Antibodies Flashcards
What are antibodies, vaccines, and adjuvants collectively referred to as?
They are collectively referred to as “biologics.”
How have traditional polyclonal antibody preparations been used?
Used for passive immunization against infectious diseases and harmful agents.
Passive immunization - Phrophylactically
To prevent a future medical episode
e.g. administration of a specific anti-snake toxin antibody preparation prior to travel to a region in which the snakes are commonly found.
Passive immunization - Therapeutically
To treat a medical condition that is already established
e.g. administration of the anti-venom antibody immediately after the individual has experienced a snake bite.
What are the two categories of antibody preparations used for passive immunity based on their source?
Antisera
- obtained from animals
Immunoglobulin preparations
- obtained from humans
What is the predominant antibody type in both animal-origin and human-origin preparations?
IgG
What are some potential side effects of using specific antisera?
Hypersensitivity reactions such as “serum sickness” and, in severe cases, life-threatening anaphylaxis.
What are the major categories of polyclonal antibody preparations used therapeutically?
- Specific microbial or viral pathogens
- Microbial toxins
- Snake/spider venoms (antivenins)
When was monoclonal antibody technology first developed?
The mid 1970s.
Kohler and Milstein
How were monoclonal antibodies first produced?
Fusing immortal myeloma cells with antibody-producing B-Lymphocytes,
resulting in hybridoma cells that produce monospecific (monoclonal) antibodies.
What are the therapeutic applications of monoclonal antibodies?
- induction of passive immunity,
- diagnostic imaging
- treatment of conditions such as cancer, transplantation, and cardiovascular disease.
How do monoclonal antibodies interact with target cells in the body?
Selectively interact with specific target cells in the body
How can monoclonal antibodies be modified for specific applications?
Can be conjugated to a radioisotope, drug, or toxin, acting as “magic bullets” to deliver a radioactive or drug load to specific target cells in the body.
Name two FDA-approved monoclonal antibody products and their uses.
Remicade (Infliximab) is used for the treatment of Crohn’s disease
Herceptin (Trastuzumab) is used for the treatment of metastatic breast cancer.
What is the most significant indication for antibody-based products currently in clinical trials?
Cancer
What is the majority of monoclonal antibodies approved to date?
Majority
are engineered chimeric or humanized antibodies or antibody fragments,
Minority
Intact antibodies produced by classical hybridoma technology.
What is one of the limitations associated with the administration of murine monoclonal antibodies to human subjects?
Antibody immunogenicity
The immune response elicited by murine monoclonal antibodies in human subjects.
What percentage of patients typically exhibit an immune response after a single injection of a mouse monoclonal antibody?
Approximately 50-80% of patients
What are human anti-mouse antibodies (HAMA), and when are they generally detected?
- Antibodies produced by human subjects in response to mouse monoclonal antibodies.
- Generally detected within 14 days of antibody administration.
How many doses of murine monoclonal antibodies are typically effective due to immunogenicity limitations?
First and, at most, the second dose administered.
What is an alternative approach to overcome the immunogenicity problem associated with murine monoclonal antibodies?
Chimeric and humanized antibodies,
- antibodies that combine mouse and human components to reduce immunogenicity.
How can human antibody-producing lymphocytes potentially be rendered immortal?
- transformation through Epstein-Barr virus infection
- fusion with murine monoclonals
- fusion with human lymphoblastoid cell lines.
What is the purpose of using chimeric and humanized antibodies?
Chimeric and humanized antibodies are used to minimize immunogenicity and enhance the therapeutic potential of antibodies in human subjects.
What is the first strategy used to reduce the immunogenicity of murine monoclonal antibodies?
The production of “chimeric” antibodies, which consist of mouse variable regions and human constant regions.
What are the expected benefits of using chimeric antibodies compared to murine antibodies?
Chimeric antibodies are:
- Significantly less immunogenic
- Display a prolonged serum half-life
- Allow activation of various Fc-mediated functions.
What is the rate of immune response observed after a single dose administration of chimeric antibodies?
80% for murine
5% for chimeric
How does chimerization affect the serum half-life of antibodies?
Increases the serum half-life of antibodies by approximately 5-fold, with typical values of 230 hours being recorded.
What is the purpose of humanizing murine antibodies?
Involves transferring the nucleotide sequences coding for the CDRs of the murine antibody into a human antibody gene,
reducing their antigenicity.
What is the role of Avastin, a humanized monoclonal antibody developed by Genentech?
Treats metastatic colorectal cancer
- Inhibits angiogenesis by binding to human vascular endothelial growth factor (VEGF),
- preventing it from binding to its cell surface receptor and inhibiting new blood vessel formation.
When was Avastin approved for medical use in the US and the EU?
US in 2004 and in the EU in 2005.
How does Avastin act to inhibit tumor growth?
Avastin acts by inhibiting angiogenesis, which is the formation of new blood vessels.
It prevents the binding of VEGF to its receptor, which is necessary for triggering new blood vessel formation in both normal and diseased tissue.
Why is there interest in using antibody fragments in antibody-mediated treatment of solid tumors?
Physical size of intact antibodies can hinder their penetration into the tumor mass.
What are some examples of antibody fragments generated by recombinant DNA technology?
- F(ab)
- F(ab)2
- Fv fragments.
What are some limitations of antibody fragments compared to intact antibodies?
- Greatly reduced half-lives
- Cannot initiate effector functions like intact antibodies.
For what purpose are radiolabeled antibody fragments better suited?
For diagnostic imaging purposes due to their reduced half-lives and limited effector functions.
