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Therapeutic Monoclonal Antibodies as Immunomodulators and Anti-Cancer Agents: Development, Evidence of Efficacy, Mechanisms of Actions, Adverse Effects

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Antibody Therapy

Abstract

Immunotherapy has been a long wish among immunologists. In the late 19th century, the first proof of immunotherapy was probably the successful treatment of diphtheria by Emil von Behring, using serum (Behring and Kitasato 1890). In 1952, Ogden Bruton showed that patients devoid of immunoglobulins (X-linked agammaglobulinemia) can successfully be treated with plasma containing polyclonal antibodies (Bruton et al. 1952). In 1981, Paul Imbach and colleagues demonstrated that polyclonal antibody preparations can be used to treat immune-mediated disease (idiopathic thrombocytopenic purpura (ITP)) (Imbach et al. 1981).

Declaration COI: Tim Niehues is receiving honoraria from Up2date.com as a reviewer and author.

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Abbreviations

Abs:

Antibodies

ACR:

American College of Rheumatology

ADAs:

Anti-drug antibodies

ADCC:

Antibody-dependent cellular cytotoxicity

ADCP:

Antibody dependent cellular phagocytosis

AEs:

Adverse events

AML:

Acute myeloid leukemia)

APC:

Antigen-presenting cell

BRM:

Biological response modifiers

CDC :

Complement Dependent Cytotoxicity

CDCC:

Complement Dependent Cell mediated Cytotoxicity

CDCP:

Complement Dependent Cell mediatedPhagocytosis

CDRs:

Complementarity determining regions

CMC:

Complement dependent cytotoxicity

CSA:

Ciclosporine A

DAMP:

Damage-associated molecular pattern

EGFR (synonymserbb1, HER1):

Epithelial growth factor receptors

ESR:

Erythrocyte sedimentation rate

EULAR:

European League against Rheumatism

Fab:

Variable region of antibody, antigen-binding fragment

FAEs:

Fatal adverse events

Fc:

Constant region of antibody, crystalizable fragment

FcR:

Fc receptors

FcRn:

Neonatal FC receptor

FDA:

Food and Drug Administration (USA)

GD2:

Glykolipiddisialoganglioside

GMCSF:

Granulocyte macrophage colony stimulating factor

HAMAs:

Human anti-mouse antibodies

HAT:

Medium containing hypoxanthine, aminopterin, thymidine

HER-2:

Human epidermal growth factor receptor 2

IBD:

Inflammatory bowel disease

Ig:

Immunoglobulin

irAEs:

Immune related adverse events

ITP:

Idiopathic thrombocytopenic purpura

IVIG:

Intravenous immunoglobulins

JAK:

Janus Kinase

JC virus:

John Cunningham virus

JiA:

Juvenile idiopathic arthritis

mAbs:

Monoclonal antibodies

MAC:

Membrane attack complex

MS:

Multiple sclerosis

MTX:

Methotrexate

NSAIDS:

Non-steroidal and anti-inflammatory drugs

PAMP:

Pathogen-associated molecular pattern

PDGFR:

Platelet-derived growth factor receptor

PEG:

Polyethylene glycol

PJP:

Pneumocystis jiroveci pneumonia

PIGF:

Placental growth factor

PML:

Progressive multifocal leukoencephalopathy

PRRs:

Pathogen recognition receptors

RA:

Rheumatoid arthritis

RANK:

Receptor activator of nuclear factor kappaB

RANKL:

Receptor activator of NFκb ligand

SIRs:

Standard infusion reactions

sJIA:

Systemic onset JIA

SLE:

Systemic lupus erythematosus

SYK:

Spleen tyrosine kinases

TAA:

Tumor associated antigens

TCR:

T-cell receptor

TDM:

Therapeutic drug monitoring

TNF:

Tumor necrosis factor

Tregs:

T-regulatory cells

VEGF:

Vascular endothelial growth factor

References

  • Anderson C. Measuring what works in health care. Science. 1994;263(1080):1082.

    Google Scholar 

  • Anonymous. WHO Expert committee on biological standardization guidelines on evaluation of similar biotherapeutic products. In: WHO technical report series no. 977. Geneva; 2009.

    Google Scholar 

  • Anonymous Monoclonal Antibodies. In: Association AM (ed) USAN Naming Guidelines for monoclonal antibodies; https://www.ama-assn.org/about/monoclonal-antibodies

  • Ballow M. ximab this and -zumab that! Has the magic bullet arrived in the new millennium of medicine and science? J Allergy Clin Immunol. 2005;116:738–43.

    Article  CAS  PubMed  Google Scholar 

  • Batlevi CL, Matsuki E, Brentjens RJ, et al. Novel immunotherapies in lymphoid malignancies. Nat Rev Clin Oncol. 2016;13:25–40.

    Article  CAS  PubMed  Google Scholar 

  • Beck A, Wurch T, Bailly C, et al. Strategies and challenges for the next generation of therapeutic antibodies. Nat Rev Immunol. 2010;10:345–52.

    Article  CAS  PubMed  Google Scholar 

  • Behring E, Kitasato S. Ueber das Zustandekommen der Diphtherie-Immunität und der Tetanus-Immunität bei Thieren. Dtsch Med Wochenschr. 1890;16:1113–4.

    Article  Google Scholar 

  • Boyman O, Comte D, Spertini F. Adverse reactions to biologic agents and their medical management. Nat Rev Rheumatol. 2014;10:612–27.

    Article  CAS  PubMed  Google Scholar 

  • Bradshaw MJ, Mobley BC, Zwerner JP, et al. Autopsy-proven demyelination associated with infliximab treatment. Neurol Neuroimmunol Neuroinflamm. 2016;3:e205.

    Article  PubMed Central  PubMed  Google Scholar 

  • Bruton OC, Apt L, Gitlin D, et al. Absence of serum gamma globulins. AMA Am J Dis Child. 1952;84:632–6.

    CAS  PubMed  Google Scholar 

  • Burmester GR, Pope JE. Novel treatment strategies in rheumatoid arthritis. Lancet. 2017;389:2338–48.

    Article  PubMed  Google Scholar 

  • Burmester GR, Feist E, Dorner T. Emerging cell and cytokine targets in rheumatoid arthritis. Nat Rev Rheumatol. 2014;10:77–88.

    Article  CAS  PubMed  Google Scholar 

  • Chan AC, Carter PJ. Therapeutic antibodies for autoimmunity and inflammation. Nat Rev Immunol. 2010;10:301–16.

    Article  CAS  PubMed  Google Scholar 

  • Chen DS, Mellman I. Elements of cancer immunity and the cancer-immune set point. Nature. 2017;541:321–30.

    Article  CAS  PubMed  Google Scholar 

  • Chingcuanco F, Segal JB, Kim SC, et al. Bioequivalence of biosimilar tumor necrosis factor-alpha inhibitors compared with their reference biologics: a systematic review. Ann Intern Med. 2016;165:565–74.

    Article  PubMed  Google Scholar 

  • Cholapranee A, Hazlewood GS, Kaplan GG, et al. Systematic review with meta-analysis: comparative efficacy of biologics for induction and maintenance of mucosal healing in Crohn’s disease and ulcerative colitis controlled trials. Aliment Pharmacol Ther. 2017;45:1291–302.

    Article  CAS  PubMed  Google Scholar 

  • Davies R, Gaynor D, Hyrich KL, et al. Efficacy of biologic therapy across individual juvenile idiopathic arthritis subtypes: a systematic review. Semin Arthritis Rheum. 2017;46:584–93.

    Article  CAS  PubMed  Google Scholar 

  • Davis BP, Ballas ZK. Biologic response modifiers: indications, implications, and insights. J Allergy Clin Immunol. 2017;139:1445–56.

    Article  CAS  PubMed  Google Scholar 

  • De Benedetti F, Brunner HI, Ruperto N, et al. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N Engl J Med. 2012;367:2385–95.

    Article  PubMed  Google Scholar 

  • Dotan I, Ron Y, Yanai H, et al. Patient factors that increase infliximab clearance and shorten half-life in inflammatory bowel disease: a population pharmacokinetic study. Inflamm Bowel Dis. 2014;20:2247–59.

    Article  PubMed  Google Scholar 

  • Ecker DM, Jones SD, Levine HL. The therapeutic monoclonal antibody market. MAbs. 2015;7:9–14.

    Article  CAS  PubMed  Google Scholar 

  • Eisenberg R. Immune compromise associated with biologics. In: Stiehm ER, Sullivan KE, editors. Stiehm’s immune deficiencies. London: Elsevier; 2014. p. 889–904.

    Chapter  Google Scholar 

  • Fagraeus A. The plasma cellular reaction and its relation to the formation of antibodies in vitro. J Immunol. 1948;58:1–13.

    CAS  PubMed  Google Scholar 

  • Feldman SR. Epidemiology, clinical manifestations, and diagnosis of psoriasis. In: Dellavalle R, editor; 2017.

    Google Scholar 

  • Fonollosa A, Artaraz J, Les I, et al. Sarcoid intermediate uveitis following etanercept treatment: a case report and review of the literature. Ocul Immunol Inflamm. 2012;20:44–8.

    Article  CAS  PubMed  Google Scholar 

  • Golay J, Semenzato G, Rambaldi A, et al. Lessons for the clinic from rituximab pharmacokinetics and pharmacodynamics. MAbs. 2013;5:826–37.

    Article  PubMed Central  PubMed  Google Scholar 

  • Gomez-Garcia F, Ruano J, Aguilar-Luque M, et al. Systematic reviews and meta-analyses on psoriasis: role of funding sources, conflict of interest and bibliometric indices as predictors of methodological quality. Br J Dermatol. 2017;176:1633–44.

    Article  CAS  PubMed  Google Scholar 

  • Hendriks D, Choi G, De Bruyn M, et al. Antibody-based cancer therapy: successful agents and novel approaches. Int Rev Cell Mol Biol. 2017;331:289–383.

    Article  CAS  PubMed  Google Scholar 

  • Her M, Kavanaugh A. Alterations in immune function with biologic therapies for autoimmune disease. J Allergy Clin Immunol. 2016;137:19–27.

    Article  CAS  PubMed  Google Scholar 

  • Imbach P, Barandun S, D'apuzzo V, et al. High-dose intravenous gammaglobulin for idiopathic thrombocytopenic purpura in childhood. Lancet. 1981;1:1228–31.

    Article  CAS  PubMed  Google Scholar 

  • Jones PT, Dear PH, Foote J, et al. Replacing the complementarity-determining regions in a human antibody with those from a mouse. Nature. 1986;321:522–5.

    Article  CAS  PubMed  Google Scholar 

  • Kay J. Editorial: biosimilars: new or Deja Vu? Arthritis Rheumatol. 2016;68:1049–52.

    PubMed  Google Scholar 

  • Kohler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975;256:495–7.

    Article  CAS  PubMed  Google Scholar 

  • London NJ, Garg SJ, Moorthy RS, et al. Drug-induced uveitis. J Ophtha Inflamm Infect. 2013;3:43.

    Article  Google Scholar 

  • Majzner RG, Simon JS, Grosso JF, et al. Assessment of programmed death-ligand 1 expression and tumor-associated immune cells in pediatric cancer tissues. Cancer. 2017.

    Google Scholar 

  • Martin-Liberal J, Ochoa De Olza M, Hierro C, et al. The expanding role of immunotherapy. Cancer Treat Rev. 2017;54:74–86.

    Article  CAS  PubMed  Google Scholar 

  • Merrill JT, Neuwelt CM, Wallace DJ, et al. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum. 2010;62:222–33.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Molinelli E, Campanati A, Ganzetti G, et al. Biologic therapy in immune mediated inflammatory disease: basic science and clinical concepts. Curr Drug Saf. 2016;11:35–43.

    Article  CAS  PubMed  Google Scholar 

  • Moreland LW. General principles of management of rheumatoid arthritis in adults. In: O’Dell JR, editor. uptodate; 2016.

    Google Scholar 

  • Morrison SL, Johnson MJ, Herzenberg LA, et al. Chimeric human antibody molecules: mouse antigen-binding domains with human constant region domains. Proc Natl Acad Sci U S A. 1984;81:6851–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Nam JL, Takase-Minegishi K, Ramiro S, et al. Efficacy of biological disease-modifying antirheumatic drugs: a systematic literature review informing the 2016 update of the EULAR recommendations for the management of rheumatoid arthritis. Ann Rheum Dis. 2017;76:1113–36.

    Article  PubMed  Google Scholar 

  • Niehues T. Optimizing treatment in paediatric rheumatology--lessons from oncology. Nat Rev Rheumatol. 2015;11:493–9.

    Article  CAS  PubMed  Google Scholar 

  • Olek MJ. Disease-modifying treatment of relapsing-remitting multiple sclerosis in adults. In: González-Scarano F, editor; 2017.

    Google Scholar 

  • Oosting SF, Brouwers AH, Van Es SC, et al. 89Zr-bevacizumab PET visualizes heterogeneous tracer accumulation in tumor lesions of renal cell carcinoma patients and differential effects of antiangiogenic treatment. J Nucl Med Off Publ Soc Nucl Med. 2015;56:63–9.

    CAS  Google Scholar 

  • Oude Munnink TH, Henstra MJ, Segerink LI, et al. Therapeutic drug monitoring of monoclonal antibodies in inflammatory and malignant disease: translating TNF-alpha experience to oncology. Clin Pharmacol Ther. 2016;99:419–31.

    Article  CAS  PubMed  Google Scholar 

  • Parren P, Carter PJ, Pluckthun A. Changes to international nonproprietary names for antibody therapeutics 2017 and beyond: of mice, men and more. mAbs. 2017:1–9.

    Google Scholar 

  • Patterson H, Nibbs R, Mcinnes I, et al. Protein kinase inhibitors in the treatment of inflammatory and autoimmune diseases. Clin Exp Immunol. 2014;176:1–10.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Picard M, Galvao VR. current knowledge and management of hypersensitivity reactions to monoclonal antibodies. J Allergy Clin Immunol Pract. 2017;5:600–9.

    Article  PubMed  Google Scholar 

  • Ramanan AV, Dick AD, Jones AP, et al. Adalimumab plus Methotrexate for Uveitis in Juvenile Idiopathic Arthritis. N Engl J Med. 2017;376:1637–46.

    Article  CAS  PubMed  Google Scholar 

  • Rovin BH, Furie R, Latinis K, et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum. 2012;64:1215–26.

    Article  CAS  PubMed  Google Scholar 

  • Ruperto N, Brunner HI, Quartier P, et al. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. N Engl J Med. 2012;367:2396–406.

    Article  CAS  PubMed  Google Scholar 

  • Sanz-Cabanillas JL, Ruano J, Gomez-Garcia F, et al. Author-paper affiliation network architecture influences the methodological quality of systematic reviews and meta-analyses of psoriasis. PLoS One. 2017;12:e0175419.

    Article  PubMed Central  PubMed  Google Scholar 

  • Shoushtari AN, Wolchok J, Hellman M. Principles of cancer immunotherapy. In: Atkins MB, editor; 2017.

    Google Scholar 

  • Singh JA, Hossain A, Mudano AS, et al. Biologics or tofacitinib for people with rheumatoid arthritis naive to methotrexate: a systematic review and network meta-analysis. Cochrane Database Syst Rev. 2017;5:CD012657.

    PubMed  Google Scholar 

  • Smith CH, Jabbar-Lopez ZK, Yiu ZZ, et al. British Association of Dermatologists guidelines for biologic therapy for psoriasis 2017. Br J Dermatol. 2017.

    Google Scholar 

  • Suntharalingam G, Perry MR, Ward S, et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med. 2006;355:1018–28.

    Article  CAS  PubMed  Google Scholar 

  • Weiner GJ. Building better monoclonal antibody-based therapeutics. Nat Rev Cancer. 2015;15:361–70.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Windeler J. No new Insights. Dtsch Arztebl Int. 2014;111:646.

    PubMed Central  PubMed  Google Scholar 

  • Wu P, Nielsen TE, Clausen MH. FDA-approved small-molecule kinase inhibitors. Trends Pharmacol Sci. 2015;36:422–39.

    Article  CAS  PubMed  Google Scholar 

  • Yarur AJ, Jain A, Sussman DA, et al. The association of tissue anti-TNF drug levels with serological and endoscopic disease activity in inflammatory bowel disease: the ATLAS study. Gut. 2016;65:249–55.

    Article  CAS  PubMed  Google Scholar 

  • Young L, Czarnecki D. The rapid onset of multiple squamous cell carcinomas in two patients commenced on ustekinumab as treatment of psoriasis. Australas J Dermatol. 2012;53:57–60.

    Article  PubMed  Google Scholar 

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Acknowledgement

Without the careful and skillful help of Andrea Groth the preparation of this manuscript would not have been possible. I thank Kathrin Siepermann, Gregor Dückers, and Antje Ballauff for discussing interesting cases of treatment with biologics within our team at the HELIOS Children’s Hospital in Krefeld, Germany. I thank Ina Bruins for her additional help in manuscript preparation.

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Authors and Affiliations

  1. Zentrum für Kinder- und Jugendmedizin, HELIOS KLINIKUM Krefeld, Lutherplatz 40, 47805, Krefeld, Germany

    Tim Niehues

  2. Akad. Lehrkrankenhaus, RWTH Aachen, Aachen, Germany

    Tim Niehues

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  1. Tim Niehues
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Correspondence to Tim Niehues .

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Editors and Affiliations

  1. Department of Pediatrics, Medical Faculty of the University of Basel, Basel, Switzerland

    Paul Imbach

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Niehues, T. (2018). Therapeutic Monoclonal Antibodies as Immunomodulators and Anti-Cancer Agents: Development, Evidence of Efficacy, Mechanisms of Actions, Adverse Effects. In: Imbach, P. (eds) Antibody Therapy. Springer, Cham. https://doi.org/10.1007/978-3-319-68038-5_20

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  • DOI: https://doi.org/10.1007/978-3-319-68038-5_20

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