The impact of antibodies on clinical outcomes in diseases treated with therapeutic protein: lessons learned from infantile Pompe disease

Abstract

Purpose: Enzyme replacement therapy with rhGAA (Myozyme®) has lead to improved survival, which is largely attributable to improvements in cardiomyopathy and skeletal muscle function. However, crossreactive immunologic material-negative patients have a poor clinical response to enzyme replacement therapy secondary to high sustained antibody titers. Furthermore, although the majority of crossreactive immunologic material-positive patients tolerize or experience a downtrend in anti-rhGAA antibody titers, antibody response is variable with some crossreactive immunologic material-positive infants also mounting high sustained antibody titers.

Methods: We retrospectively analyzed 34 infants with Pompe disease: 11 crossreactive immunologic material-negative patients, nine high-titer crossreactive immunologic material-positive patients, and 14 low-titer crossreactive immunologic material-positive patients. Clinical outcome measures were overall survival, ventilator-free survival, left ventricular mass index, Alberta Infant Motor Scale score, and urine Glc(4) levels.

Results: Clinical outcomes in the high-titer crossreactive immunologic material-positive group were poor across all areas evaluated relative to the low-titer crossreactive immunologic material-positive group. For the crossreactive immunologic material-negative and high-titer crossreactive immunologic material-positive groups, no statistically significant differences were observed for any outcome measures, and both patient groups did poorly.

Conclusions: Our data indicate that, irrespective of crossreactive immunologic material status, patients with infantile Pompe disease with high sustained antibody titer have an attenuated therapeutic response to enzyme replacement therapy. With the advent of immunomodulation therapies, identification of patients at risk for developing high sustained antibody titer is critical.

Conflict of interest statement

Disclosure

This potential conflict for Duke University has been resolved through monetization. S. G. Banugaria, S. N. Prater, Y-K. Ng, J. A. Kobori, R.S. Finkel, R. L. Ladda and A. S. Rosenberg have no financial or proprietary interest in the materials presented herein.

Figures

Fig. 1

Antibody titers for CN (black), HTCP (red), and LTCP (green) at various time points. Primary y axis shows antibody titers, and secondary y axis shows corresponding log-transformed antibody titer value. CN, CRIM negative; HTCP, high-titer CRIM positive; LTCP, low-titer CRIM positive.

Fig. 2

Kaplan-Meier curves for (A) overall survival and (B) ventilator-free survival for CN (black), HTCP (red), and LTCP (green). CN, CRIM negative; HTCP, high-titer CRIM positive; LTCP, low-titer CRIM positive.

Fig. 3

Left ventricular mass index (LVMI) in g/m2 at baseline (A), 26 weeks (B), and 52 weeks (C) of rhGAA treatment in CRIM negative (CN), high-titer CRIM-positive (HTCP) patients, and low-titer CRIM-positive (LTCP) patients.

Fig. 4

Alberta Infant Motor Scale (AIMS) scores at baseline (A), 26 weeks (B), and 52 weeks (C) of rhGAA treatment in CRIM negative (CN), high-titer CRIM-positive (HTCP) patients, and low-titer CRIM-positive (LTCP) patients.

Fig. 5

Urine Glc4 in mmol/mol creatinine at baseline (A), 26 weeks (B), and 52 weeks (C) of rhGAA treatment in CRIM negative (CN), high-titer CRIM-positive (HTCP) patients, and low-titer CRIM-positive (LTCP) patients.