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.

Wheeler Bio’s Portable CMC® open-source upstream and downstream platform processes generates a predictable, reliable, and scalable approach for accelerating the movement of molecules from discovery, through lead candidate selection, and into clinical manufacturing. The Portable CMC® platform and hybrid-mechanistic process model was developed using data from both stable bulk cultures (SBCs, also known as bulk pools) and derivative clones to enable well-controlled cell lines, high titers, process robustness, scalability, and speed-to-clinic

Each immune complex is unique and affects its own set of Fc functions. To treat the antibody as a sum of two independent domains, the Fab and Fc, is fraught with false assumptions that could negatively impact therapeutic development. SeromYx’s high-throughput GCLP platform enables the empirical and comprehensive determination of the antigen-specific Fc functional profile of therapeutic antibodies uncovering vital insights into their safety and immune mechanisms of efficacy upfront.

MYTX-011 is an investigational, pH-sensitive, vcMMAE ADC. It has been designed to benefit a broader population of patients whose tumors express lower/moderate levels of cMET. MYTX-011 drives increased internalization and cytotoxicity and shows robust activity in xenograft models across a range of levels of cMET expression. Early clinical data demonstrate a differentiated profile: extended PK, low free MMAE release, and low incidence of side effects commonly associated with vcMMAE ADCs.

Chain exchange technologies can be used to generate binder-format matrices of bispecific antibodies. Similar to the optimization of bsAbs, chain-exchange can also generate ADC-matrices by combining different binders, formats, attachment-positions and payloads. As an example, a Her2-ADC matrix with payloads attached in different formats, positions and stoichiometries reveals that ‘format-defines-function’ applies not only to bsAbs but also to ADCs.

Payload resistance is a critical concern for ADCs. Combinations may be beneficial but therapeutic windows are limited. Hummingbird Bioscience's dual-payload ADC platform is a targeted, single-agent approach designed to overcome resistance and maximize therapeutic window. HMBD-802, an anti-HER2 dual-payload ADC shows robust efficacy in trastuzumab deruxtecan resistant models and good tolerability.

99% of a dose of an ADC is eliminated by normal tissues, causing efficacy limiting toxicities. Shasqi has developed an approach to overcome this problem by separating tumor binding from the payload and enabling selective payload activation at the tumor using click chemistry. This approach maximizes efficacy and therapeutic index by reducing toxicities.

Radiolabeled antibodies are essential in cancer theranostics and radio-immunotherapy (RIT) due to their high specificity for cancer antigens. While promising, RIT faces challenges including long half-life leading to prolonged radioactivity exposure. This presentation explores strategies to improve RIT efficacy and safety, including combination therapies with drugs that modulate radiation response or interact with the immune system, as well as antibody modifications, and optimized administration techniques.

Immunostimulatory antibody conjugates (ISACs) often rely on Fcγ receptor (FcγR) interactions to activate immune cells and drive tumor regression. However, these interactions may also contribute to immune-related side effects. To address this, we are developing deglycosylated ISACs that bypass FcγR binding. Tested in HER2+ breast and Trop2+ pancreatic cancer models, these ISACs maintained potent tumor-specific immune activation while potentially minimizing off-target effects. Ongoing studies are exploring the link between immunogenicity and FcγR binding.