Bortezomib in the rapid reduction of high sustained antibody titers in disorders treated with therapeutic protein: lessons learned from Pompe disease

Abstract

Purpose: High sustained antibody titers complicate many disorders treated with a therapeutic protein, including those treated with enzyme replacement therapy, such as Pompe disease. Although enzyme replacement therapy with alglucosidase alfa (Myozyme) in Pompe disease has improved the prognosis of this otherwise lethal disorder, patients who develop high sustained antibody titers to alglucosidase alfa enter a prolonged phase of clinical decline resulting in death despite continued enzyme replacement therapy. Clinically effective immune-tolerance induction strategies have yet to be described in the setting of an entrenched immune response characterized by high sustained antibody titers, wherein antibody-producing plasma cells play an especially prominent role.

Methods: We treated three patients with infantile Pompe disease experiencing marked clinical decline due to high sustained antibody titers. To target the plasma cell source of high sustained antibody titers, a regimen based on bortezomib (Velcade) was used in combination with rituximab, methotrexate, and intravenous immunoglobulin.

Results: The treatment regimen was well tolerated, with no obvious side effects. Patient 1 had a 2,048-fold, and patients 2 and 3 each had a 64-fold, reduction in anti-alglucosidase alfa antibody titer, with concomitant sustained clinical improvement.

Conclusion: The addition of bortezomib to immunomodulatory regimens is an effective and safe treatment strategy in infantile Pompe disease, with potentially broader clinical implications.

Figure 1. Trends in anti–recombinant human alglucosidase alfa (anti-rhGAA) IgG antibody titers and left-ventricular mass index (LVMI; (a and b) or urine Glc₄ (c) over time are shown by a solid black line and a dashed gray line, respectively (the upper limit of normal LVMI is 65 g/m^2; control range of urine Glc₄ for age >3 years is 3 mmol/mol of creatinine)

(a) In patient 1, following unsuccessful immunomodulation with two doses of cyclophosphamide (250 mg/m² i.v.) and four weekly doses of rituximab (375 mg/m² per dose i.v.) during weeks 86 to 95, monotherapy with bortezomib (Velcade) was initiated. Bortezomib was administered twice weekly (1.3 mg/m² of body surface area i.v.) according to a standard dosing regimen (days 1, 4, 8, and 11; equivalent to one cycle of bortezomib) during weeks 99 and 100 (cycle 1), weeks 110 and 111 (cycle 2), and weeks 127 and 128 (cycle 3) of enzyme replacement therapy (ERT). Monthly intravenous immunoglobulin (IVIG) was administered at the start of the first cycle of bortezomib. Following a second cycle of bortezomib with continued ERT, a total of four weekly doses of i.v. rituximab (375 mg/m² per dose) were administered in addition to biweekly methotrexate (15 mg/m²) orally. Rituximab was thereafter administered on a monthly basis. (b) In patient 2, following unsuccessful immunomodulation with rituximab (375 mg/m², i.v.) and methotrexate (15 mg/m² s.c.), bortezomib was administered as described in patient 1. Following the first cycle of bortezomib, a total of four weekly doses of rituximab (375 mg/m² per dose, i.v.) were administered in addition to biweekly methotrexate (15 mg/m², s.c.). Rituximab was thereafter administered on a monthly basis. Monthly IVIG was administered as described for patient 1. (c) In patient 3, bortezomib was administered as described for patient 1. Six such cycles were administered between weeks 88 and 153. Rituximab was administered (375 mg/m² per dose, i.v.) approximately every month except after the first and third cycle of bortezomib, at which time a total of four weekly doses were administered after the last bortezomib injection. Methotrexate and IVIG were administered as described in patients 1 and 2.

Figure 1. Trends in anti–recombinant human alglucosidase alfa (anti-rhGAA) IgG antibody titers and left-ventricular mass index (LVMI; (a and b) or urine Glc₄ (c) over time are shown by a solid black line and a dashed gray line, respectively (the upper limit of normal LVMI is 65 g/m^2; control range of urine Glc₄ for age >3 years is 3 mmol/mol of creatinine)

(a) In patient 1, following unsuccessful immunomodulation with two doses of cyclophosphamide (250 mg/m² i.v.) and four weekly doses of rituximab (375 mg/m² per dose i.v.) during weeks 86 to 95, monotherapy with bortezomib (Velcade) was initiated. Bortezomib was administered twice weekly (1.3 mg/m² of body surface area i.v.) according to a standard dosing regimen (days 1, 4, 8, and 11; equivalent to one cycle of bortezomib) during weeks 99 and 100 (cycle 1), weeks 110 and 111 (cycle 2), and weeks 127 and 128 (cycle 3) of enzyme replacement therapy (ERT). Monthly intravenous immunoglobulin (IVIG) was administered at the start of the first cycle of bortezomib. Following a second cycle of bortezomib with continued ERT, a total of four weekly doses of i.v. rituximab (375 mg/m² per dose) were administered in addition to biweekly methotrexate (15 mg/m²) orally. Rituximab was thereafter administered on a monthly basis. (b) In patient 2, following unsuccessful immunomodulation with rituximab (375 mg/m², i.v.) and methotrexate (15 mg/m² s.c.), bortezomib was administered as described in patient 1. Following the first cycle of bortezomib, a total of four weekly doses of rituximab (375 mg/m² per dose, i.v.) were administered in addition to biweekly methotrexate (15 mg/m², s.c.). Rituximab was thereafter administered on a monthly basis. Monthly IVIG was administered as described for patient 1. (c) In patient 3, bortezomib was administered as described for patient 1. Six such cycles were administered between weeks 88 and 153. Rituximab was administered (375 mg/m² per dose, i.v.) approximately every month except after the first and third cycle of bortezomib, at which time a total of four weekly doses were administered after the last bortezomib injection. Methotrexate and IVIG were administered as described in patients 1 and 2.