikipedia , lookup

Transcript
UCL
Antibody targeted Cancer Therapy
Kerry Chester
Tuesday 25th April 2006. 4pm-5pm
Chemistry Auditorium
CANCER BIOLOGY MODULE
Antigen Binding
VH
VH
CH1
VL
CL
CL
S-S
S-S
CH3
S-S
S-S
S-S
S-S
CH2
VL
CH1
CH2
CH3
Antibodies can
Native antibodies
•Recruit natural effectors (e.g. ADCC, Complement mediated lysis)
•Neutralize growth factors (e.g. VEGF)
•Block receptors/signal transduction
•Stimulate apoptotic signaling
•Activate T-cells
•Act as catalysts (catalytic antibodies or abzymes)
Conjugated Antibodies
•Deliver radioactivity
•Deliver drugs or toxins
•Pre-targeted therapies eg ADEPT
•Target genes
•Recombinant bi-specifics (eg anti tumour linked to anti T-cell)
Most clinically useful antibodies………
Native antibodies
•Recruit natural effectors (e.g. ADCC, Complement mediated lysis)
•Neutralize growth factors (e.g. VEGF)
•Block receptors/signal transduction
•Stimulate apoptotic signaling
Conjugated Antibodies
•Deliver radioactivity
•Deliver drugs or toxins
•Pre-targeted therapies eg ADEPT
Antibody dependant cellular cytotoxicity (ADCC)
(a) MAbs bind to antigen on the tumour cell surface, providing the target for Fc
receptors on the surface of natural killer (NK) cells.
Cross-linking of Fc receptors triggers release of molecules that lyse tumour
cells.
(b) Cell debris is taken up by APC
(c) APC present the tumour antigens to B cells, triggering the release of
antibodies
(d) APC present to cytotoxic T lymphocytes (CTLs) that can recognize and
kill cells that express the target antigen
Adams & Weiner (2005) Nat biotech
Native Monoclonal Antibodies can
•Recruit natural effectors (e.g. ADCC, Complement mediated lysis)
•Neutralize growth factors
•Block receptors/signal transduction
•Stimulate apoptotic signaling
but……..
Definitions
Monoclonal antibody
Antibody produced from a single B-lymphocyte
Murine monoclonal antibody
Monoclonal antibody derived entirely from mice
Chimeric antibody
Monoclonal antibody constructed from Mouse V-regions and human C-regions
Humanized antibody
Monoclonal antibody constructed with only antigen binding regions (CDRs)
from mouse. Remainder is human
Rituximab
•
•
•
The original ®ituximab (Rituxan)
FDA approved 1997
Indication: Lymphoma
Anti-CD 20
CD20 expressed on 95% of malignant Bcell lymphomas, but also on normal B-cells
Human IgG1 C-regions
mouse
human
Chimeric antibody
Monoclonal antibody constructed from
Mouse V-regions and human C-regions
Therapeutic mechanism:
Complement mediated cytotoxicity
Antibody dependent cell-mediated cytotoxicity
Induction of apoptosis
Trastuzumab
(Herceptin)
•
•
•
FDA approved 1998
Indication: Breast cancer
Anti HER2 (human epidermal growth factor
receptor 2)
HER2 is a gene that helps control how cells
cells grow, divide and repair themselves
Human IgG1 C-regions
Therapeutic mechanism:
mouse
human
Humanized antibody
Monoclonal antibody constructed with only
antigen binding regions (CDRs) from
mouse. Remainder is human
Inhibit growth signals
Antibody dependent cell-mediated cytotoxicity
Other mechanisms are also possible
Bevacizumab
(Avastin)
FDA approved 2004
Indication: Colorectal and lung cancer
Avastin
•
•
•
Anti VEGF (vascular endothelial growth factor)
VEGF stimulates growth of tumour blood vessels
Humanized with human IgG1 C-regions
Therapeutic mechanism:
Tumor growth is dependent on angiogenesis. Angiogenesis is dependent on VEGF.
Avastin directly binds to VEGF to directly inhibit angiogenesis
(See R. B. Pedley and T. Meyer Lecture)
First anti-angiogenesis therapy to increase
survival in cancer patients
Conjugated Antibodies
•Deliver radioactivity
•Deliver drugs or toxins
•Pre-targeted therapies eg ADEPT
Radioimmunotherapy
• Radionuclide attached to antibody
• Usually ß-emitters, e.g. 131I, 90Y
• Cytotoxic over a distance from its source
depending on path length
Experimental radioimmunotherapy in IL2Rexpressing lymphomas (Phase I study)
• IL2R (CD25) expressed on tumour cells
• 131I anti-IL2R antibody
UCL
Engineered scFv antibodies and
filamentous bacteriophage
Genes encoding V regions can be obtained by PCR
using primers in conserved (framework) regions
flanking CDRs (hypervariable regions).....see diagram
on next slide
mRNA from mice or humans is commonly used as a
source of V regions that are being expressed by
plasma cells......see diagram on next slide
The amplified V regions are linked by PCR into scFv
format and cloned into filamentous bacteriohage phage
(virus that grows in bacteria). Here genotype is linked
to phenotype – each phage expresses an scFv on its
surface and carries the gene for that scFv in its DNA.
.....see diagram on next slide
A phage antibody library contains millions of different
antibody specificities in just a 1ml tube
It is therefore relatively simple to get cloned scFvs to
any antigen or tumour cell by selecting phage which
bind to that antigen or tumour cell......see diagram on
next slide
•After each round of selection with antigen the selected
phage are amplified in number by growing in bacteria
The phage system has been used to make an MFE-23, an scFv
antibody to the tumour associated antigen CEA (carcinoembryonic
antigen), which is overexpressed in many GI carcinomas ......see
next slide
MFE-23 targets to tumours in man
i.v. injection of
MFE-23
Tumor
UCL
Engineered antibodies in
ADEPT
In ADEPT, an antibody directed against a tumour associated
antigen is linked to an enzyme and given intravenously, resulting in
selective accumulation of enzyme in the tumour. When the
discrimination between tumour and normal tissue enzyme levels is
sufficient a prodrug is given intravenously, which is converted to an
active cytotoxic drug by enzyme within the tumour. This gives
higher tumour to normal tissue ratios at the time when therapy is
given than can be achieved with direct tumour targeting. ......see
next slide
ADEPT also has the advantage of achieving a bystander effect.
ADEPT
Antibody directed enzyme prodrug therapy
prodrug
toxic drug
enzyme
antibody
Amplification effect:
High concentration of
drug within tumours
Bagshawe 1987
Bystander effect:
Cancer
cell
death
cell
Neighbouring tumour
cells are also killed by
diffusing active drug.
Important as all cells may
not be reached by
antibody-enzyme
Summary
Antibodies: are complex protein based molecules produced by Blymphocytes as part of the immune response. Their normal function
is to bind to and help eliminate foreign and infectious agents in the
body
Antibodies are increasingly used in cancer treatment
Examples:
•Recruit natural effectors (ADCC, Complement mediated lysis)
•Neutralize growth factors (eg VEGF)
•Block a receptor
•Stimulate apoptotic signaling
•Deliver radioactivity (RIT)
•Deliver a toxin
•Pre-targeted therapies eg ADEPT
Definitions
Monoclonal antibody
Antibody produced from a single B-lymphocyte
Murine monoclonal antibody
Monoclonal antibody derived entirely from mice
Chimeric antibody
Monoclonal antibody constructed from Mouse V-regions and human C-regions
Humanized antibody
Monoclonal antibody constructed with only antigen binding regions (CDRs)
from mouse. Remainder is human
Further reading
UCL
Allen TM (2002) Ligand-targeted therapeutics in anticancer therapy. Nat Rev
Cancer 2: 750-763
Adams GP, Weiner LM (2005) Monoclonal antibody therapy of cancer. Nat
Biotechnol 23: 1147-1157
The antibody resource page:
http://www.antibodyresource.com/educational.html
(Contains links to many interesting antibody sites)