Immunogenicity to Biotherapeutics – The Role of Anti-drug Immune Complexes

Short-term data on the immunogenicity of monoclonal antibodies showed associations between the development of antidrug antibodies and diminished serum drug levels, and a diminished treatment response. Little is known about the clinical relevance of antidrug antibodies against these drugs during long-term follow-up. To examine the course of antidrug antibody formation against fully human monoclonal antibody adalimumab and its clinical relevance during long-term (3-year) follow-up of patients with rheumatoid arthritis (RA). Prospective cohort study February 2004-September 2008; end of follow-up was September 2010. All 272 patients were diagnosed with RA and started treatment with adalimumab in an outpatient clinic. Disease activity was monitored and trough serum samples were obtained at baseline and 8 time points to 156 weeks. Serum adalimumab concentrations and antiadalimumab antibody titers were determined after follow-up. Treatment discontinuation, minimal disease activity, and clinical remission were compared for patients with and without antiadalimumab antibodies. After 3 years, 76 of 272 patients (28%) developed antiadalimumab antibodies--51 of these (67%) during the first 28 weeks of treatment. Patients without antiadalimumab antibodies had much higher adalimumab concentrations (median, 12 mg/L; IQR, 9-16 mg/L) compared with patients with antibody titers from 13 to 100 AU/mL (median, 5 mg/L; IQR, 3-9 mg/L; regression coefficient, -4.5; 95% CI, -6.0 to -2.9; P < .001) and also those greater than 100 AU/mL (median, 0 mg/L; IQR, 0-3 mg/L; regression coefficient, -7.1; 95% CI, -8.4 to -5.8; P < .001). Patients with antiadalimumab antibodies more often discontinued participation due to treatment failure (n = 29 [38%]; hazard ratio [HR], 3.0; 95% CI, 1.6-5.5; P < .001) compared with antiadalimumab antibody-negative ones (n = 28 [14%]). Ninety-five of 196 patients (48%) without antiadalimumab antibodies had minimal disease activity vs 10 of 76 patients (13%) with antiadalimumab antibodies; patients with antiadalimumab antibodies less often had sustained minimal disease activity score in 28 joints (DAS28) (< 3.2; HR, 3.6; 95% CI, 1.8-7.2; P < .001) compared with antiadalimumab antibody-negative ones. Three of 76 patients (4%) with antiadalimumab antibodies achieved sustained remission compared with 67 of 196 (34%) antiadalimumab antibody-negative ones; patients with antiadalimumab antibodies less often achieved remission (DAS28 < 2.6; HR, 7.1; 95% CI, 2.1-23.4; P < .001) compared with antiadalimumab antibody-negative ones. Among outpatients with RA in whom adalimumab was started over 3 years, the development of antidrug antibodies was associated with lower adalimumab concentration and lower likelihood of minimal disease activity or clinical remission.

FcgammaRIIB is the only inhibitory Fc receptor. It controls many aspects of immune and inflammatory responses, and variation in the gene encoding this protein has long been associated with susceptibility to autoimmune disease, particularly systemic lupus erythematosus (SLE). FcgammaRIIB is also involved in the complex regulation of defence against infection. A loss-of-function polymorphism in FcgammaRIIB protects against severe malaria, the investigation of which is beginning to clarify the evolutionary pressures that drive ethnic variation in autoimmunity. Our increased understanding of the function of FcgammaRIIB also has potentially far-reaching therapeutic implications, being involved in the mechanism of action of intravenous immunoglobulin, controlling the efficacy of monoclonal antibody therapy and providing a direct therapeutic target.

Protein therapeutics, such as monoclonal antibodies, enzymes and toxins, hold significant promise for improving human health. However, repeated administration of protein therapeutics, whether natural or recombinant, often leads to the induction of undesirable anti-drug antibodies (ADAs), which interfere with or neutralize the effect of the drug. Although an immune response to foreign proteins can be expected and is well understood, the basis for the development of responses to therapeutic autologous proteins is the subject of some debate. Inflammatory components of the drug delivery vehicle, T cell responses, T and B cell epitopes in the protein drug, and the associated B cell response are all targets for interventions aimed at reducing ADA responses. Here, we review some theories put forward to explain the immunogenicity of therapeutic proteins and describe some emerging protein-engineering approaches that might prevent the development of anti-drug antibodies.