Advertisement

Human Monoclonal Antibodies: The Benefits of Humanization

  • Herman Waldmann
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1904)

Abstract

The major reasons for developing human monoclonal antibodies were to be able to efficiently manipulate their effector functions while avoiding immunogenicity seen with rodent antibodies. Those effector functions involve interactions with the complement system and naturally occurring Fc receptors on diverse blood white cells. Antibody immunogenicity results from the degree to which the host immune system can recognize and react to these therapeutic agents. Thus far, there is still no generally applicable technology guaranteed to render therapeutic antibodies antigenically silent. This is not to say that the task is impossible, but rather that we need to train the immune system to help us. This can be achieved if we take advantage of natural mechanisms by which an individual can be rendered tolerant of “foreign” antigens, and as a corollary minimize the potential immunogenicity of any contaminating protein aggregates, or “aggregates” arising from antibodies complexing with their antigen. I here summarize our efforts to engineer antibodies to harness optimal effector functions, while also minimizing their immunogenicity. Potential avenues to achieve the latte are predicted from classical work showing that monomeric “foreign” immunoglobulins are good tolerogens, while aggregates of immunoglobulins ate intrinsically immunogenic. Consequently, I argue that one solution to the immunogenicity problem lies in ensuring a temporal quantitative advantage of tolerogenic non-cell-bound monomer over the cell-binding immunogenic form.

Key words

Therapeutic antibodies Complement system Fc receptors Immunogenicity Adjuvanticity High dose tolerance Humanized and human antibodies 

References

  1. 1.
    Kohler G, Milstein C (1975) Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256(5517):495–497CrossRefGoogle Scholar
  2. 2.
    Steinitz M et al (1977) EB virus-induced B lymphocyte cell lines producing specific antibody. Nature 269(5627):420–422CrossRefGoogle Scholar
  3. 3.
    Bruggemann M et al (1989) The immunogenicity of chimeric antibodies. J Exp Med 170(6):2153–2157CrossRefGoogle Scholar
  4. 4.
    Jones PT et al (1986) Replacing the complementarity-determining regions in a human antibody with those from a mouse. Nature 321(6069):522–525CrossRefGoogle Scholar
  5. 5.
    Riechmann L et al (1988) Reshaping human antibodies for therapy. Nature 332(6162):323–327CrossRefGoogle Scholar
  6. 6.
    Lonberg N (2005) Human antibodies from transgenic animals. Nat Biotechnol 23(9):1117–1125CrossRefGoogle Scholar
  7. 7.
    Winter G et al (1994) Making antibodies by phage display technology. Annu Rev Immunol 12:433–455CrossRefGoogle Scholar
  8. 8.
    Bruggemann M et al (1989) A repertoire of monoclonal antibodies with human heavy chains from transgenic mice. Proc Natl Acad Sci U S A 86(17):6709–6713CrossRefGoogle Scholar
  9. 9.
    Clark M (2000) Antibody humanization: a case of the ‘Emperor’s new clothes’? Immunol Today 21(8):397–402CrossRefGoogle Scholar
  10. 10.
    Chiller JM, Habicht GS, Weigle WO (1970) Cellular sites of immunologic unresponsiveness. Proc Natl Acad Sci U S A 65(3):551–556CrossRefGoogle Scholar
  11. 11.
    Cobbold SP et al (1984) Therapy with monoclonal antibodies by elimination of T-cell subsets in vivo. Nature 312(5994):548–551CrossRefGoogle Scholar
  12. 12.
    Neuberger MS, Williams GT, Fox RO (1984) Recombinant antibodies possessing novel effector functions. Nature 312(5995):604–608CrossRefGoogle Scholar
  13. 13.
    Bruggemann M et al (1989) A matched set of rat/mouse chimeric antibodies. Identification and biological properties of rat H chain constant regions mu, gamma 1, gamma 2a, gamma 2b, gamma 2c, epsilon, and alpha. J Immunol 142(9):3145–3150PubMedGoogle Scholar
  14. 14.
    Morrison SL et al (1984) Chimeric human antibody molecules: mouse antigen-binding domains with human constant region domains. Proc Natl Acad Sci U S A 81(21):6851–6855CrossRefGoogle Scholar
  15. 15.
    Bruggemann M et al (1987) Comparison of the effector functions of human immunoglobulins using a matched set of chimeric antibodies. J Exp Med 166(5):1351–1361CrossRefGoogle Scholar
  16. 16.
    Bindon CI et al (1988) Human monoclonal IgG isotypes differ in complement activating function at the level of C4 as well as C1q. J Exp Med 168(1):127–142CrossRefGoogle Scholar
  17. 17.
    Bolt S et al (1993) The generation of a humanized, non-mitogenic CD3 monoclonal antibody which retains in vitro immunosuppressive properties. Eur J Immunol 23(2):403–411CrossRefGoogle Scholar
  18. 18.
    Kuhn C et al (2011) Human CD3 transgenic mice: preclinical testing of antibodies promoting immune tolerance. Sci Transl Med 3(68):68ra10CrossRefGoogle Scholar
  19. 19.
    Friend PJ et al (1999) Phase I study of an engineered aglycosylated humanized CD3 antibody in renal transplant rejection. Transplantation 68(11):1632–1637CrossRefGoogle Scholar
  20. 20.
    Keymeulen B et al (2005) Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med 352(25):2598–2608CrossRefGoogle Scholar
  21. 21.
    Routledge EG et al (1991) A humanized monovalent CD3 antibody which can activate homologous complement. Eur J Immunol 21(11):2717–2725CrossRefGoogle Scholar
  22. 22.
    Beers SA, Glennie MJ, White AL (2016) Influence of immunoglobulin isotype on therapeutic antibody function. Blood 127(9):1097–1101CrossRefGoogle Scholar
  23. 23.
    Benjamin RJ et al (1986) Tolerance to rat monoclonal antibodies. Implications for serotherapy. J Exp Med 163(6):1539–1552CrossRefGoogle Scholar
  24. 24.
    Waldmann H, Adams E, Cobbold S (2008) Reprogramming the immune system: co-receptor blockade as a paradigm for harnessing tolerance mechanisms. Immunol Rev 223:361–370CrossRefGoogle Scholar
  25. 25.
    Rebello PR et al (1999) Anti-globulin responses to rat and humanized CAMPATH-1 monoclonal antibody used to treat transplant rejection. Transplantation 68(9):1417–1420CrossRefGoogle Scholar
  26. 26.
    Eichmann K (1973) Idiotype expression and the inheritance of mouse antibody clones. J Exp Med 137(3):603–621CrossRefGoogle Scholar
  27. 27.
    Somerfield J et al (2010) A novel strategy to reduce the immunogenicity of biological therapies. J Immunol 185(1):763–768CrossRefGoogle Scholar
  28. 28.
    Feldmann M, Maini RN (2001) Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned? Annu Rev Immunol 19:163–196CrossRefGoogle Scholar
  29. 29.
    Jefferis R (2011) Aggregation, immune complexes and immunogenicity. MAbs 3(6):503–504CrossRefGoogle Scholar
  30. 30.
    Joubert MK et al (2012) Highly aggregated antibody therapeutics can enhance the in vitro innate and late-stage T-cell immune responses. J Biol Chem 287(30):25266–25279CrossRefGoogle Scholar
  31. 31.
    Moussa EM et al (2016) Immunogenicity of therapeutic protein aggregates. J Pharm Sci 105(2):417–430CrossRefGoogle Scholar
  32. 32.
    Sauerborn M et al (2010) Immunological mechanism underlying the immune response to recombinant human protein therapeutics. Trends Pharmacol Sci 31(2):53–59CrossRefGoogle Scholar
  33. 33.
    St Clair JB et al (2017) Immunogenicity of Isogenic IgG in Aggregates and Immune Complexes. PLoS One 12(1):e0170556CrossRefGoogle Scholar
  34. 34.
    De Groot AS, Scott DW (2007) Immunogenicity of protein therapeutics. Trends Immunol 28(11):482–490CrossRefGoogle Scholar
  35. 35.
    Harding FA et al (2010) The immunogenicity of humanized and fully human antibodies: residual immunogenicity resides in the CDR regions. MAbs 2(3):256–265CrossRefGoogle Scholar
  36. 36.
    Griswold KE, Bailey-Kellogg C (2016) Design and engineering of deimmunized biotherapeutics. Curr Opin Struct Biol 39:79–88CrossRefGoogle Scholar
  37. 37.
    Nagata S, Pastan I (2009) Removal of B cell epitopes as a practical approach for reducing the immunogenicity of foreign protein-based therapeutics. Adv Drug Deliv Rev 61(11):977–985CrossRefGoogle Scholar
  38. 38.
    Isaacs JD, Waldmann H (1994) Helplessness as a strategy for avoiding antiglobulin responses to therapeutic monoclonal antibodies. Ther Immunol 1(6):303–312PubMedGoogle Scholar
  39. 39.
    Gilliland LK et al (1999) Elimination of the immunogenicity of therapeutic antibodies. J Immunol 162(6):3663–3671PubMedGoogle Scholar
  40. 40.
    Waldmann HF, Gillilkand MK, Graca L (2008) Therapeutic antibodies. Patent US 7,465,790 B2Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Sir William Dunn School of Pathology, Oxford UniversityOxfordUK

Personalised recommendations