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Targeting IL-18 by Employing a Recombinant IL-18 Peptide-based Vaccine Ameliorates TNBS-induced Murine Acute and Chronic Colitis
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Tolerability and Efficacy of Facilitated-Subcutaneous Infusion of Immune Globulin (Human), 10% and Recombinant Human Hyaluronidase (IGHy) in a Subset of Study Patients With Primary Immunodeficiency Disease (PIDD) R. L. Wasserman1, I. Melamed2, M. Stein3, J. Puck4, S. Gupta5, W. Engl6, H. Leibl6, D. Gelmont7, R. I. Schiff7, on behalf of IGSC 10% rHuPH20 Study Group7. 1Dallas Allergy Immunology, Dallas, TX, 2Allergy Associates of the Palm beaches, North Palm Beach, FL, 3IMMUNOe, Centennial, CO, 4University of California, San Francisco, CA, 5University of California, Irvine, CA, 6Baxter BioScience, Vienna, AUSTRIA, 7Baxter BioScience, Westlake Village, CA. RATIONALE: The limited volume of subcutaneously administered IgG (IGSC) per site necessitates weekly infusions, each using several sites. rHuPH20 is a permeation enhancer that improves dispersion of SC-infused fluids. In a previous study rHuPH20-facilitated infusions of IgG (IGHy) enabled infusions at rates and frequencies equivalent to IGIV, with tolerability similar to IGSC. METHODS: Infusion parameters, tolerability and efficacy were compared in 31 PIDD patients who received IGIV, IGSC, and IGHy in two phase III studies of IGSC alone (NCT00546871) and IGHy (NCT00814320). IGIV and IGHy were infused every 3 or 4 weeks and IGSC weekly. RESULTS: Mean volume/site: 268.3 (6-716)mL for IGHy; 22.6(8-51)mL for IGSC; 300.8(75-652)mL for IGIV. Median (range) number of infusion sites/infusion: IGHy 1.0 (1-2) every 3-4weeks; IGSC 5 (2-10) weekly; IGIV 1 every 3-4weeks Mean maximum infusion rate (mL/hr/site): 244.66(90-300) for IGHy; 27.03(8-30) IGSC; 198.83(25-668) IGIV. Mean infusion duration: 2.36(1-5) hours/3-4 weeks for IGHy; 1.24(0.63.7) hours/week IGSC; and 2.65(1-5) hours/3-4 weeks IGIV. Rate of local ADRs/infusion: 0.120 for IGHy; 0.017 for IGSC; 0.008 for IGIV. Related systemic AE rate/infusion: 0.094 for IGHy; 0.037 for IGSC; 0.326 for IGIV. Efficacy: Annualized rate of all infections was 2.41 infections/subject-year (95% CI: 1.80-3.15) for IGHy; 3.77 (95% CI 2.80-4.94) for IGSC and 4.17 (95% CI: 2.73-6.05) for IGIV. CONCLUSIONS: IGHy was infused at a frequency similar to IGIV, at a faster rate and shorter time compared with both IGSC and IGIV. Local and systemic ADRs were similar to IGSC. The overall rate of infections was lower in IGHy-treated patients compared with IGSC or IGIV.
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Subcutaneous HizentraÒ (20%) Is Better Tolerated And Shares Similar Efficacy Compared To Subcutaneous VivaglobinÒ (16%) D. Nguyen, M. Dorsey, T. Alberdi, C. Duff, J. Sleasman; University of South Florida/All Children’s Hospital, St. Petersburg, FL. RATIONALE: Replacement Subcutaneous IgG (SCIG) therapy is effective treatment in reducing rates of infections in patients with primary immunodeficiency diseases (PIDD), but there are few comparative studies using different SCIG preparations. This study examines the tolerability and efficacy of Hizentra (20%) subcutaneous immune globulin (SCIG) product compared to Vivaglobin (16%). METHODS: A prospective, single-center, open-label cohort of 32 PIDD subjects, who received 16% Vivaglobin for at least 6 months and transitioned to 20% Hizentra for 24 weeks. Number of acute serious bacterial infections (aSBI) and overall tolerability on Vivaglobin was assessed for 8 weeks prior to switch and compared to Hizentra over 24 weeks. Average Hizentra dose was higher than Vivaglobin at 161.6 +/- 99.8 and 145.9 +/- 88.2 mg/kg/week, respectively (p < 0.0001). RESULTS: The study is ongoing and preliminary findings for all subjects through 12 weeks on Hizentra are reported. aSBI/subject/year while receiving Vivaglobin was 0.2 compared to 0.14 on Hizentra. Per-person annual rates of other infections were lower for Vivaglobin at 1.2 versus 2.63 for Hizentra (p 5 0.0167). There were no infusion-related serious adverse events in either group. Average infusion time decreased from 108 minutes (3.2 sites) with Vivaglobin to 72 minutes (2.1 sites) with Hizentra. Mean Vivaglobin IgG were similar to Hizentra, 1096.1 (+/- 231.2) and 1105.2 (+/- 233.3) mg/dL, respectively (p 5 0.77). Both groups had similar titers to varicella (103.1 versus 107.9 EU/mL) and tetanus (2.8 versus 2.9 IU/mL) on Vivaglobin and Hizentra, respectively.
CONCLUSIONS: Hizentra (20%) achieves better tolerability and similar efficacy to Vivaglobin (16%).
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Targeting IL-18 by Employing a Recombinant IL-18 Peptide-based Vaccine Ameliorates TNBS-induced Murine Acute and Chronic Colitis S. Moreno, Q. Guan, C. Weiss, Q. Gefei, C. Bernstein, Z. Peng; University of Manitoba, Winnipeg, MB, CANADA. RATIONALE: IL-18 plays important roles in the pathogenesis of Crohn’s disease. Blocking IL-18 with its mAb or binding protein results in an attenuation of murine colitis. We sought to develop IL-18 peptide-based virus-like particle vaccines which induce long-lasting autoantibodies to IL18 and to test the effects of the vaccine in the down-regulation of trinitrobenzene sulfonic acid (TNBS)-induced murine colitis. METHODS: A vaccine against IL-18 was constructed by inserting a peptide derived from mouse IL-18 into the carrier protein hepatitis B core antigen using gene recombination methods. Recombinant protein was expressed using E. coli and purified by chromatography. Mice were subcutaneously immunized 3 times with the vaccine, vaccine carrier or saline. Two weeks after the final immunization, mice were intra-rectally administered with increasing doses (1.0-2.3 mg) of TNBS for 2 or 7 times to induce acute or chronic colitis. One week after the last TNBS administration, mice were sacrificed. Sera and colons were collected and analyzed. RESULTS: The vaccine induced high levels of IL-18-specific IgG antibodies that inhibited IL-18-induced IFN-g secretion from splenocytes dose-dependently. In both acute and chronic colitis, mice receiving vaccine exhibited a significant decrease in intestinal inflammation (H&E staining), collagen deposition (Masson’s trichrome staining), soluble collagen production, and levels of IL-18, IL-12/IL-23p40, and TNF in colon tissue (enzyme-linked immunosorbent assays), compared to saline and carrier groups. CONCLUSIONS: IL-18 vaccine induces high levels of IL-18-specific IgG antibodies leading to the improvement of acute and chronic intestinal inflammation. This strategy may provide a potential therapeutic approach in the treatment of Crohn’s disease.
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In Patients With Hereditary Angioedema, Self-administration Of Intravenous C1 Esterase Inhibitor Decreases The Number Of Days Spent In An Emergency Room C. Rizk1, S. Santucci2, S. McDiarmid1, J. Karsh1, W. H. Yang1; 1University of Ottawa, Ottawa, ON, CANADA, 2Yang Medicine, Ottawa, ON, CANADA. RATIONALE: Hereditary Angioedema (HAE) is a rare, inherited, autosomal dominant disease caused by a deficiency in C1-esterase inhibitor. It affects one in every 50,000 to 100,000 individuals. There were no approved treatments for HAE in North America until C1-esterase inhibitor (BerinertÒ), an intravenous medication, was released. However, it requires patients to present to an emergency room (ER) for treatment. The cases of two patients with HAE are presented. Both decreased their number of emergency room visits substantially after self-administering the medications. METHODS: Cases were obtained from office visits with an allergist and continued communication with the patients. RESULTS: The first patient averaged around 17 visits to an ER annually. She and her husband are both paramedics and were able to start intravenous lines for the required infusion at home. After she began self-administering C1 esterase inhibitor, she had no further visits to an emergency room. The second patient suffered from very frequent attacks, including 37 ER visits in 2009, and 48 visits in 2010 alone. Given her poor venous access, a Hickman catheter was placed in her internal jugular vein for easy administration. After she began self-administration 6 months ago, she has had only 3 presentations to the ER. CONCLUSIONS: Self-administration of C1-esterase inhibitor (BerinertÒ) dramatically improved the lives of these two young patients, and resulted in a considerable decrease in the number of days spent in an emergency room.
SATURDAY
Abstracts AB15
J ALLERGY CLIN IMMUNOL VOLUME 129, NUMBER 2
Tolerability and Efficacy of Facilitated-Subcutaneous Infusion of Immune Globulin (Human), 10% and Recombinant Human Hyaluronidase (IGHy) in a Subset of Study Patients With Primary Immunodeficiency Disease (PIDD) R. L. Wasserman1, I. Melamed2, M. Stein3, J. Puck4, S. Gupta5, W. Engl6, H. Leibl6, D. Gelmont7, R. I. Schiff7, on behalf of IGSC 10% rHuPH20 Study Group7. 1Dallas Allergy Immunology, Dallas, TX, 2Allergy Associates of the Palm beaches, North Palm Beach, FL, 3IMMUNOe, Centennial, CO, 4University of California, San Francisco, CA, 5University of California, Irvine, CA, 6Baxter BioScience, Vienna, AUSTRIA, 7Baxter BioScience, Westlake Village, CA. RATIONALE: The limited volume of subcutaneously administered IgG (IGSC) per site necessitates weekly infusions, each using several sites. rHuPH20 is a permeation enhancer that improves dispersion of SC-infused fluids. In a previous study rHuPH20-facilitated infusions of IgG (IGHy) enabled infusions at rates and frequencies equivalent to IGIV, with tolerability similar to IGSC. METHODS: Infusion parameters, tolerability and efficacy were compared in 31 PIDD patients who received IGIV, IGSC, and IGHy in two phase III studies of IGSC alone (NCT00546871) and IGHy (NCT00814320). IGIV and IGHy were infused every 3 or 4 weeks and IGSC weekly. RESULTS: Mean volume/site: 268.3 (6-716)mL for IGHy; 22.6(8-51)mL for IGSC; 300.8(75-652)mL for IGIV. Median (range) number of infusion sites/infusion: IGHy 1.0 (1-2) every 3-4weeks; IGSC 5 (2-10) weekly; IGIV 1 every 3-4weeks Mean maximum infusion rate (mL/hr/site): 244.66(90-300) for IGHy; 27.03(8-30) IGSC; 198.83(25-668) IGIV. Mean infusion duration: 2.36(1-5) hours/3-4 weeks for IGHy; 1.24(0.63.7) hours/week IGSC; and 2.65(1-5) hours/3-4 weeks IGIV. Rate of local ADRs/infusion: 0.120 for IGHy; 0.017 for IGSC; 0.008 for IGIV. Related systemic AE rate/infusion: 0.094 for IGHy; 0.037 for IGSC; 0.326 for IGIV. Efficacy: Annualized rate of all infections was 2.41 infections/subject-year (95% CI: 1.80-3.15) for IGHy; 3.77 (95% CI 2.80-4.94) for IGSC and 4.17 (95% CI: 2.73-6.05) for IGIV. CONCLUSIONS: IGHy was infused at a frequency similar to IGIV, at a faster rate and shorter time compared with both IGSC and IGIV. Local and systemic ADRs were similar to IGSC. The overall rate of infections was lower in IGHy-treated patients compared with IGSC or IGIV.
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Subcutaneous HizentraÒ (20%) Is Better Tolerated And Shares Similar Efficacy Compared To Subcutaneous VivaglobinÒ (16%) D. Nguyen, M. Dorsey, T. Alberdi, C. Duff, J. Sleasman; University of South Florida/All Children’s Hospital, St. Petersburg, FL. RATIONALE: Replacement Subcutaneous IgG (SCIG) therapy is effective treatment in reducing rates of infections in patients with primary immunodeficiency diseases (PIDD), but there are few comparative studies using different SCIG preparations. This study examines the tolerability and efficacy of Hizentra (20%) subcutaneous immune globulin (SCIG) product compared to Vivaglobin (16%). METHODS: A prospective, single-center, open-label cohort of 32 PIDD subjects, who received 16% Vivaglobin for at least 6 months and transitioned to 20% Hizentra for 24 weeks. Number of acute serious bacterial infections (aSBI) and overall tolerability on Vivaglobin was assessed for 8 weeks prior to switch and compared to Hizentra over 24 weeks. Average Hizentra dose was higher than Vivaglobin at 161.6 +/- 99.8 and 145.9 +/- 88.2 mg/kg/week, respectively (p < 0.0001). RESULTS: The study is ongoing and preliminary findings for all subjects through 12 weeks on Hizentra are reported. aSBI/subject/year while receiving Vivaglobin was 0.2 compared to 0.14 on Hizentra. Per-person annual rates of other infections were lower for Vivaglobin at 1.2 versus 2.63 for Hizentra (p 5 0.0167). There were no infusion-related serious adverse events in either group. Average infusion time decreased from 108 minutes (3.2 sites) with Vivaglobin to 72 minutes (2.1 sites) with Hizentra. Mean Vivaglobin IgG were similar to Hizentra, 1096.1 (+/- 231.2) and 1105.2 (+/- 233.3) mg/dL, respectively (p 5 0.77). Both groups had similar titers to varicella (103.1 versus 107.9 EU/mL) and tetanus (2.8 versus 2.9 IU/mL) on Vivaglobin and Hizentra, respectively.
CONCLUSIONS: Hizentra (20%) achieves better tolerability and similar efficacy to Vivaglobin (16%).
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Targeting IL-18 by Employing a Recombinant IL-18 Peptide-based Vaccine Ameliorates TNBS-induced Murine Acute and Chronic Colitis S. Moreno, Q. Guan, C. Weiss, Q. Gefei, C. Bernstein, Z. Peng; University of Manitoba, Winnipeg, MB, CANADA. RATIONALE: IL-18 plays important roles in the pathogenesis of Crohn’s disease. Blocking IL-18 with its mAb or binding protein results in an attenuation of murine colitis. We sought to develop IL-18 peptide-based virus-like particle vaccines which induce long-lasting autoantibodies to IL18 and to test the effects of the vaccine in the down-regulation of trinitrobenzene sulfonic acid (TNBS)-induced murine colitis. METHODS: A vaccine against IL-18 was constructed by inserting a peptide derived from mouse IL-18 into the carrier protein hepatitis B core antigen using gene recombination methods. Recombinant protein was expressed using E. coli and purified by chromatography. Mice were subcutaneously immunized 3 times with the vaccine, vaccine carrier or saline. Two weeks after the final immunization, mice were intra-rectally administered with increasing doses (1.0-2.3 mg) of TNBS for 2 or 7 times to induce acute or chronic colitis. One week after the last TNBS administration, mice were sacrificed. Sera and colons were collected and analyzed. RESULTS: The vaccine induced high levels of IL-18-specific IgG antibodies that inhibited IL-18-induced IFN-g secretion from splenocytes dose-dependently. In both acute and chronic colitis, mice receiving vaccine exhibited a significant decrease in intestinal inflammation (H&E staining), collagen deposition (Masson’s trichrome staining), soluble collagen production, and levels of IL-18, IL-12/IL-23p40, and TNF in colon tissue (enzyme-linked immunosorbent assays), compared to saline and carrier groups. CONCLUSIONS: IL-18 vaccine induces high levels of IL-18-specific IgG antibodies leading to the improvement of acute and chronic intestinal inflammation. This strategy may provide a potential therapeutic approach in the treatment of Crohn’s disease.
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In Patients With Hereditary Angioedema, Self-administration Of Intravenous C1 Esterase Inhibitor Decreases The Number Of Days Spent In An Emergency Room C. Rizk1, S. Santucci2, S. McDiarmid1, J. Karsh1, W. H. Yang1; 1University of Ottawa, Ottawa, ON, CANADA, 2Yang Medicine, Ottawa, ON, CANADA. RATIONALE: Hereditary Angioedema (HAE) is a rare, inherited, autosomal dominant disease caused by a deficiency in C1-esterase inhibitor. It affects one in every 50,000 to 100,000 individuals. There were no approved treatments for HAE in North America until C1-esterase inhibitor (BerinertÒ), an intravenous medication, was released. However, it requires patients to present to an emergency room (ER) for treatment. The cases of two patients with HAE are presented. Both decreased their number of emergency room visits substantially after self-administering the medications. METHODS: Cases were obtained from office visits with an allergist and continued communication with the patients. RESULTS: The first patient averaged around 17 visits to an ER annually. She and her husband are both paramedics and were able to start intravenous lines for the required infusion at home. After she began self-administering C1 esterase inhibitor, she had no further visits to an emergency room. The second patient suffered from very frequent attacks, including 37 ER visits in 2009, and 48 visits in 2010 alone. Given her poor venous access, a Hickman catheter was placed in her internal jugular vein for easy administration. After she began self-administration 6 months ago, she has had only 3 presentations to the ER. CONCLUSIONS: Self-administration of C1-esterase inhibitor (BerinertÒ) dramatically improved the lives of these two young patients, and resulted in a considerable decrease in the number of days spent in an emergency room.
SATURDAY
Abstracts AB15
J ALLERGY CLIN IMMUNOL VOLUME 129, NUMBER 2