Antibodies

Antibodies are perhaps the therapeutic agents known to induce infusion reaction most often (Szebeni J 2012 EJN; Baldo BA 2013 Oncoimmunol). The role of the complement system for at least some antibodies is complex as complement-dependent cytotoxicity (CDC) may play a role in the mechanism of action of rituximab and ofatumomab (reviewed in Baldo BA 2013 Oncoimmunol). Importantly though, many of the antibody induced side effects such as thromocytopenia (Ram 2009 Am J Hematol), interstitial lung disease (Alho HS, Maasilta PK 2003 Transplantation) and most importantly hypersensitivity (van der Kolk LE, Grillo-López AJ 2001 Br J Haematol; Tawara T, Hasegawa K 2008 J Immunol) are thought to be mediated by complement activation. Several therapeutic Abs have been suggested to activate the complement system, resulting in the production of large amounts of C3a, C4a, and C5a which can act as anaphylatoxins and induce the release of chemical mediators such as histamine and leukotriene (Raasveld MH, Bemelman FJ 1993 Kidney Int, van der Kolk LE, Grillo-López AJ  2001 Br J Haematol). In addition, antibody induced infusion reactions were inhibited in rats when complement was depleted by a cobra venom factor or in both rats and monkeys when the Fc regions of antibodies were engineered to reduce CDC (Tawara T, Hasegawa K 2008 J Immunol). This implies that complement activation is indeed a key mechanistic pathway in antibody induced infusion reactions and both in vitro and in vivo testing is available to predict probability of infusion reactions. It also suggests that antibodies can be optimized to reduce probability of infusion reactions should CDC be not required for therapeutic activity of the particular agent.

However, there is a clear difference between Ab-induced and nanoparticle-induced CARPA, inasmuch as most therapeutic Ab reaction starts somewhat later, mostly after 30 min, compared to immediate start of symptoms in the case of liposomes and micellar drugs. This difference can most easily be rationalized by the different kinetics of C activation in the case of nanoparticles and therapeutic Abs. Namely, while nanoparticles bind C almost immediately on their surface, therapeutic Abs need to undergo steric changes to become C activators (Szebeni J 2012 EJN). It is widely known in molecular immunology that when antibodies bind to foreign surfaces, steric changes in the hinge region free up the C binding site on the Fc region. With mAb therapy, the relatively slow kinetics of target binding will most likely control the rate of C activation and other immune consequences of Ab binding.

References

Alho HS, Maasilta PK, Harjula AL, Hämmäinen P, Salminen J, Salminen US Tumor necrosis factor-alpha in a porcine bronchial model of obliterative bronchiolitis. Transplantation. 2003;76(3):516-23

Baldo BA Adverse events to monoclonal antibodies used for cancer therapy: Focus on hypersensitivity responses. Oncoimmunology. 2013 ;2(10):e26333

Raasveld MH, Bemelman FJ, Schellekens PT, van Diepen FN, van Dongen A, van Royen EA, Hack CE, ten Berge IJ Complement activation during OKT3 treatment: a possible explanation for respiratory side effects. Kidney Int. 1993;43(5):1140-9

Szebeni J Haemocompatibility testing for nanomedicines and biologicals: Predictive assays for complement mediated infusion reactions. Eur. J. Nanomedicine, 2012; 4(1), 33-53

Tawara T, Hasegawa K, Sugiura Y, Harada K, Miura T, Hayashi S, Tahara T, Ishikawa M, Yoshida H, Kubo K, Ishida I, Kataoka S Complement activation plays a key role in antibody-induced infusion toxicity in monkeys and rats. J Immunol. 2008;180(4):2294-8

van der Kolk LE, Grillo-López AJ, Baars JW, Hack CE, van Oers MH Complement activation plays a key role in the side-effects of rituximab treatment. Br J Haematol. 2001;115(4):807-11.