Progress and challenges for the machine learning-based design of fit-for-purpose monoclonal antibodies

Although the therapeutic efficacy and commercial success of monoclonal antibodies (mAbs) are tremendous, the design and discovery of new candidates remain a time and cost-intensive endeavor. In this regard, progress in the generation of data describing antigen binding and developability, computational methodology, and artificial intelligence may pave the way for a new era of in silico on-demand immunotherapeutics design and discovery. Here, we argue that the main necessary machine learning (ML) components for an in silico mAb sequence generator are: understanding of the rules of mAb-antigen binding, capacity to modularly combine mAb design parameters, and algorithms for unconstrained parameter-driven in silico mAb sequence synthesis. We review the current progress toward the realization of these necessary components and discuss the challenges that must be overcome to allow the on-demand ML-based discovery and design of fit-for-purpose mAb therapeutic candidates

Computational antibody repertoire analysis and design

Antibodies are the core element of human humoral immunity. Advancements in sequencing technologies coupled with a remarkable decline in sequencing cost have been fueling the interest in B cell receptor (BCR) and antibody sequencing. Indeed, BCR sequencing have been rapidly improving our understanding of humoral immune responses in health and disease, as well as aiding the development of novel antibody therapeutics and diagnostics. However, the application of BCR sequencing have just been adopted in the last decade. Thus, several questions in human immunology remains unanswered. Within the scope of this thesis, we firstly aim to study the effect of antiretroviral therapy on the BCRs of a large cohort of HIV patients. Secondly, we harness the power of BCR sequencing for the characterisation of novel memory B cells of the IgD antibody isotype. Lastly, we suggest a new approach to utilise the BCR sequencing public data to understand the developability of the native antibody repertoire, and leverage this knowledge for the design of new antibody medicines

Adaptive immune receptor repertoire analysis

B cell and T cell receptor repertoires compose the adaptive immune receptor repertoire (AIRR) of an individual. The AIRR is a unique collection of antigen-specific receptors that drives adaptive immune responses, which in turn is imprinted in each individual AIRR. This supports the concept that the AIRR could determine disease outcomes, for example in autoimmunity, infectious disease and cancer. AIRR analysis could therefore assist the diagnosis, prognosis and treatment of human diseases towards personalized medicine. High-throughput sequencing, high-dimensional statistical analysis, computational structural biology and machine learning are currently employed to study the shaping and dynamics of the AIRR as a function of time and antigenic challenges. This Primer provides an overview of concepts and state-of-the-art methods that underlie experimental and computational AIRR analysis and illustrates the diversity of relevant applications. The Primer also addresses some of the outstanding challenges in AIRR analysis, such as sampling, sequencing depth, experimental variations and computational biases, while discussing prospects of future AIRR analysis applications for understanding and predicting adaptive immune responses

Individualized VDJ recombination predisposes the available Ig sequence space

The process of recombination between variable (V), diversity (D), and joining (J) immunoglobulin (Ig) gene segments determines an individual's naive Ig repertoire and, consequently, (auto)antigen recognition. VDJ recombination follows probabilistic rules that can be modeled statistically. So far, it remains unknown whether VDJ recombination rules differ between individuals. If these rules differed, identical (auto)antigen-specific Ig sequences would be generated with individual-specific probabilities, signifying that the available Ig sequence space is individual specific. We devised a sensitivity-tested distance measure that enables inter-individual comparison of VDJ recombination models. We discovered, accounting for several sources of noise as well as allelic variation in Ig sequencing data, that not only unrelated individuals but also human monozygotic twins and even inbred mice possess statistically distinguishable immunoglobulin recombination models. This suggests that, in addition to genetic, there is also nongenetic modulation of VDJ recombination. We demonstrate that population-wide individualized VDJ recombination can result in orders of magnitude of difference in the probability to generate (auto)antigen-specific Ig sequences. Our findings have implications for immune receptor–based individualized medicine approaches relevant to vaccination, infection, and autoimmunity