New biological therapies: introduction to the basis of the risk of infection Mario FERNÁNDEZ RUIZ, MD, PhD Unit of Infectious Diseases Hospital Universitario “12 de Octubre”, Madrid ESCMIDInstituto de Investigación eLibraryHospital “12 de Octubre” (i+12) © by author Transparency Declaration Over the last 24 months I have received honoraria for talks on behalf of • Astellas Pharma • Gillead Sciences • Roche • Sanofi • Qiagen Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author Paul Ehrlich (1854-1915) • “side-chain” theory (1897) • receptor-ligand concept (1900) • “magic bullet” theory • foundation for specific chemotherapy (1906) • Nobel Prize in Physiology and Medicine (1908) (together with Metchnikoff) Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author 1981: B-1 antibody (tositumomab) anti-CD20 monoclonal antibody 1997: FDA approval of rituximab for the treatment of relapsed or refractory CD20-positive NHL 2001: FDA approval of imatinib for the treatment of chronic myelogenous leukemia Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author Functional classification of targeted (biological) agents • Agents targeting soluble immune effector molecules • Agents targeting cell surface receptors and antigens • Agents targeting intracellular signalling pathways • Agents targeting other intracellular pathways Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author Agents targeting soluble immune effector molecules • Pro-inflammatory cytokines • TNF-α infliximab, adalimumab, golimumab, certolizumab pegol, etanercept • IFN-γ fontolizumab • Interleukins and their corresponding receptors • IL-1β canakinumab, anakinra, rilonacept, gevokizumab • IL-5 mepolizumab, reslizumab • IL-6 tocilizumab, siltuxumab, olamkicept • IL-12/23 ustekinumab • IL-17A secukinumab, ixekizumab, brodalumab • Immunoglobulins • IgE omalizumab • Complement factors • C5 eculizumab Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author Agents targeting cell surface receptors and antigens • Growth factor receptors • ErbB2/HER2 trastuzumab, pertuzumab • EGFR cetuximab, panitumumab • VEGFR ramucirumab • Inhibitory coreceptors (immune checkpoints) • CTLA-4 ipilimumab, tremelimumab • PD-1/PD-L1 nivolumab, pembrolizumab, atezolizumab • Cell-adhesion molecules • α4 integrins natalizumab, vedolizumab • CD11a efalizumab • Chemokine receptors • CCR4 mogalizumab Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author Agents targeting cell surface receptors and antigens • Lymphoid and myeloid cells surface antigens • CD19 blinatumomab, inebilizumab, combotox • CD20 rituximab, 131I-tositumomab, ocrelizumab, ofatumumab, veltuzumab, ocrelizumab, obinutuzumab, ocaratumomab, • CD22 epratuzumab, inotuzumab ozogamicin, moxetumomab pasedotox, combotox • CD30 brentuximab vedotin • CD33 gemtuzumab ozogamicin • CD38 daratumumab, isatuxumab • CD40 lucatumumab, dacetuzumab • CD52 alemtuzumab • SLAMF7 elotuzumab Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author Agents targeting intracellular signalling pathways • Cell-surface receptor-associated tyrosine kinases • VEGF receptor sorafenib, sunitinib, axitinib, pazopanib, regorafenib, cabozantinib • ErbB receptor erlotinib, gefitinib, afatinib, osimertinib, lapatinib, neratinib • Bruton’s TK ibrutinib, acalabrutinib • Signalling pathway-associated tyrosine kinases • BCR-ABL imatinib, dasatinib, nilotinib, bosutinib, ponatinib • BRAF/MEK vemurafenib, dabrafenib, trametinib, cobimetinib, selumetinib, encorafenib • Bruton’s TK ibrutinib, acalbrutinib • PI3K idelalisib, buparlisib, rigosertib, duvelisib • Janus kinases ruxolitinib, tofacitinib, baricitinib • Other signalling pathway-associated molecules • mTOR everolimus, temsirolimus Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author What is the infection risk attributable to each of these targeted agents? Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author What is the infection risk (if any) attributable to each of these targeted agents? Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author Factors to be accounted for… • Structure of the agent Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author complementarity- determining regions Mouse origin Human origin Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author Applications of engineered mAb technology Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author Antibody-dependent cell-mediated cytotoxicity Complement-dependent cytotoxicity Surface IgG FcγRIII antigen C1q NK cell Antibody-dependent cell-mediated phagocytosis Membrane attack IgG complex FcγRI Phagocyte Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author Structure of different anti-TNF-α agents Lacks CH1 domain of Fc fragment: lower complement activation than full-length antibodies Lacks Fc fragment: no complement- dependent cytotoxicity or antibody- dependent cell-mediated cytotoxicity Adalimumab and Infliximab Etanercept golimumab Certolizumab pegol Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author Anti-CD20 monoclonal antibodies First generation Increasing murine or chimeric antibodies Increasing Rituximab 90Y-ibritumomab potential Second generation B - Ofatumumab humanized or fully human antibodies cell with reduced immunogenicity Ocrelizumab depletion Veltuzumab for 131 I-tositumomab HGG Third generation antibodies with an engineered Fc Obinutuzumab region to boost CDC and ADCC Ocaratuzumab Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author Etanercept Dimeric soluble form of TNF-α receptor linked to hinge and Fc portions of IgG1 Rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, spondylitis, psoriasis Embrel® 50 mg twice weekly for 12 weeks 51-kDa homotrimer allowing simultaneous TNFα binding to 3 receptor molecules one receptor-binding site remains free 1:1 stoichiometric complexes Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author Etanercept versus anti-TNFα mAbs no receptor- binding sites left free TNFα 1:1 stoichiometric complexes lower infection risk with etanercept 3:1 stable complexes Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author Factors to be accounted for… • Structure of the agent • Mechanism of action: the presumable impact on immune response… Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author Transmembrane heterodimer Cell-adhesion molecule Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author Natalizumab Monoclonal antibody targeting α4-integrins Relapsing multiple sclerosis and Crohn’s disease Tysabri® 300 mg IV every 4 weeks Leukocyte Endothelial cell α4β1 integrin (VLA-4) V-CAM Blocks translocation of activated VLA-4-expressing leukocyte across de blood-brain barrier Langer-Gould et al. N Engl J Med 2005;353:375-81. Van Assche et al. N Engl J Med 2005;353:362-8. Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author Vedolizumab Monoclonal antibody targeting α4β7-integrin Leukocyte Endothelial cell Crohn’s disease and ulcerative colitis Entyvio® 300 mg IV at weeks 0, 2 and 6; then every 8 weeks α4β1 integrin (VLA-4) V-CAM Overall infection: 7.8% Infection leading to drug discontinuation: 1% Opportunistic infectiona: 0.5% α4β7 integrin MadCAM No cases of PML reported to date mesenteric lymph nodes a and Peyer’s patches CMV colitis,