21- Immune technology-modify.ppt

NEW CHAPTER Recombinant protein based Applications 1 Part One Immune Technology 2 Learning objectives • What is the function of antibodies • Learn about the characteristics of monoclonal antibodies • Generation of monoclonal antibodies. • Therapeutic application of MAbs. 3 The immune syst...

NEW CHAPTER Recombinant protein based Applications 1 Part One Immune Technology 2 Learning objectives • What is the function of antibodies • Learn about the characteristics of monoclonal antibodies • Generation of monoclonal antibodies. • Therapeutic application of MAbs. 3 The immune system • The immune system response to an infection is generally highly specific. It discriminates not only between pathogen species, but often also between different strains within one species. • This specificity maintains a balance between response to foreign antigens and tolerance with respect to self-antigens. • Antibodies? 4 * Current antibody engineering efforts target both the variable and Fc regions of the molecule. ** Complementarity Determining Region (CDR) ? Biotechnology by D. Clark and N. Pazdernik , 2011 5 The use of antibodies for therapeutic application 6 Monoclonocal Antibody (MAbs) 7 Monoclonal Antibodies (MAbs) • MAbs are monospecific antibodies produced in vitro by a clone of “B cells” hybridized with cancerous cells. • MAbs are useful because they are 1- Uniform 2- Highly specific 3- Can be produced readily in large quantities 8 9 http://www.accessexcellence.org/RC/VL/GG/monoclonal.php • Clinical challenge: When murine monoclonal antibodies (MAbs produced from mice/rats) were injected into humans the result was: 1- rapid removal from the blood or destruction of the MAb itself 2- systemic inflammatory effects 3- production of human anti-mouse antibodies 4- occasional kidney failure * Solution: use antibody engineering to make a human murine hybrid (next slides) 10 Omab Ximab Zumab Mumab 11 Transgenic Mouse to Generate Human MAbs 1. Inactivate mouse heavy and light chain genes. 2. Introduce human heavy and light chain genes into mouse genome. 3. Transgenic mouse may be immunized with target antigens to generate human MAbs. 13 14 Therapeutic Applications of MAbs 15 Alteplase (Activase) • The concept of Antibody-Directed Enzyme Prodrug Therapy, (ADEPT) is utilized. • Altiplase is an Immunoconjugate which consists of an antibody with an intact variable region to recognize and bind a specific target (e.g. an antifibrin antibody) along with an enzyme (e.g. tissue plasminogen activator, tPA) resulting in activation of plasminogen (e.g. a fibrin specific thrombolytic agent). In other words, the antibody first attaches the enzyme (tPA) specifically to fibrin clots. tPA will activate circulating plasminogen by converting it from plasminogen into plasmin. This plasmine locally attacks fibrin clots and dissolves them. It is used to treat acute myocardial infarctions (heart attacks) 16 Abciximab (Reopro) • It is a chimeric monoclonal antibody. A glycoprotein IIb/IIIa receptor antagonist (glycoprotein IIb/IIIa inhibitor). It is a platelet aggregation inhibitor mainly used during and after coronary artery procedures like angioplasty to prevent platelets from sticking together and causing thrombus (blood clot) formation within the coronary artery. 17 Daclizumab (Zenapax) • It is a humanized monoclonal antibody • It was approved and used to prevent acute rejection of kidney transplant, along with cyclosporine and corticosteroids. 18 Biopharmaceutical products (biologics) available in Omani market (Khoula, Royal, ROP, Muscat Hospitals) • LeukoScan Sulesomab (Murine) – diagnosis of Oseomyelitis • Remicade Infliximab (Chimeric)– Rheumatoid arithritis • Xolair Omalizumab (humanized)- Asthma • Tysabri Natalizumab (humanized)- Multiple sclerosis (MS) • Raptiva Efalizumab (Humanized) – Psoriasis for adult patients (>18 years) • Humera Adalimumab (Human) - Rheumatoid arithritis 19