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Alternatives to Monoclonal Antibody Production (Proceedings)

Monoclonal Production--An Industrial Perspective

DeWayne H. Walker, DVM
Laboratory Animal Research Service
 3M Corporation
 Minneapolis, MN

Let me commence this presentation by noting that I shall primarily dwell upon the generic big picture of monoclonal antibody (MAB) production in industry. I shall leave the more in depth, in the trenches, picture to my colleagues on the panel who have vastly more hands-on experience derived from their respective academic institutions.

I think first we need to define the term "industry" and gather an appreciation and realization of its typical goals and general mode of operation. From this start point we can perhaps begin to draw some conclusions about MAB production in an industrial setting. Secondly, we shall look generically at the Institutional Animal Care and Use Committee (IACUC), defining its role and responsibilities in relation to MAB production. And finally we will make a stab at the future of MAB production activity from an industrial perspective.

Although sheer size and name recognition gives the clear edge to pharmaceutical companies, the word "industry" is a composite. It includes cosmetic companies, household product and specialty chemical companies and medical device companies, augmented with biotechnology and contract service laboratories. Each industry that possesses in-house animal use capabilities for regulated species shares in common the mandates of the Animal Welfare Act, while falling under countless other regulatory mandates unique to the given industry. However, in the context of MAB production, the field narrows primarily to pharmaceuticals, biotechnology, and contract service laboratories.

I have purposely drawn my information from multiple sources, making Ma Bell wealthy in the process. I sought consensus opinion and perhaps had a premature expectation of a clear trend for MAB applications as the following statement best sums it up, "the only consistent thing is inconsistency." Despite this phone survey exercise being anything but conclusive, I will share the following perceptions:

  1. I have likely been naive in assuming that MAB production, whether it be via ascites production or in vitro methodologies, was a tool of primarily benchtop basic scientists with ownership primarily on the academic side of the ledger. Although my "n" was too small to draw any objective conclusions, my impression was that MAB production was a mainstay in the pharmaceutical and biotech industries not only in diagnostic production application but often being an integral part of drug discovery and testing.
  2. In-house MAB ascites production was, for the most part, centralized to gain operational efficiency. This is not unexpected given the industrial philosophy to avoid departmental redundancy and make cost-effective use of typically a large centralized animal facility. At the same time, industry appears to have a high trust in the quality of contract service laboratories supplying off-the-shelf MABs.
  3. What was a pleasing consistent finding was that industry, when using ascites production, invariably sought high ground on welfare concerns. The ILAR guidelines were routinely the minimum standard with corporate policies undergoing frequent updating to incorporate welfare-oriented refinements.
  4. Finally, although not sensing a feeling of urgency, I sensed that my colleagues in industry take the issue of ascites production very seriously. They recognize the ethical sensitivity of the issue and in numbers admit frustration with previous failed attempts at in-house in vitro methods. I found often that units possessed both in vivo and in vitro capabilities with the former supporting research and the later supporting high-volume diagnostics.

As the first speaker on this panel, I suggested to Drs. Etheridge and DeTolla that perhaps it would be of value to briefly discuss on behalf of academia and industry what the IACUC is all about. Whereas academia typically falls under the Office for Protection from Research Risk (OPRR) guidelines, consequential to National Institute of Health (NIH) funding, industry does not, given their intent to be profitable, and therefore, self-sufficient, and whereas industry is burdened with unique regulations such as those imposed by the Food and Drug Administration (FDA) and academia typically is not, the common ground is the Animal Welfare Act (AWA) and its mandates for an effective and accountable IACUC. Time does not permit a detailing of the multiple roles of this committee; however, it suffices to say that the committee has a significant fiduciary role in insuring the ethical and sensitive care and use of animals in research. When one gets into chapter and verse, there are several sections in which there are MAB production implications:

  1. The AWA regulations require the IACUC to determine that the Principal Investigator (PI) has considered alternatives to procedures that cause more than momentary or slight pain or distress to the animals and has provided a written narrative description of the methods and sources used to determine that alternatives were not available. This is the tough one for academia and industry alike. On paper the square can be filled by a PI providing a list of "key words" and a list denoting scientific databases that have been searched. The square has been filled but is this where the responsibility of the IACUC ends? This is the point when the investigator has the upper hand, especially in industry where the PI may represent the only "braintrust" on site possessing the status of expert on a given molecule. It would be my experience, exclusively on industrial IACUC's, that if a PI was advocating the need for ascites MAB production and if experts were not available, training of investigative staff was adequate with satisfactory veterinary care, an IACUC would be hard pressed to challenge the protocol. Academia may fare better given its basic science theme and departmental structure versus industry's individualized intense and exacting research.
  2. The AWA regulations also require that the PI provide written assurance that the activities do not unnecessarily duplicate previous experiments. Industry is generally very much in tune with meeting this IACUC requirement. A competitive edge goes to those staying well abreast of the literature and tight research and development timelines are not aided with duplicative efforts. Thus, I believe this requirement to be a relatively minor point in industry.
  3. The IACUC during the evaluation of a given protocol must evaluate and be assured that qualified and trained personnel are involved with the procedures. Industry prides itself on the skill level of those entrusted with animal care and manipulations. Centralization of facilities allows for better accountability and the unique regulations dictated by other agencies create an environment that encourages the enhancement of training skills and thorough scrutiny of same.

Future of MAB Production from Industry's Perspective

Bad News

  1. Industry has little to gain from being the benchtop basic scientist working on enhanced in vitro applications. The "publish or perish" philosophy is not pushed in industry as it is in academia.
  2. Industry has a good comfort level and track record with how they conduct ascites MAB production and has developed confidence in contract service laboratories which likewise may generate MAB by ascites production.
  3. Industry is very time conscious. Products may have great humanitarian incentives in addition to monetary gains but regardless of the motive, market timing is critical. This being the real world case, time and resources are prioritized to product development, not project development.
  4. And perhaps most important, industry has to generally have a cautious conservative approach to new technology. The impact of regulatory oversight and the concern about product litigation does not encourage the "risk taking" that may be necessary to embrace those in vitro technologies that may still be in the validation process.

Good news

  1. Industry typically moves en masse. Successes in in vitro MAB production in a company's laboratory will typically drive competitors to match the stakes thereby creating a flood of positive momentum.
  2. When "the rubber hits the road" it is profit that drives industrial incentives.

At the point when in vitro MAB can be demonstrated to provide a unit cost savings over existing in vivo methodologies, prior preferences, scientific freedom, and weak justifications for the ascites methodology will succumb to the push to enhance the bottom line.

This may be wishful thinking but I believe that industry will continue to be a reluctant but eventual momentum player in in vitro MAB technology.

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