B and T cells collaborate to drive autoimmune disease (AID). Anti-CD20 antibodies provide targeted B-cell depletion (BCD), but some patients have refractory AID due to incomplete BCD. Novel therapies using T cells as effectors may disrupt B-T cell collaboration and overcome rituximab-resistant AID.

T cell activation is strictly regulated to allow for the development of adaptive immune responses. Excessive T cell activation underpins many autoimmune diseases. At the heart of the activation paradigm are co-stimulatory molecules, for example CD28, that act with signals from the T cell receptor (TCR) to promote adaptive immunity. Conversely, inhibitory receptors, for example, cytotoxic T lymphocyte associated protein 4 (CTLA-4) and programmed cell death-1 (PD-1) down-regulate T cell receptor (TCR) activation levels limiting adaptive immune responses and unwanted normal tissue damage. SAB03 is an anti PD-1 agonistic monoclonal antibody with a fully enabled Fc domain for the suppression and depletion of PD-1+pathogenic T cells.

The interleukin-2 (IL-2) cytokine plays an essential role in preventing the development of autoimmune disorders by supporting growth and activity of regulatory T cells (Tregs). IL-2 has great potential for autoimmune disease mitigation; however, its simultaneous stimulation of effector immune cells and short half-life limit clinical promise. We developed cytokine/antibody fusion proteins that bias IL-2 towards Tregs while also extending half-life, leading to clinically promising therapies to treat autoimmune diseases.

Nipocalimab is a fully human IgG1 monoclonal antibody that exhibits high specificity and affinity for the neonatal Fc receptor at both neutral and acidic pH. Nipocalimab facilitates a significant reduction in circulating IgG levels, including pathogenic IgG, which is implicated in various IgG-driven auto- and allo- antibody diseases. This investigational therapy is being evaluated across three critical disease segments: Rare Autoantibody—ranging from neurologic to hematologic diseases; Maternal Fetal Immunology and Prevalent Rheumatological autoantibody-driven diseases, in multiple potential indications, each with high unmet need. This presentation will delve into its molecular properties and highlight pivotal clinical data.

Neonatal Fc receptor is a popular target for treatment of autoimmune disorders due to its role in maintaining IgG levels. Development of next-generation FcRn blockers with improved pharmacodynamic effects and reduced frequency of dosing could be highly beneficial for patient quality of life and patient satisfaction. To achieve this, we generated and optimized Fc-ABDEGs equipped with albumin binding VHHs. Step-wise engineering was applied to optimize the position and number of VHHs, their affinity to albumin, and the linker connecting it to Fc-ABDEG. Novel FcRn-based cellular assays and human FcRn transgenic mice will also be addressed.

Specific inhibition of TNF receptor 1 has been challenging using conventional antibody-based therapeutics, due to potentially dangerous agonistic activity. We have successfully generated  de novo miniproteins that specifically inhibit TNFR1 but not TNFR2 with picomolar affinity in vitro and  in vivo, blocking pathogenic TNF-α signaling. This work reveals a novel mechanism of action for alleviating autoimmune disease by blocking TNFR1 activity while regulatory beneficial signaling through TNFR2 remains intact.

Venom-derived cysteine-rich miniproteins (knottins) have potential as therapeutic agents to block ion channels, but suffer from manufacturing difficulties, short half-lives, and a lack of specificity. Maxion has developed a novel molecular format wherein a peripheral CDR loop of an antibody has been replaced by a knottin. This format, termed a KnotBody, combines the benefits of both scaffolds with the antibody gaining the functionality of a scaffold pre-disposed to the blockade of ion channels—and the knottin enjoying the extended half-life and the additional specificity conferred by the antibody molecule. This presentation illustrates the generation and optimization of KnotBody inhibitors.

The agonistic activity of anti-CD40 antibodies is often linked to FcγR-mediated cross-linking. However, some anti-CD40 agonists, such as CP-870,893 (Selicrelumab), exhibit agonistic activity in vitro without FcγR crosslinking. In this study, we solved the crystal structure of CP-870,893 Fab in complex with CD40 receptor, revealing a unique mechanism of action, which was validated by mutagenesis. Furthermore, to address the short half-life and dose-limiting toxicities, we developed conditionally activated CP-870,893 variants.

Existing IBD therapeutics exhibit high costs, systemic safety risks, and require injections. Here, we present a workflow to develop oral VHHs via simultaneous optimization of the affinity and protease stability. This oral VHH matches the efficacy of an injected antibody in a murine colitis model and exerts a strong pharmacodynamic effect in non-human primates. With high potency, gut stability, and favorable developability, oral VHHs offer a promising approach for IBD.

Complex of HLA-DQ2.5/gluten peptides elicits gluten-specific CD4+ T cells activation in celiac disease patients. DONQ52 is a novel multispecific antibody aimed to bind cross-reactively to multiple gluten peptide loaded HLA-DQ2.5. DONQ52 has potential to neutralize immune response to gluten. Here we introduce antibody engineering strategy, including lead identification and lead optimization as well as broad reactive characteristics of DONQ52.

Antibodies specific to oxidative post-translational modifications (oxPTM) of insulin (oxPTM-INS) are present in most individuals with Type 1 diabetes (T1D), even before the clinical onset. We then observed antibody response to three oxPTM-INS neoepitope peptides (oxPTM-INSP) and evaluated their ability to stimulate both humoral and T cell responses in T1D. oxPTM-INS neo-antigenic epitopes, may be involved in the immunopathogenesis of Type 1 diabetes and potentially become targets for precision medicine.

Succinate, a metabolite produced by both the host and the microbiota, is not a mere TCA metabolite since it plays roles in cellular signaling of an inflammation. Chronic elevations of succinate, observed in various disorders, contribute to disease progression, highlighting the need for interventions able to modulate its effects, which have so far been unsuccessful. At SUCCIPRO we are developing first-in-class drugs able to directly modulate succinate, an undruggable target to date. Current candidates are in the final stage of lead optimization, and this talk will cover the journey from early in silico identification to successful in vivo efficacy studies.