Groundbreaking immunotherapies known as immune checkpoint inhibitors mobilize the immune system against cancer by blocking the protein interactions that suppress immune cell activation. However, limited response rates to these therapies necessitate the development of new molecules that act through alternative mechanisms. Here, we describe the discovery and design of multispecific antibody fusion proteins incorporating single-domain shark antibodies that improve upon clinical drugs, presenting a novel modality to advance cancer treatment.

A subset of cow antibodies have a heavy chain “ultralong” CDR3 region that can be over 70 amino acids in length, with a disulfide-bonded “knob” domain that protrudes far from the antibody surface. These knob domains can be produced independently of the antibody to generate tiny, high affinity, binding fragments. The novel genetics, structural biology, and biomedical applications of ultralong CDR3 antibodies will be discussed.

Ion channels are an important target class which are under-served by biologics. Maxion have shown that small cys rich peptides with ion-channel modulating activity can be inserted into antibody CDRs while retaining their function. The resulting molecules modulate ion channel activity while benefitting from the optimal drug-like properties of antibodies. This presentation will illustrate the generation and optimisation of KnotBody inhibitors to therapeutically relevant ion channel targets.

The pathogenicity of autoreactive antibodies has been demonstrated for many autoimmune diseases and the isotype/subclass profile can potentially influence the disease pathophysiology. Although often overlooked, IgA autoantibodies are increasingly recognized in different autoimmune indications. Here, we describe the development of anti-IgA monoclonal antibodies that can actively remove IgA from the circulation and block binding of IgA to its main Fc receptor FcαRI. Given the abundancy of IgA in human serum (1-3 mg/mL), both Fab and Fc engineering were optimized to design a monoclonal antibody with the desired properties.

Inhibitory checkpoint receptor (IR) agonists have the potential to restore immune homeostasis for patients with autoimmunity but are limited by their ability to non-discriminately bind activating FcγRs. IR agonists anchored to FcγRIIb, the inhibitory Fc receptor, have the potential to provide superior agonism by avoiding inflammatory cytokine responses and limiting APC activation. Discovery and development of a Dual-cell Bidirectional PD-1 FcγRIIb agonist antibody that activates multiple inhibitory pathways in more than one cell type to regulate both sides of the immune cell synapse will be discussed.

Although antibodies are actively explored as therapeutic for bacterial infections, their narrow specificity poses a challenge due to the broad diversity between bacterial species. We reveal that conversion of highly specific anti-staphylococcal IgGs into IgM induced cross-reactivity with a range of bacterial species.