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Alternatives to Monoclonal Antibody Production (Proceedings)

Alternatives in Monoclonal Antibody Production

Louis R. Sibal, PhD
Director
 Office of Laboratory Animal Research
National Institutes of Health

Regulatory Issues

ISSUE: Using the Administrative Procedures Act to formally request regulatory amendments, the American Anti-Vivisection Society (AAVS) asked the National Institutes of Health (NIH) to ban the production and use of monoclonal antibodies (MAB) resulting from the (mouse) ascites method. It is highly unusual for the NIH to receive such a petition since this agency seldom issues regulations. Nevertheless, the NIH is required to respond to the petitions and to take any action as may be required.

RESPONSE: The NIH has given serious consideration to the petition from the AAVS and prepared a substantive response (24 page report with 10 appendices) in support of its position-- denying the AAVS request. This decision is based examples provided by experienced investigators using alternative methods that either:

  1. failed to produce MAB (4-5%); and/or
  2. failed to produce MAB with proper reactivity (antigen-binding capacity) to answer important research questions.

This document, however, clearly recognizes the validity, reliability, and availability of many non-animal methods for producing MAB and strongly encourages their use.

ISSUE: The petition also invoked The Health Research Extension Act of 1985, which established guidelines for the proper care and treatment of animals used in research and vested authority in Institutional Animal Care and Use Committees (IACUC) assure compliance with them. The Act specifically states: the guidelines shall not be construed to prescribe (proscribe) methods of research.

RESPONSE: Most IACUCs have addressed the use using animals for the ascites method and have developed SOPs to minimize any pain and distress associated with this procedure. Moreover, the policy of the NIH has always been to allow investigators to select and justify (scientifically) the methods needed to solve a problem. Therefore, NIH's determination not to prohibit the use of mice in MAB production and not to propose a rule requiring the use of alternative methods is a reasonable exercise of its discretionary activity.

ISSUE: The Health Revitalization Act of 1993 does impose certain requirements on the NIH and briefly stated, they are:

  1. conduct and support research on methods to replace, reduce, and refine animal use;
  2. establish their validity and reliability;
  3. encourage their acceptance; and
  4. train scientists in their use.

RESPONSE: The NIH is already meeting these requirements for the production of MAB. (This statement is expanded below).

  1. Conduct and support research on alternative methods for producing MAB:

    Based on a survey of NIH-supported investigators and review of current literature: the NIH concludes that validated in vitro methods (ranging from static cultures to bioreactors) are available and used successfully by scientists to produce MAB. The NIH has supported hundreds of investigators who have contributed to the development of new or improved methods that permit further reduction in the use of living animals. These advances are often achieved in connection with other research goals aimed at the understanding human diseases. Literally, there is an "explosion" of recent literature on this topic that may be found in recent bibliographies and databases. This information is readily accessible or will be as publications or as listings on a Web-sites in Internet:

    • USDA, National Agricultural Library, Animal Welfare Information Center
    • NIH-Office of Extramural Research -- Computer Retrieval of Information on Scientific Projects (CRISP System)
    • Community of Science
    • National Academy of Sciences, Institute for Laboratory Animal Resources
    • NIH-National Library of Medicine
  2. Confirm validity and reliability of alternative methods for producing MAB:

    In addition to investigator-initiated grants, NIH core and center grants support Hybridoma Monoclonal Antibody facilities. Clearly these facilities are on the cutting edge of tissue culture-monoclonal antibody technology. One of the principal objectives of the cores and centers is the development of alternative methodologies for MAB production. At the present time 13 NIH Institutes and Centers support 64 projects in 20 states totaling over $10 M.

  3. Encourage acceptance of alternative methods for producing MAB:

    NIH Hybridoma Monoclonal Antibody facilities collect, store, distributes well-characterized cell lines to qualified scientists throughout the world. They also operate as a service to investigators and/or train them in the use of alternative methods.

    Support for MAB databases (see above).

    Recent support for a new database established by collaboration with other government, academic, private industry, and animal protection groups.

    Sponsor or co-sponsor congresses, meetings, workshops, symposia, such CAAT/OPRR, SCAW, PRIM&R, NIEHS, OPRR.

    Update Plan for the Use of Animals in Research in next NIH biennial report.

  4. Initiate training programs at the NIH on alternative methods for producing MAB:

    This requirement is fully met through the support of core facilities which provide training for scientists, including NIH intramural scientists, across the Nation.

Conclusions on the Use of Alternative Methods for Mab Production

  • The NIH:
    • Recognizes that valid, reliable alternative methods for MAB production are available and being used successfully by hundreds of scientists in many laboratories.
    • Will continue to support investigator-initiated research projects to develop new and improve current methodology for MAB production to replace, reduce, and refine the use of animals.
    • Will continue collect and distribute information on alternative methods for MAB production through its database accessible via Internet.
    • Will continue to fund hybridoma core and center facilities that support and train researchers in the use of alternative methods for MAB production.
    • Does not recommend prohibiting the use of the mouse ascites method for MAB production at this time, since a total ban could impede important biomedical research.

Regulatory Issues

Administrative Procedures Act: allows individuals to request regulatory amendments.

Health Research Extension Act of 1985: empowers the Secretary through the NIH Director to establish guidelines and vests authority in Institutional Animal Care and Use Committees to assure local compliance with the guidelines. The Act specifically states that the guidelines shall not be construed to prescribe methods of research.

Health Revitalization Act of 1993: Imposes certain requirements on the NIH to conduct and support research on; to establish the validity and reliability of; to encourage acceptance of; and to train scientists in the use of alternative methods.

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