AntibodiesasDrugs

,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Antibodies as Drugs,Lauren Lahey,Overview,An emerging theme,Historical breakthroughs,Terms to know,A look at antibody structure,Production of monoclonal antibodies,Antibodies as biopharmaceutical,Autoimmune Disease,Rheumatoid Arthritis,Variations and future directions,Emerging Themes,Antibodies are naturally occurring,Discovery of their innate properties hinted at great therapeutic potential,High-specificity in binding,Already present in the body,Can activate and couple components of the immune system,Modification to structure and refinement in production methods have made antibodies a viable modern drug,At the turn of the 20,th,century:,Emil Adolf von Behring,Developed serum therapy as an effective treatment against diphtheria and tetanus,For this,he received the first ever Noble Prize in Physiology or Medicine in 1901,The serum derived from immunized animals was latter shown to be effective because of the antibodies it contained,Paul Ehrlich,Side-chain theory:,Toxins and antitoxins were chemical substances,Antitoxins were side-chains on cells that could bind with a toxin like a lock and key,Predicted autoimmunity or“horror,autotoxicus,”,Received the 1908 Nobel Prize in Physiology or Medicine for his work in immunity,More recently:,“,Discovery”of antibody chemical structure,Gerald Edelman,and,Rodney Porter,circa 1961,Received the 1972 Nobel Prize in Physiology or Medicine,Development of,hybridoma,technology,Jerne,Kohler,and Milstein,1975,Received the 1984 Nobel Prize in Physiology or Medicine,Production of the 1,st,monoclonal antibody,In 1986,OKT-3 was approved for use in organ transplant rejection,Important Terms,Antibody,immunoglobulin secreted by B cells,Antigen(,anti,body,gen,erator),any substance capable of eliciting an adaptive immune response,Monoclonal antibodies(,mAbs,),antibodies secreted from a single B cell,have identical paratopes,Epitope,region of the antigen recognized by an antibody,Paratope,region of the antibody that binds the epitope,The Structure of an Antibody,2 identical light chains(220 amino acids long),Variable domain:V,L,Constant domain:C,L,2 identical heavy chains(440 amino acids long),Variable domain:V,H,3 Constant domains:C,H,1,C,H,2,C,H,3,Covalent,disulfide bonds between,cysteine,residues,Flexible“hinge region”,Formation of Disulfide Bonds,Catalyzed in the Endoplasmic Reticulum,Do,not,change the proteins conformation,Reinforce a favored conformation,Disulfide bonds are sensitive to reduction,Immunoglobulin,(,Ig,)Class,Heavy Chain,Diagram,Distribution,Biological Activity,IgA,or,External Secretions,IgD,B Cell surface receptor,IgE,Cells that secrete histamines,IgG,Main antibody in serum,Most Stable,Promotes antibody-dependent cellular cytotoxicity(ADCC),Compliment fixation,IgM,First antibody secreted in development,Compliment fixation,Hypervariable Loops,A.k.a,:,Complementarity,-Determining Regions(,CDRs,),Regions of increased amino acid sequence variability,In each variable region,3,CDRs,interspersed in between framework regions,Each CDR is between 5-10 amino acids long,A Dynamic Binding Site,The functional groups of the,paratope,(,Fab,)interact with the epitope(antigen),Hydrogen bonding,Van,der,Waals forces,Ionic interactions,The,CDRs,are necessary for antigen binding,The tertiary structure of this region can contain pockets,undulating flatter surfaces,and even protrusions,Small antigens typically bind in deep pockets,Antibody,Pharmokinetics,Antigen binding is reversible,Antigen(Ag)+Antibody(,Ab,),AntigenAntibody,(,AgAb,)bound,K,affinity,=,AgAb,AgAb,For some therapeutic,mAbs,the affinity must be balanced so that effective antigen binding occurs while tissue penetration is allowed,Cross-linking,All antibodies are at least bivalent,Two paratopes can bind with two epitopes,With 2 epitopes on a single antigen,cyclic or linear cross-linking can occur.,Three or more epitopes on an antigen leads to formation of large three-dimensional lattices,Mechanisms of Action,Blocking action of molecular targets,Can work antagonistically by binding a,receptor,to prevent activation,Can also bind the,antigen,and prevent activation,“Magic Bullet”,Compound with target specificity is coupled with various effector groups,Toxins,radionuclei,enzymes,DNA,Signal molecules,Coupled to mediators of apoptosis,cell division,etc.,“,Humanizing”Antibodies,Chimeric Antibodies,Murine Fv+human,Fc,Human anti-chimeric antibodies(HACA)still observed,Humanized Antibodies,Murine,CDRs,+human framework and,Fc,Production of Human Antibodies,Pharmaceutical Antibodies,The fastest growing segment of the biopharmaceutical market,$14 billion in sales for 2005,Expected to grow to$30 billion by 2010,Today,20 therapeutic,mAbs,are on the market in the US,However,an estimated 500 antibody-based therapies are currently under development,Nomenclature of Monoclonal Antibodies,Prefix,Target,Source,Suffix,variable,-,o(s,)-