Antibodies as drugs-a Keystone Symposia report.

Therapeutic antibodies have broad indications across diverse disease states, such as oncology, autoimmune diseases, and infectious diseases. New research continues to identify antibodies with therapeutic potential as well as methods to improve upon endogenous antibodies and to design antibodies de novo. On April 27-30, 2022, experts in antibody research across academia and industry met for the Keystone symposium "Antibodies as Drugs" to present the state-of-the-art in antibody therapeutics, repertoires and deep learning, bispecific antibodies, and engineering.

Antibody recognition of the Pneumovirus fusion protein trimer interface.

Human metapneumovirus (hMPV) is a leading cause of viral respiratory infection in children, and can cause severe lower respiratory tract infection in infants, the elderly, and immunocompromised patients. However, there remain no licensed vaccines or specific treatments for hMPV infection. Although the hMPV fusion (F) protein is the sole target of neutralizing antibodies, the immunological properties of hMPV F remain poorly understood. To further define the humoral immune response to the hMPV F protein, we isolated two new human monoclonal antibodies (mAbs), MPV458 and MPV465. Both mAbs are neutralizing in vitro and were determined to target a unique antigenic site using competitive biolayer interferometry. We determined both MPV458 and MPV465 have higher affinity for monomeric hMPV F than trimeric hMPV F. MPV458 was co-crystallized with hMPV F, and the mAb primarily interacts with an alpha helix on the F2 region of the hMPV F protein. Surprisingly, the major epitope for MPV458 lies within the trimeric interface of the hMPV F protein, suggesting significant breathing of the hMPV F protein must occur for host immune recognition of the novel epitope. In addition, significant glycan interactions were observed with a somatically mutated light chain framework residue. The data presented identifies a novel epitope on the hMPV F protein for epitope-based vaccine design, and illustrates a new mechanism for human antibody neutralization of viral glycoproteins.

Next-Generation Influenza HA Immunogens and Adjuvants in Pursuit of a Broadly Protective Vaccine.

Influenza virus, a highly mutable respiratory pathogen, causes significant disease nearly every year. Current vaccines are designed to protect against circulating influenza strains of a given season. However, mismatches between vaccine strains and circulating strains, as well as inferior vaccine effectiveness in immunodeficient populations, represent major obstacles. In an effort to expand the breadth of protection elicited by influenza vaccination, one of the major surface glycoproteins, hemagglutinin (HA), has been modified to develop immunogens that display conserved regions from multiple viruses or elicit a highly polyclonal antibody response to broaden protection. These approaches, which target either the head or the stalk domain of HA, or both domains, have shown promise in recent preclinical and clinical studies. Furthermore, the role of adjuvants in bolstering the robustness of the humoral response has been studied, and their effects on the vaccine-elicited antibody repertoire are currently being investigated. This review will discuss the progress made in the universal influenza vaccine field with respect to influenza A viruses from the perspectives of both antigen and adjuvant, with a focus on the elicitation of broadly neutralizing antibodies.