The Binding Landscape of Serum Antibodies: How Physical and Mathematical Concepts Can Advance Systems Immunology

Abstract

Antibodies constitute a major component of serum on protein mass basis. We also know that the structural diversity of these antibodies exceeds that of all other proteins in the body and they react with an immense number of molecular targets. What we still cannot quantitatively describe is how antibody abundance is related to affinity, specificity, and cross reactivity. This ignorance has important practical consequences: we also do not have proper biochemical units for characterizing polyclonal serum antibody binding. The solution requires both a theoretical foundation, a physical model of the system, and technology for the experimental confirmation of theory. Here we argue that the quantitative characterization of interactions between serum antibodies and their targets requires systems-level physical chemistry approach and generates results that should help create maps of antibody binding landscape.

Deep physico-chemical characterization of individual serum antibody responses against SARS-CoV-2 RBD using a dual titration microspot assay

“…On the other hand, it is this [Ab] that efficiently maintains [Ag] at this level. Changing [Ag] will trigger B-cell receptor signals in memory B cells, leading to expansion and Ab production (43). Thus, the standard state corresponds to maximal relative thermodynamic activity and represents a steady state the immune system ideally maintains towards this particular antigen.…”

“…Again, we assume k=1. In this parametrization 𝜈 is the asymmetry parameter in the Richards function and the exponent of the corresponding Richards differential equation (43).…”

“…We assumed that the deconvolution of thermodynamic activity into quality and quantity, i.e., thermodynamic activity coefficient and concentration, would provide a solution for quantitative serology. We have recently developed a microspot-based, dual-titration immunoassay for the estimation of affinity distribution for multiple immunoglobulin classes (42) utilizing an advanced fitting algorithm (43). Here we describe a further improvement of the assay and its application for the characterization of anti-SARS-CoV-2 antibody response, by the estimation of chemical thermodynamic variables of SARS-CoV-2 RBD specific antibodies of various classes.…”

Complex Physical Properties of an Adaptive, Self-Organizing Biological System

“…Contraction comprises the death of B cell clones and concomitant selection for survival of those that contribute to thermodynamic steady state maintenance. During both the expansion and contraction phase, chains of biochemical interactions shape the landscape of chemical potentials as a result of overlapping conformational landscapes [3,6,7].…”

“…Therefore maintenance of molecular integrity requires the maintenance of constant concentrations of effector molecules, which are called antibodies in the case of humoral adaptive immunity. This is achieved by the adjustment of chemical potentials with the help of a sensor-effector feedback mechanism [3], which is the essence of the phenomenon we call immunity. The immune system is dynamic, continuously responding to environmental stimuli, but also shows a tendency to come to "rest", contract and reach a quiescent state.…”