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Toxic Effects of Immunogenicity to Biopharmaceuticals

Ana T. Menendez, PhD

Biopharmaceuticals developed by recombinant DNA technology are delivering their great promise in therapeutics because of their excellent targeting and their ability to mimic endogenous protein counterparts. Such drugs have been successfully marketed for years, and currently dozens of novel biopharmaceuticals are undergoing clinical trials.

The advantage of biopharmaceuticals is tempered with the danger of inducing immune responses that can lead to serious adverse events (AEs) because the biopharmaceutical is recognized as “non-self.” Although classic small molecule drugs can induce immunologic responses that produce AEs, these incidents are far more common with biopharmaceuticals. The immune response principally involves generating antibodies to the biopharmaceutical with the potential to induce acute life-threatening anaphylactic Type I reactions (if IgE antibodies are generated) or less dangerous but more common infusion reactions, consisting of symptoms such as headache, nausea, fever, chills, dizziness, flushing, pruritus, and chest or back pain. Nonacute consequences are generated from delayed T-cell hypersensitivity and immune complexes, which result in myalgia, arthralgia with fever, skin rash, pruritus, and other symptoms. The worst immunological safety situation occurs when patients begins to produce antibodies to their own endogenous proteins, in which case all treatment needs to be halted and immunosuppressive lifesaving support must be given.

All antibodies bind the therapeutic drug and can cause antibody–drug immune complexes that are cleared quickly from the serum and decrease efficacy. Immune complexes may also produce toxicity by producing renal damage in sensitive populations. A subset of these antibodies is called neutralizing because they can also directly block the interaction of the drug with its therapeutic target. Neutralizing antibodies have a clear effect on efficacy and may also be responsible for toxicity if they obliterate the endogenous protein.

Various external factors, such as the patient population, the disease being treated, the dose, the administration route, etc., can play a role in the immunogenicity of the drug. Product quality issues, such as inappropriate impurity clearance processes and improper handling of the vial, can also induce aggregation or abnormal forms of the biopharmaceutical before it is administered to the patient. Deviations from the recommended instructions for storing and preparing the biopharmaceutical can also produce safety problems. U.S. Food and Drug Administration (FDA), European Medicines Agency (EMA), and other agencies require that immunogenicity issues be characterized as best as possible during development as well as after marketing begins. A Risk Evaluation and Mitigation Strategy/Risk Management Plan (REMS/RMP) is also required in most cases with the marketing application. This document is project-specific and must contain a communication strategy covering any immunogenicity issues previously identified, expected, or discovered after commercialization. Risk minimization and mitigation efforts, in addition to communication measures, include specific investigation tools like antibody testing assays. Case studies on various biopharmaceuticals follow, illustrating the varied immunologic consequences seen with biopharmaceuticals.

Recombinant G-CSF is used to boost neutrophil production in patients undergoing chemotherapy. The binding antibody rate was low (3%) during clinical trials, as expected in an immunosuppressed population, and the antibodies were not neutralizing. Infusion reactions were rare. A biosimilar was recently approved that demonstrated no sign of immunogenicity.

Endogenous TPO is required for the growth of megakaryocytes, the precursor of platelets found in bone marrow. Clinical trials with exogenous TPO or pegylated TPO demonstrated a high immunogenic incidence of neutralizing antibodies to endogenous TPO. The treatment caused severe thrombocytopenia in both healthy volunteers and cancer patients due to marked reduction of megakaryocytes. Elevated levels of inactive TPO were also observed. TPO has the potential to be an important therapeutic protein, but despite many clinical trials, currently no approved forms of TPO are on the market because of its high immunogenicity risk.

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