IgA is the most prevalent antibody at mucosal sites, with important roles in immune defense by preventing invasion of pathogens. We previously demonstrated that IgA is a very potent stimulus to trigger myeloid immune cell activation, most notably as it induces neutrophil migration through interaction with the IgA Fc receptor (FcaRI). Unleashing the destructive capacity of neutrophils through IgA anti-tumour antibodies may represent an attractive opportunity in anti-cancer therapy.

Immunogenicity is one of the most complex issues to address in drug design and development and requires application of integrated platforms to mitigate the risk to your biologic. In this talk I will present our extensive experience using case studies to illustrate the range of solutions that ProImmune offers.

Immune-stimulating antibody conjugates (ISACs) are tumor-targeting antibodies conjugated with powerful innate immune stimulants, such as TLR7/8 agonists, and are capable of invoking localized, potent myeloid cell activation and the production of pro-inflammatory cytokines that favor a productive anti-tumor immune response. ISACs are active in preclinical in vivo models of cancer, and are highly efficacious by enhancing ADCP, promoting antigen presentation, immunological memory, and epitope spreading.

BioAtla pioneered the development of conditionally active antibodies (CAB) that are reversibly activated by the acidic tumor microenvironment in order to increase the therapeutic index of these cancer therapeutics. Preclinical and selected clinical data will be presented demonstrating the reduction of on-target, off-tumor toxicity, allowing for increased exposure and potency, while maintaining safety in all formats, including bispecific, ADC, CAR T and naked antibodies.

Death receptor 5 (DR5) is a TNF-family receptor that binds TRAIL, induces receptor trimerization and apoptosis in tumor cells. IgM efficiently clusters DR5 with enhanced cellular cytotoxicity, resulting in 5,000 fold increased potency compared to IgGs. Anti-DR5 IgM (IGM-8444) was efficacious in mouse xenograft tumor models. Combination of anti-DR5 IgM with chemotherapeutic agents enhanced the cytotoxicity in vitro and in vivo. IGM-8444 exhibited with little/no in vitro cytotoxicity using primary human hepatocytes. These data support clinical development of IGM-8444 for treatment of solid and hematologic malignancies, with an IND filing in 2020.

Antibody therapeutics are important for prevention or treatment of viral disease, especially for those people who haven't been or can't be vaccinated. Challenges to provision of antibody therapy, however, include how to best use in vitro data and animal models to adequately forecast human protection, and how to identify those molecules or cocktails potent enough to lower cost-of-goods for use in low to middle income countries. Thousands of antibody candidates have been mobilized by international groups of researchers against emerging and re-emerging viral threats like SARS-CoV-2, Ebola and Lassa viruses. We describe efforts of two international consortia, CoVIC and VIC, to identify and evaluate antibody cocktails against these viruses, with a particular focus on what structural biology reveals about epitopes recognized and cocktail choice.

Monoclonal antibodies have revolutionized the treatment of several human diseases, including cancer, autoimmunity, and inflammatory conditions and represent a new frontier for the treatment of infectious diseases. In the last decade, new methods have allowed the efficient interrogation of the human antibody repertoire from immune individuals and the swift isolation of potent, neutralizing monoclonal antibodies, including rare antibodies able to target conserved sites in highly variable viruses. In addition, new antibody engineering technologies have been and are developed to improve half-life and effector functions, to generate multi-specific antibodies, thus providing a potential for further augmented in vivo activity and reduced risk of viral escape. In the coming years, neutralizing monoclonal antibodies have the potential to be developed for the prophylaxis and therapy of viral infections, including those caused by newly emerging pathogens with a pandemic potential. In this presentation, Dr. Corti will provide an overview of the specificity, antiviral and immunological mechanisms of action of neutralizing monoclonal antibodies directed against multiple viral targets. The presentation will also introduce the concept of antibody-driven vaccine design, i.e. how the analysis of the human immune response have provided an innovative approach to the identification of protective antigens, which are the basis for the design of vaccines capable of eliciting effective B cell immunity.

The recurrent zoonotic spillover of coronaviruses into the human population underscores the need for broadly active countermeasures. Although we and others have identified broadly neutralizing antibodies that cross-neutralize SARS-CoV-2 and other SARS-related coronaviruses, in general, these antibodies achieve neutralization breadth at the cost of potency. Here I will describe our efforts to improve the SARS-CoV-2 neutralization potency of one such antibody by two orders of magnitude while retaining breadth across other sarbecovirueses. The affinity-matured antibody, ADG-2, displays strong binding activity to a large panel of sarbecovirus receptor binding domains, neutralizes representative sarbecoviruses with remarkable potency, and optimally triggers Fc-mediated effector functions. Structural and biochemical studies demonstrate that ADG-2 employs a unique angle of approach to recognize a highly conserved epitope overlapping the receptor binding site. In murine models of SARS-CoV and SARS-CoV-2 infection, passive transfer of ADG-2 provided complete protection against respiratory burden, viral replication in the lungs, and lung pathology. Altogether, ADG-2 represents a promising broad-spectrum therapeutic candidate for the treatment and prevention of SARS-CoV-2 and future emerging SARS-like CoVs.

We have characterized the humoral immune response in patients acutely infected with SARS-CoV-2 displaying a range of disease severity. Longitudinal samples spanning 1-6 weeks following symptom onset were obtained when available. Patient samples were evaluated by analyzing expressed IgG sequences from isolated blood plasmablasts. Plasmablast levels ranged from 0.3% to 28% of total blood B cells. Notably, higher plasmablast levels were associated with increased disease severity. We processed between 300 and 2,000 plasmablasts per sample and natively paired heavy and light chain IgG sequences were generated. Analysis of the IgG repertoires revealed expanded clonal lineages representing a majority of blood plasmablasts. Sequences from expanded clonal lineages displayed high levels of somatic hypermutation (SHM), although expanded lineages with low levels of SHM were also present. Further characterization of recombinant antibodies expressed from many of these lineages will be described.

In the absence of approved drugs or vaccines, there is a pressing need to develop tools for therapy and prevention of Covid-19. Human monoclonal antibodies have very good probability of being safe and effective tools for therapy and prevention of SARS-CoV-2 infection and disease. PBMCs from people who survived Covid-19 infection were used to isolate several hundreds of human monoclonal antibodies able to neutralize SARS-CoV-2.