AIPPI Forum 2011 - Hyderabad
Pharma Workshop 3 - 14 Oct 2011
Therapeutic Antibodies –
Technical Introduction
by
Claire Baldock
cbaldock@boult.com
© Boult Wade Tennant 2011
What is an antibody?
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Produced by B-Lymphocytes
Immunoglobulin family
Bind antigen; in particular, specific
sequences or structures within the
antigen termed epitopes
5 major classes: IgG, IgM, IgA, IgE
and IgD
Structure of an antibody – (1)
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Ig domain
Adapted from Janeway 4th edition
An archetypal IgG antibody has 2
heavy chains and 2 light chains,
linked by disulphide bonds
Each heavy chain consists of 4
immunoglobulin (Ig) domains;
each light chain consists of two
Ig domains
Each heavy and each light chain
have constant (C; Blue) and
variable (V; Red) domains
Structure of an antibody – (2)
VH
VL
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HV region
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The variable domains of each Ab chain
(VH and VL) combine to create the site
of antigen recognition
Each variable domain can be divided
into 3 hypervariable (HV) regions
situated on the outer surface of each
variable region
The HV regions of VH and VL combine
in 3 areas termed complementaritydetermining regions (CDRs) to
determine antigen specificity
Fab and Fc fragments
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Fab
F(ab)2
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Fc
Adapted from Janeway 4th edition
Antibody structure is often also divided
into the antigen-binding and
crystallisable fragments, or Fab and Fc
respectively
Fab or F(ab)2 consist of the VH and VL
regions from one or both arms of the
antibody respectively, along with the
corresponding CH and CL regions. Fabs
are able to bind antigen
The Fc fragment consists only of the 2nd
and 3rd CH domains and is recognised by
effector molecules and cells carrying an
Fc receptor (FcR)
Monoclonal antibodies
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Antibodies produced from a single B-cell clone
following immunisation with a target antigen
All antibodies specific to the same epitope on
the target antigen
Much work on and production of monoclonals
has been performed using mice, whether by
inducing ascites or making hybridomas
Chimeric, humanised and “fully human” monoclonals
Murine
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Chimeric
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Humanised
Murine antibodies often suffer from
immune rejection
Chimeric antibodies consisting of
human constant domains and murine
variable domains fare better but
unwanted immunogenicity is still a
problem
Humanised monoclonals, where only
the CDRs are of murine origin,
demonstrate a further reduction in
immunogenicity
“Fully human” monoclonals
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In recent years so-called “fully human” antibodies
have been developed
Technologies such as MedImmune’s phage display
library or Amgen’s transgenic XenoMouse, carrying
most of the human antibody genes, allow
production of monoclonals containing only human
sequences
In theory such technologies are able to generate
antibodies with high specificity, optimal affinity and
with the desired effector functions, but without any
of the unwanted immunogenicity of chimeric or
humanised monoclonals
Monoclonal product development
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Herceptin – Genentech anti-HER-2/Neu antibody for use
in cancer treatment
1987
Parent mouse anti-HER-2 antibody
developed by Genentech
1990
Parent mouse HER-2 antibody
humanised to generate Herceptin
1998
Phase III clinical trial completed and
FDA approval received
2000
EC approval received
2008
$1.8 billion worth of sales of Herceptin
Total R&D costs for the same year were $2.8
billion
Other Genentech monoclonals include Avastin
and Rituxan, each with higher $ sales than
Herceptin
AIPPI Forum 2011 - Hyderabad
Pharma Workshop 3 - 14 October 2011
Therapeutic Antibodies –
Technical Introduction
by
Claire Baldock
cbaldock@boult.com
© Boult Wade Tennant 2011