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, essential for adaptive immunity, is tightly regulatedsince excessive activation can drive autoimmune diseases. Co-stimulatory molecules, such as CD28, enhance TCR signals tosupport immune responses, while inhibitory receptors like CTLA-4and PD-1 limit TCR activation, preventing tissue damage. SAB03,an anti-PD-1 agonistic monoclonal antibody, features an enabledFc domain to suppress and deplete pathogenic PD-1+ T cells,mitigating autoimmune effects.

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.

Existing strategies for cytokine delivery require extensive molecular engineering and format optimization, which necessitates intensive mutagenesis and adds immunogenicity and manufacturing risk. Here, we develop a novel highly modular platform for wild-type cytokine activation. We build prototype versions for four diverse cytokines to demonstrate selective activity (>1000-fold) in vitro and in vivo, as well as efficacy in a mouse disease model.

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-a 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.

Mast cells (MCs) play a significant role in various immune-related disorders. Their survival depends on KIT receptor activation by Stem Cell Factor (SCF). TSLP neutralization has demonstrated activity in asthma. CDX-622, a bispecific antibody, neutralized both SCF and TSLP in functional assays and resulted in MC depletion in a non-human primate study. CDX-622 offers potential benefits by targeting complementary pathways in chronic inflammation. A phase 1 clinical study is underway.

We have targeted the cannabinoid GPCR CB2R as a therapeutic approach in IBD. CB2R expression is upregulated with intestinal inflammation and chronic receptor activation worsens disease. Previous work shows CB2R drives T cell metabolism and promotes gut homing of T cells with formation of memory T cells. We describe here functional characterisation of candidate receptor antagonists selected from libraries of engineered peptides presented as stabilised, constrained loops with therapeutic potential.

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.

Myocardial infarction (MI) is a leading cause of heart failure. Emerging data shows that persistent inflammation after an MI contributes to heart failure. We find that an infarct targeted immunocytokine can dampen inflammation, promote cardiac tissue repair, and even prevent heart failure in mice after permanent ligation of the left coronary artery. This targeted immunotherapy offers an approach distinct from current interventions to address heart failure.

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.