Natural antibodies against bone morphogenic proteins and interferons in healthy donors and in patients with infections linked to type-1 cytokine responses

In patients receiving recombinant therapeutic proteins, the production of antibodies against the therapeutics is a rising problem. The antibodies can neutralize and interfere with the efficacy and safety of drugs and even cause severe side effects if they cross-react against the natural, endogenous protein. Various factors have been identified to influence the immunogenic potential of recombinant human therapeutics, including several patients' characteristics. In recent years, so-called naturally occurring antibodies against cytokines and growth factors have been detected in naive patients before start of treatment with recombinant human therapeutics. The role of naturally occurring antibodies is not well understood and their influence on production of anti-drug antibodies is not known. One might speculate that the presence of naturally occurring antibodies increases the likelihood of eliciting anti-drug antibodies once treatment with the corresponding recombinant therapeutic protein is started. We screened serum samples from 410 healthy controls and patients for auto-antibodies against bone morphogenetic proteins (BMPs) 2 and 7 and interferon (IFN)-α, -β, and -γ in a new 3-step approach: rough initial screening, followed by competition and protein A/G depletion. Naturally occurring antibodies against these proteins were detected in 2% to 4% of the tested sera. Individuals who are 65 years or older had a slightly higher occurrence of naturally occurring antibodies. Auto-antibodies against BMP-7 and IFN-α were mainly comprised of IgM isotypes, and natural antibodies against BMP-2, IFN-β, and -γ were mainly IgG. To ensure assay specificity, assays were also used to detect antibodies against BMP-7 in patients being treated with rhBMP-7 before and after surgical procedure. Fifty percent of the treated patients had persistent anti-BMP-7 antibodies over time. The 3-step approach provides an attractive tool to identify naturally occurring antibodies in naive patients.