Pharmacokinetics of Human Recombinant Anti-Botulinum Toxin Antibodies in Rats
Botulinum neurotoxins (BoNT) are potential biothreat agents due to their high lethality, potency, and ease of distribution, thus the development of antitoxins is a high priority to the US government. This study examined pre-clinical pharmacokinetic studies in rats of four oligoclonal anti-BoNT mAb-b...
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-06-01
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| Series: | Toxins |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6651/11/6/345 |
| _version_ | 1811187869094510592 |
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| author | Yero Espinoza David Wong Ago Ahene Kenneth Der Zachary Martinez John Pham Ronald R. Cobb Shauna Farr-Jones James. D. Marks Milan T. Tomic |
| author_facet | Yero Espinoza David Wong Ago Ahene Kenneth Der Zachary Martinez John Pham Ronald R. Cobb Shauna Farr-Jones James. D. Marks Milan T. Tomic |
| author_sort | Yero Espinoza |
| collection | DOAJ |
| description | Botulinum neurotoxins (BoNT) are potential biothreat agents due to their high lethality, potency, and ease of distribution, thus the development of antitoxins is a high priority to the US government. This study examined pre-clinical pharmacokinetic studies in rats of four oligoclonal anti-BoNT mAb-based therapeutics (NTM-1631, NTM-1632, NTM-1633, NTM-1634) for five BoNT serotypes (A, B, E, C, and D). NTM-1631, NTM-1632, and NTM-1633 each consist of three IgG1 mAbs, each with a distinct human or humanized variable region which bind to distinct epitopes on BoNT serotype A, B, or E respectively. NTM-1634 consists of four human immunoglobulin G1 (IgG1) mAbs binding BoNT C/D mosaic toxins. The mechanism of these antitoxins requires that three antibodies simultaneously bind toxin to achieve rapid clearance. Rats (total 378) displayed no adverse clinical signs attributed to antibody treatment from any of the antitoxins. Pharmacokinetic evaluation demonstrated that the individual mAbs are slowly eliminated, exhibiting dose-dependent exposure and long elimination half-lives ranging from 6.5 days to 10 days. There were no consistent differences observed between males and females or among the individual antibodies in each formulation in half-life. Anti-drug antibodies (ADA) were observed, as expected for human antibodies administered to rats. The results presented were used to support the clinical investigation of antibody-based botulism antitoxins. |
| first_indexed | 2024-04-11T14:09:51Z |
| format | Article |
| id | doaj.art-086a1b33951547fc8503f1a30d1a4591 |
| institution | Directory Open Access Journal |
| issn | 2072-6651 |
| language | English |
| last_indexed | 2024-04-11T14:09:51Z |
| publishDate | 2019-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Toxins |
| spelling | doaj.art-086a1b33951547fc8503f1a30d1a45912022-12-22T04:19:44ZengMDPI AGToxins2072-66512019-06-0111634510.3390/toxins11060345toxins11060345Pharmacokinetics of Human Recombinant Anti-Botulinum Toxin Antibodies in RatsYero Espinoza0David Wong1Ago Ahene2Kenneth Der3Zachary Martinez4John Pham5Ronald R. Cobb6Shauna Farr-Jones7James. D. Marks8Milan T. Tomic9Ology Bioservices Inc., 630 Bancroft Way, Suite D, Berkeley, CA 94710, USAOlogy Bioservices Inc., 630 Bancroft Way, Suite D, Berkeley, CA 94710, USAFiveprime Therapeutics Inc., 111 Oyster Point Blvd, South San Francisco, CA 94080, USAPortola Pharmaceuticals Inc., 270 E Grand Ave, South San Francisco, CA 94080, USAOlogy Bioservices Inc., 630 Bancroft Way, Suite D, Berkeley, CA 94710, USAOncoMed Inc., 800 Chesapeake Dr, Redwood City, CA 94063, USAOlogy Bioservices Inc., 13200 NW Nano Ct, Alachua, FL 32615, USADepartment of Anesthesia and Perioperative Care, University of California, San Francisco, 1001 Potrero Ave, San Francisco, CA 94110, USADepartment of Anesthesia and Perioperative Care, University of California, San Francisco, 1001 Potrero Ave, San Francisco, CA 94110, USAOlogy Bioservices Inc., 630 Bancroft Way, Suite D, Berkeley, CA 94710, USABotulinum neurotoxins (BoNT) are potential biothreat agents due to their high lethality, potency, and ease of distribution, thus the development of antitoxins is a high priority to the US government. This study examined pre-clinical pharmacokinetic studies in rats of four oligoclonal anti-BoNT mAb-based therapeutics (NTM-1631, NTM-1632, NTM-1633, NTM-1634) for five BoNT serotypes (A, B, E, C, and D). NTM-1631, NTM-1632, and NTM-1633 each consist of three IgG1 mAbs, each with a distinct human or humanized variable region which bind to distinct epitopes on BoNT serotype A, B, or E respectively. NTM-1634 consists of four human immunoglobulin G1 (IgG1) mAbs binding BoNT C/D mosaic toxins. The mechanism of these antitoxins requires that three antibodies simultaneously bind toxin to achieve rapid clearance. Rats (total 378) displayed no adverse clinical signs attributed to antibody treatment from any of the antitoxins. Pharmacokinetic evaluation demonstrated that the individual mAbs are slowly eliminated, exhibiting dose-dependent exposure and long elimination half-lives ranging from 6.5 days to 10 days. There were no consistent differences observed between males and females or among the individual antibodies in each formulation in half-life. Anti-drug antibodies (ADA) were observed, as expected for human antibodies administered to rats. The results presented were used to support the clinical investigation of antibody-based botulism antitoxins.https://www.mdpi.com/2072-6651/11/6/345botulinum neurotoxinpharmacokineticsrecombinant antibodyratoligoclonal antibodyanti-botulinum neurotoxin antibody |
| spellingShingle | Yero Espinoza David Wong Ago Ahene Kenneth Der Zachary Martinez John Pham Ronald R. Cobb Shauna Farr-Jones James. D. Marks Milan T. Tomic Pharmacokinetics of Human Recombinant Anti-Botulinum Toxin Antibodies in Rats Toxins botulinum neurotoxin pharmacokinetics recombinant antibody rat oligoclonal antibody anti-botulinum neurotoxin antibody |
| title | Pharmacokinetics of Human Recombinant Anti-Botulinum Toxin Antibodies in Rats |
| title_full | Pharmacokinetics of Human Recombinant Anti-Botulinum Toxin Antibodies in Rats |
| title_fullStr | Pharmacokinetics of Human Recombinant Anti-Botulinum Toxin Antibodies in Rats |
| title_full_unstemmed | Pharmacokinetics of Human Recombinant Anti-Botulinum Toxin Antibodies in Rats |
| title_short | Pharmacokinetics of Human Recombinant Anti-Botulinum Toxin Antibodies in Rats |
| title_sort | pharmacokinetics of human recombinant anti botulinum toxin antibodies in rats |
| topic | botulinum neurotoxin pharmacokinetics recombinant antibody rat oligoclonal antibody anti-botulinum neurotoxin antibody |
| url | https://www.mdpi.com/2072-6651/11/6/345 |
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