Huggins Lectureship Lecture

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Huggins LectureshipLecture 7

• Saturdays
• January 12-March 1, 2008
• Judy Cannon Ph.D.
• Postdoctoral Fellow
• Department of Medicine, Section of Pulmonary and
  Critical Care Medicine

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Quiz-from Week 6 lecture

• T cells recognize target cells by
• Antigen on the target cell surface
• Antibodies to the target cell
• Chemokine receptors on the target cell
• T cells use these to kill target cells
• Proteins that punch holes in the target cell
• Induce target cells to commit suicide
• Help B cells produce antibodies which lead to
  target cell death
• All of the above
• What happens to immune cells once the pathogen is
  cleared?
• (A) All the expanded T and B cells hang around
  waiting for the next infection
• (B) Most T and B cells die off, leaving very few
  behind to respond to the next infection
• (C) T and B cells kill any cell they come into
  contact with
• Cancer cells use the following tactics to evade
  the immune system
• (A) Increase regulatory T cells to block T cell
  killing
• (B) Enhance proteins that block T cell function
• (C) Turn off display of antigens on the cancer
  cells
• (D) All of the above

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Questions from Week 6

• Temperature and immunity Fever helps protect
  host from inflammatory responses inhibits
  pathogen growth.
• Cells participate in organism, cells die unless
  they are doing their job in organism.

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Why do cells present antigen?

• T cell Custom officer.
• Cant patrol the border, pathogens can invade in
  any number of places.
• Constantly ask for identification, ID.
• ID- Antigens. If all checks out, then T cell will
  not activate. When they see antigen that isnt
  self, they can then activate.

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T cell recognition Self and nonself component

• T cell recognition is based on recognition of
  antigen on a self protein Major
  Histocompatibility Complex (MHC).

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The Immune System and Cancer A Civil War

• Lecture 1 The NorthImmune system and the
  South tumors.
• Lecture 2 Danger signals Inflammation. How
  the immune systems recognizes something is going
  wrong.
• Lecture 3 Is this me? Or something bad? Antigen
  recognition of self vs. non-self.
• Lecture 4 The more the merrier Immune cell
  expansion.
• Lecture 5 Location, location, location T cell
  trafficking.
• Lecture 6 At the infection/tumor site.
• Lecture 7 Using the immune system to treat
  cancer How antibodies has led to the creation of
  cancer therapeutics.
• Lecture 8 Who will win in this Civil War?

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February 23rd 2008Huggins Lecture
7Monoclonal antibodies
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The B cell

• A cell in the adaptive immune system
• Makes antibodies (immunoglobulins)

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Clonal Theory

• One antibody, one antigen
• Nobel prize to Burnet and Medawar in 1960 for the
  discovery that antibodies arise randomly, then
  are expanded in response to antigen

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Normal antibody immune response

• Every B cell that recognizes a specific pathogen
  can activate and proliferate.
• Normal immune response is polyclonal poly-many
  clonal-individual clones or cells.

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Antibodies in therapy

• 1890s Immunized sheep or horses with diphtheria.
  Extracted serum from infected sheep or horses and
  injected serum into individuals with diphtheria.
  In 1894, mortality of diphtheria in Paris fell
  from 52 to 25.
• Now
• Immunodeficient patients who cannot make
  antibodies are given large doses of total pooled
  human antibodies. Regenerates immunity.
• Rh factor disease. Mothers who do not express a
  certain factor, Rh, can develop potent immune
  responses to fetuses after exposure (first
  child). Mothers given antibodies to Rh factor to
  block immune recognition of Rh positive fetus.

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Monoclonal antibody

• Mono one
• Clonal from one original clone, or cell with one
  specificity
• Antibody that sees only one (mono) specificity
  (clonal).

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How is a monoclonal antibody made?
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HGPRT Necessary for cell growth.
http//www.nature.com/nri/journal/v4/n2/images/nri
1265-f3.jpg
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Myeloma cells without spleen cells DEATH Does
not contain essential cell growth gene
spleen cells without myeloma cells DEATH Not
cancerous so cannot keep living
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Monoclonal antibodies

• Every B cell produces antibodies that sees only
  one antigen.
• In 1975, George Kohler and Cesar Milstein found a
  way to make a large quantity of antibody all of
  the same specificity monoclonal antibody.
• Nobel prize in 1984 Milstein and Kohler
  (production of monoclonal antibodies), and Jerne
  (theoretical basis for antibody clonal
  recognition)

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How do antibodies work?
Helps macrophages and other cells eat up more
pathogens
Brings in new proteins that punch holes in
pathogens to kill pathogens directly
Blocks ability of pathogens to bind to new targets
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Therapeutic potential of antibodies
Binds cells that cause disease and helps
macrophages eat cells
Binds cells responsible for disease and leads to
direct death of disease causing cells
Blocks disease causing factor to cause disease
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Monoclonal antibodies in therapy

• Need spleen cells. Initially used animal spleens.
• But, mouse/sheep/horse/rat antibodies are rapidly
  eliminated in human blood.
• How to get human antibodies?

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984-f2.gif
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What can monoclonal antibodies do?

• Detect presence of proteins and antigens
• Used extensively in clinical and research fields
  for diagnostics.
• In therapeutics
• Block function of proteins and cells.
• Target cells for destruction.
• What proteins and cells should be blocked in
  disease?
• Monoclonals are a tool, still need understanding
  of disease.
• Need to know the underlying causes of diseases to
  target.

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Monoclonal antibody therapeutics
1975
1986
Present Day
First monoclonal antibody produced in large
quantities
More than 200 monoclonal antibodies approved or
in clinical trials. More than 4 billion dollars
in sales in 2005.
First FDA approved monoclonal antibody
therapeutic. Used in transplant patients
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Transplantation
In immunodeficient mice (mice without T cells),
transplants are well tolerated.
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First monoclonal therapeutic

• T cells responsible for transplant rejection.
• Monoclonal target T cells. Eliminates all T
  cells.
• Muromonab CD-3 (OKT3) (CD3 is a component of the
  T cell receptor).
• Immunosuppressive therapy.

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Mab Monoclonal Antibody
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Uses of monoclonal antibodies now

• Transplantation
• Cancer
• Infectious Disease
• Autoimmune disorders
• Other chronic diseases

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Monoclonal Antibodies Used to Treat Cancer
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Modification of monoclonal antibody therapy

• Monoclonal antibodies coupled to killing factors.
  Directly deliver killing factors to cancer cells.

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Pros and cons of antibodies

• Advantages
• High specificity.
• Limited side effects.
• Disadvantages
• Hard to produce quickly.

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Variations on monoclonal antibodies

• Other biological tools being developed that can
  mimic antibody specificity.
• Aptamers small synthetic and highly specific
  molecules that can couple to particles and use to
  isolate specific types of cells, e.g. cancer
  cells. Mostly diagnostic.

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Key points Lecture 7

• Researchers discovered a way to combine a
  specific B cell with cancer cells, to produce
  large amounts of antibody that recognizes only
  one antigen monoclonal antibodies.
• Monoclonal antibodies can specifically target
  proteins or cells that can be used in diagnostics
  or therapy.

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Next week Lecture 8Who will win the civil war?
March 1st 2008