Abstract
As we continue to explore the merits of hybridoma technology in our 40th year of publication celebration, we do so realizing that antibodies have become critical reagents and transformative tools used to diagnose and treat disease. In this issue, Srini Kaveri and colleagues highlight the elements of polyclonal and monoclonal antibodies in disease treatment. In this context, the merits of antibody presentation—poly versus mono—depends on the context that takes advantage of their inherent properties. The core benefits of polyclonal antibodies center on two inherent properties: clonal and biophysical diversity. The “poly” clonality of polyclonal antibodies allows the binding of multiple antigenic determinants of a target. While arising from different immune cells they can have avidity for the same antigen but different epitopes. Monoclonal antibodies being made from identical immune cells are all clones of a specific parent cell. These two properties are the basis of numerous advantages that polyclonal antibodies offer relative to their monoclonal or recombinant counterparts.(1,2)
The multiepitope binding properties of polyclonal antibodies have clear benefits. Polyclonal antibodies frequently have better specificity than monoclonal antibodies because they are produced by a large number of B cell clones each generating antibodies to a specific epitope, and polyclonal sera are a composite of diverse antibodies with some having unique specificities. The heterogeneous interaction of several different epitopes and/or antigens by polyclonal antibodies renders these reagents more likely to successfully interact with a specific antigen. Hence, vaccines for SARS-CoV-2 emphasize responses to the spike protein in a poly-determinate way that has been emulated by the use of multiple monoclonal antibodies or cocktails for SARS-CoV-2 treatment. This suggests that “more” can be better.
The “more” may be related to antigen presentation as can be observed in tumor antigens. Antigens can be multivalent, presenting multiple identical epitopes (homopolymeric), or they can present multiple distinct epitopes. Low-affinity antibodies may yield high avidity because of multivalent interactions. This is best illustrated by the successful use of therapeutic IVIG composed of polyclonal natural antibodies with low affinity but higher avidity. This aspect might be related to the successful use of convalescent plasma antibodies derived from SARS-CoV-2–infected patients to treat other patients.(3) Substantial evidence of benefit with prior use for viral infections offered strong precedent for such an approach.
There are many antibody-based molecules that are in different stages of phase I/II/III clinical trials targeting new unique targets.(4,5) Every year a good percentage of approved drugs comprised monoclonal antibodies. Monoclonal antibodies, in contrast, function well with homopolymeric antigens when epitopes are presented in a manner that does not sterically inhibit binding. The idea of a cocktail of monoclonal antibodies can relate to the emergence of new variants in the context of SARS-CoV-2. In this context, the ability to generate monoclonal antibodies in a rapid way can lend to higher ordered cocktail numbers of a precise nature because of their inherent clonality over polyclonal antibodies, especially when there is concern for variants of a virus. Yet, in the end, the use of cocktails of monoclonal antibodies can be described as a mimic application of the inherent clonal and biophysical diversity of polyclonal responses to antigens.