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Herceptin and Monoclonal Antibodies

As per usual, Dr Ringach has told only half the story about monoclonal antibodies and Herceptin.

Antibodies are immunoglobulins and were historically referred to as gamma globulin or more accurately gamma globulin proteins. Immunoglobulins are made by the body’s immune system to kill invaders like viruses. Monoclonal antibodies (MAbs) are antibodies that have been manufactured from just one kind of immunoglobulin and thus are very specific in what they target.

In 1975, Köhler and Milstein described how MAbs could be manufactured. Their research was performed on mice and the first MAbs given to humans were mouse MAbs. That is when the trouble started.

I have always said that animals could be used to learn about properties that are common among species. (The fact that blood goes in a circle was learned by experimenting on frogs and horses, among other animals.) The problem with this kind of trans-species extrapolation is that one does not know which properties are common until one has studied both animals and humans. Many times scientists could have skipped the animal step. (See Strip Mining For Oil.) Regardless, science has used animals in the past to learn things that eventually were applied to humans. I have stated this repeatedly. (See The 9 Ways Animals Are Used in Science as well as Animal Models in Light of Evolution and FAQs About the Use of Animals in Science: A handbook for the scientifically perplexed.)

I have also stated repeatedly (see references above) that animals could be used as bioreactors to manufacture chemicals of importance to humans. For example, insulin was harvested from pigs and cows for decades in order to treat diabetes. It worked! Similarly, MAbs could be harvested from mice. But they did not work in humans. (Even bovine and porcine insulin were problematic as some humans suffered adverse reactions similar to what I am about to describe for MAbs.)

In the 1980s MAbs were thought to be a promising area of exploration for cancer treatment. The MAbs were made by injecting mice and having them produce the antibody. Problem was, when the antibodies that came from mice were injected into humans, the small pieces of protein molecules that came with the antibodies from the mice produced an immune reaction. HAMA (human anti-mouse antibodies) reactions in the humans rendered the treatment useless. Research sagged after that (another delay due to animal use). Huls et al. in 1999:

Despite their enormous potential as therapeutic agents, monoclonal antibodies of nonhuman origin have performed poorly in clinical trials as a result of immunogenicity, poor pharmacokinetic properties, and inefficiency in recruiting effector functions. (Huls et al. 1999)

Herceptin, and other MAbs, are now made by substituting human proteins where the mouse proteins were and by using recombinant DNA technology. Monoclonal antibodies can now be made without animals thus obviating the problem altogether. (Hoyle 1998)

The comments of Loisel et al. in Crit Rev Oncol Hematol 2007 are relevant for my position on using animal models:

Animal models are not suitable for predicting the immunogenicity of therapeutic mAbs in humans, and transposition of the immunogenic potential of therapeutic antibodies in animals to the human situation has no scientific rationale, even in primates. (Emphasis added.)

Animals simply cannot predict human response to drugs and disease and yet that is how their use is sold to society. This fact is not disputed except by those whose livelihoods depend (or used to depend), directly or indirectly on the process. A second issue, which we address in our article Is the use of sentient animals in basic research justifiable? is whether the return on basic research using sentient animals is justifiable given society’s position on using animals in ways unlikely to produce treatments and cures. This article, contrary to the way it was described by Dr Ringach, is not an ethics article per se (hence no ethics arguments) rather it is a discussion about societal norms and how science and scientists should respond. I think what upset Dr Ringach was seeing, in a peer reviewed, indexed journal, the argument, with supporting references, outlining just how poor a track record basic science using sentient animals really has.

Thus the straw man arguments conflating using animals as bioreactors with using animals as predictive models and or using animals in basic research in general. (For more on this topic in general see Claims Versus Proof and Past Research Using Animals and Specific Claims About Basic Research.)

As you can see from the many above links to previous blogs, I am repeating myself as many of Dr Ringach’s criticisms have been addressed many times. (The surfactant story is similar to what I have written before but since I have not addressed it specifically, I will write it about later.) His posts rely on an uncritical and superficial examination of a breakthrough or treatment with appeal to emotion and on lumping all uses of animals together in order to make sweeping generalizations. People who use arguments like that can never be convinced by science and reason. But I will continue to address his arguments until he lapses into argument ad nauseam, which he surely will.


Hoyle, R. 1998. Genentech is poised for an anti-cancer breakthrough. Nat Biotechnol 16 (10):887.

Huls, G. A., I. A. Heijnen, M. E. Cuomo, J. C. Koningsberger, L. Wiegman, E. Boel, A. R. van der Vuurst de Vries, S. A. Loyson, W. Helfrich, G. P. van Berge Henegouwen, M. van Meijer, J. de Kruif, and T. Logtenberg. 1999. A recombinant, fully human monoclonal antibody with antitumor activity constructed from phage-displayed antibody fragments. Nat Biotechnol 17 (3):276-81.


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