Therapeutic antibodies, vaccines and antibodyomes

Abstract

The potential for antibodies to act as "magic bullets" for treatment of human disease was recognized a century ago, but its full realization has began to occur only during the last decade. A key to their current success is the ability to make libraries of antibodies/B cells, isolate a single species, and engineer it to be safe, efficacious and of high quality. Despite this progress, major challenges to the effective prevention, diagnosis and treatment of a vast majority of diseases remain. Limited success in the development of effective vaccines against diseases such as AIDS and cancer reflects our incomplete understanding of how antibodies are generated and function. Only a miniscule number of antibodies are characterized out of the universe of antibodies generated by the immune system. Knowledge of antibodyomes-the complete sets of antibodies-could help solve these and other challenges.

Figure 1

Generation of libraries of engineered antibody domains for selection of small-size high-affinity binders of minimal immunogenicity by grafting or by gene synthesis using information for human CDRs from antibodyome explorations.

Figure 2

Enhanced elicitation of known antibodies by using primary and secondary immunogens. B cells expressing germline BCRs are activated by binding to a primary immunogen. The maturation pathway through intermediate antibody(ies) to the mature antibody is denoted by black lines. The intermediate BCR(s) cross-reacts with a secondary immunogen(s) leading to further diversification until the mature antibody is elicited. An example with eight mutations is shown where (1) denotes the space of all possible mutants for one mutation (about 200 positions × 20 residues = 4 × 10³ possible mutants); (2) (denoted by –) corresponds to x i.e., about 16 × 10⁶ etc., schematically showing the exponentially increasing number of possible mutants and complexity of possible maturation pathways.

Figure 3

Possible implications of antibodyome exploration.