Biologic therapies, large molecules made in living cells, rather than small molecules synthesized by chemists, are now used in the management of many illnesses, including rheumatologic diseases, respiratory diseases, cancer, and a large number of rare diseases. Patients with lysosomal storage diseases (LSDs) are treated with large molecules – enzymes – to replace those that are defective due to genetic mutations.  All of these therapies are highly effectively, but they can be complicated by the development of so-called anti-drug antibodies (ADAs). These occur when the body recognizes the large molecule as “foreign” and mounts an immune response to it. This immune response and the resulting ADAs can adversely impact the safety and efficacy of therapy.


Patient monitoring has shown that as many as 75% of patients with LSDs may develop ADAs to enzyme replacement therapy (ERT). In many patients, these antibodies have no adverse effects, but in others they may neutralize the replacement enzyme and interfere with its clinical benefit.


Given the potentially important impact of ADAs, substantial attention has been paid strategies for the prevention of ADA formation in ERT-naïve patients and reduction of existing ADAs in patients who have developed them. Both prevention and management of ADAs has focused on modulation immune system function in conjunction with ERT administration. For example, it has been shown the delivery of a low dose of methotrexate (MTX) when ERT is initiated can prevent the formation of ADAs. It has been suggested that the addition MTX of activates the formation of B-regulatory cells, which might mediate an antigen-specific tolerance to the replacement enzyme. Increasing the duration of exposure to replacement enzyme also has the potential to decrease the risk for development of ADAs, and the short elimination half-life for these medications in plasma might be prolonged by concomitant administration of a chaperone. Pegylation (adding molecules of polyethylene glycol to the replacement enzyme) can also prolong half-life, but this approach has the risk of development of anti-Peg antibodies that can interfere with efficacy and increase the risk for infusion reactions.


It is possible to overcome ADAs once they form. The simplest approach to achieving this is to increase the dose of ERT to supersaturate the ADAs. However, if the ADA titer is high, this may not be possible.  In this case, patients might be managed with immunosuppressive regimens similar to those employed in individuals who have undergone organ transplantation. Specific regimens shown to be effective include combination of cyclophosphamide with intravenous immunoglobulin or with rituximab; and bortezomib plus rituximab and MTX.


Increased understanding of patient- and product-associated factors that increase the risk for ADA development will help individualize treatment to avoid the development of these antibodies.