“Why Not Hybridomas”

As we begin our 40th year of publication, we will highlight important aspects of “Why Hybridomas.” On our journal webpage, we republish the very first article of our journal authored by George Köhler with that title.⁽¹⁾ Monoclonal antibodies have become our mainstay in understanding immunology and as therapeutics and diagnostics.⁽²⁾ They can serve as substitutes of immune-generated polyclonal antibodies, mimicking the immune system in targeting antigens. The development of monoclonal antibodies is often touted as giving rise to some of the greatest achievements in biological sciences in the 21st century, especially as drugs. Their unlimited production with predetermined specificity has opened up completely new fields for theoretical and applied biomedical research and allows precise diagnosis and treatment of disease.^(3,4) Yet we did know a lot before monoclonal antibodies. Polyclonal antibodies provided insight into immunological complexities and did provide the ability to identify and quantify specific proteins of interest within complex biological environments.

Niels Jerne who shared the 1985 Nobel Prize with Köhler, and Millstein relied on polyclonal antibodies to interrogate three theories (1) that antibody specificity is predetermined, (2) that reactivity against self-antigens creates diversity, and (3) that antibody interactions with each other provide for immune system regulation. It is this third theory that provides the backdrop of the perspective “The impact of the hybridoma technology on the R&D of idiotypic antibodies” written by Heinz Köhler in this issue. Heinz is an acknowledged thought leader in understanding the immunobiology of idiotypes and in developing anti-Id vaccines, being among the first to show that indeed they can be developed.

In The Network Theory from 1974, Jerne explained how the specific immune response is regulated.⁽⁵⁾ In this theory, networks are formed by antibodies eliciting anti-antibodies directed against antigen binding structures on the first antibody. Moreover, anti-antibodies can stimulate the production of generations of antibodies. Theoretically, this antibody cascade is endless, successively adding new specific properties to the immune system. Jerne's and other investigators' observations are the epidemy of systems immunology.

Medically, polyclonal antibodies have been less forthcoming principally because of regulatory issues, although intravenous immunoglobulin (IVIg) is medically useful and in our present pandemic, convalescent plasma antibodies have shown utility.^(6,7) Examples where the network theory has been applied to experimental and clinical settings while noteworthy are also less than stellar as discussed in Kohler's perspective. Nevertheless, applications can be found in arenas associated with Infectious diseases, Allergy, Autoimmune disease, Transplantation, Endocrinology, and Cancer. Although hybridoma technology is giving way to antibody development from phage display technology, the “Why Hybridomas” article originally was a question of choosing a technology to generate antibodies over other approaches.⁽¹⁾ “Why Hybridomas” might also be a question in a different setting. Is it always easier to generate monoclonals to protect a population at the time of an outbreak in a much shorter time as compared with vaccine production? Interestingly, passive administration of a monoclonal antibody has the potential to start a cascade as effective as vaccines that are designed to stimulate antibodies. Finding the right monoclonal or a cocktail of antibodies to stimulate the cascade was and remains the challenge. Consequently, antibody discoveries are made every day to support a wide range of in vivo applications.