New Biological Therapies: Introduction to the Basis of the Risk of Infection

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

• 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 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

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

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 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, herpes zoster Bye et al. Aliment Pharmacol Ther 2017;46:3-15.

Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author Dasatinib BCR-ABL tyrosine kinase inhibitor Newly diagnosed Ph+ CML, resistant Ph+ CML or ALL, intolerance to prior therapy Sprycel® 100 mg PO daily BCR/ABL kinase phosphorylate immunoreceptor SRC family kinases tyrosine-based activation motifs (ITAMs) on the T-cell receptor DDR1 c-Kit (CD117) PDGFR-α and -β Ephrin receptor Prestes et al. Clin Infect Dis 2017;65:510-3. Rix et al. Blood 2007;110:4055-63.

Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author Lucatumumab and dacetuzumab Monoclonal antibodies targeting CD40 Phase 1-2 trials for B-cell lymphoma and multiple myeloma Not currently approved

Dendritic cell

cytoquines Enhanced T-cell activation and differentiation CD40

CD28 CD40 ligand

T-cell

CD40 ligand

cytokines peptide TCR CD40 ligand BCR CD40 CD40

Not currently approved Febrile neutropenia: 12% Neutropenia (grade 3-4): 33% Leukopenia: 19% Infection-realted death: 4%

Hyper-IgM syndrome (primary immunodeficiency) Mutations in CD40 or CD40L Severe opportunistic infections (PCP, CMV, cryptococcosis, protozoa...) Neutropenia

Fayad et al. Leuk Lymphoma 2015;56:2569-78. Qamar N, et al. Clin Rev Allergy Immunol 2014;46:120-30

Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author Secukinumab, ixekizumab and brodalumab Monoclonal antibodies targeting IL17A or IL17-RA Plaque psoriasis, ankylosing spondylitis and psoriatic arthritis Cosentyx®, Taltz®, Siliq®

Mild to moderate Candida infection (%)

Secukinumab

Brodalumab

Ixekizumab

Saunte et al. Br J Dermatol 2016;45:345-56.

Chronic mucocutaneous candidiasis Inherited deficiencies in the IL-17 pathway

Saunte et al. Br J Dermatol 2016;45:345-56. Huppler, et al. Curr Opin Allergy Clin Immunol 2012;12:616-22.

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… • ...and the “unexpected” effect: off-targed inhibition • A “biological model”: the mirror of primary immunodeficiencies • Dose and mode of administration

Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author CD52 Alemtuzumab humanized IgG1 mAb mature lymphocytes, monocytes/macrophages Chronic lymphocytic leukaemia and thymocytes

MabCampath® 30 mg three times weekly for up to 12 Serious infection: 56% weeks (total dose of 1,080 mg per year) CMV infection: 6% IFI, VZV, tuberculosis…

Multiple sclerosis

Lemtrada® 12 mg for 5 days (x2), followed 12 months later Serious infection: 3% by 12 mg daily for 3 days (total dose of 36 mg) CMV infection: 0%

Wendtner et al. Leukemia 2004;18:1093-101. Skoetz et al. Cochrane Database Syst Rev 2012;(2):CD008078. Coles et al. Lancet 2012;380:1829-39.

Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author Blinatumomab

B-lymphoblast CD3 cytotoxic T-cell CD19

bispecific T-cell engager (BiTE)

granzyme B and perforin

Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author Blinatumomab

Relapsed or refractory B-cell acute lymphoblastic leukemia Blincyto® 9 or 28 mcg/day by continuous intravenous infusion over 28 days

Overall infection: 34% Pneumonia: 6% Febrile neutropenia: 24% Oral herpes: 5.6% CVC-related bacteremia: 6%

Kantarjian et al. N Eng J Med 2017;376:836-47.

Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author Ibrutinib Bruton’s tyrosine kinase inhibitor CLL, mantle cell lymphoma and Waldenstroem’s macroglobulinemia Imbruvica® 420 or 560 mg/day PO

Single-center retrospective study of 378 patients (%) Any infection

Serious infection: 11.4% incidence Bacterial infection Invasive fungal infection: 4.2% Fungal infection Invasive aspergillosis: 2.1%

Cumulative Viral infection

Days from ibrutinib initiation Varughese et al. Clin Infect Dis 2018 [epub ahead of print].

Single-center retrospective study of 378 patients

Odds ratio (95% CI) P-value

Previous receipt of >3 chemoterapy regimens2.03 (1.17 - 3.52) 0.012 Neutropenia 2.78 (1.34 - 5.76) 0.006 Lymphopenia 2.02 (0.84 - 2.77) 0.11 Anti-PCP prophylaxis 1.30 (0.61 - 2.77) 0.49

Varughese et al. Clin Infect Dis 2018 [epub ahead of print].

Resolved granuloma

TNF-α

Balance between pro- inflamatory and anti- Granuloma inflamatory mediators breakdown and bacilli dissemination Tuberculous granuloma

Cadena et al. Nat Rev Immunol 2017;17:691-702.

Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author Infliximab Monoclonal antibody targeting TNF-α IBD, rheumatoid arthritis, psoriatic arthritis, spondylitis, psoriasis Remicade® 3-5 mg/Kg at weeks 0, 2 and 6

No reports on the occurrence of tuberculosis in patients treated with infliximab

Elliot et al. Lancet 1994;344:1105-10. Lipsky et al. N Engl J Med 2000;343:1594-602. Present et al. N Engl J Med 1999;340:1398-405.

Data from the FDA’s Adverse Events Reporting

System (spontaneous AE reporting program)No infliximab

After infliximab

Keane et al. N Engl J Med 2001;345:1098-104.

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… • ...and its “unexpected” effects: off-targed actions • A “biological model”: the mirror of primary immunodeficiencies • Cumulative doses administered • Previous or concomitant therapies • Statistical power of pivotal RCTs: the hidden threat of rare adverse events • Impact of geographical variations on incidence rates

Tuberculosis incidence rates in the overall population Canada 2.19 x 1,000 patient-years Portugal 13.3 x 1,000 patient-years South Korea 19.9 x 1,000 patient-years India 8.8% of treated patients

Brassard et al. Clin Infect Dis 2006;43:717-22. Abreu et al. J Crohnd Colitis 2013;7:e486-92. Kim et al. World j Gastroenterol 2015;21:3308-16. Puri et al. J Gastroenterol Hepatol 2017;32:1191-4. Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the Safety of targeted and biological therapies: an infectious diseases perspective

Editorial Coordinators: • Jose María Aguado (Madrid, Spain) • Oriol Manuel (Lausanne, Switzerland)

Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author CMI theme issue 8 sections

Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author General scheme for each individual agent (or therapeutic family):

• Mechanism of action, approved indications and off-label uses • Expected impact on the susceptibility to infection • Evidence of increased risk of infection associated with targeted • Pivotal clinical trials • Post-marketing studies • Case series and single case reports • Suggested prevention strategies

Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author Some take-home messages… • Ever increasing number of therapeutic families and indications: real challenge for the ID clinician

• Relative value of pivotal trials to detect rare infectious events

• Role of post-marketing surveillance and open label extension studies

• Complexities in the assessment of attributable risk of infection

• Contributing factors beyond specific mode of action

• Need for multicenter registries and multidisciplinary approaches

Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author Thank you for the attention [email protected]

Two-hour symposium:Infections Invasive and biologicals: candidiasis a real concern? in(two 2017-hour symposium): New biological therapies: introduction23 to April the 2017 ESCMIDbasis of the risk of infection eLibrary © by author