The use of adeno-associated virus (AAV) for gene therapy delivery shows significant potential in treating various muscle diseases. We have developed a bispecific antibody that binds to AAVs and retargets them to skeletal muscles via a skeletal muscle-specific protein. This approach enables enhanced AAV transduction in skeletal muscles while greatly reducing off-target transduction in other tissues.

Monospecific therapeutics in inflammatory indications often are limited in their efficacy, while blockade of multiple pathways may enhance efficacy and benefit to patients. We describe design and engineering of PF-07275315 and PF-07264660, trispecific antibodies currently in Phase 2 studies in atopic dermatitis and other indications. These antibodies combine mechanisms with demonstrated efficacy across a range of atopic and inflammatory conditions by simultaneously neutralizing IL-4, IL-13, and TSLP or IL-33.

Tolerogenic cytokines play an essential role in regulating immune responses and controlling aberrant immune activation. However, natural recombinant cytokines exhibit undesirable drug-like properties with short half-lives and toxicity. Here, we describe the design and engineering of cytokine-agonistic antibodies for the treatment of autoimmune inflammation.

Most current autoimmune therapies act through nonspecific suppression of the immune response, leading to global immunosuppression and deleterious off-target effects for patients. Antigen-specific immunotherapies are needed that restore selective immune tolerance against the offending autoantigen and autoreactive cells. Certain mucosal sites such as the gut and lungs are an attractive target for antigen-specific immunotherapies as they are inherently predisposed to induce tolerance upon antigen exposure. Yet 'mucosal tolerance' approaches have yet to successfully translate to the clinic, a major barrier being the challenges of drug delivery for proteins and biologics in mucosal tissues. Antigen delivery systems that avoid degradation and mucosal clearance while achieving efficient mucosal uptake at lower doses would address this gap. Here, we present engineering strategies to restore antigen-specific tolerance in autoimmune diseases, using protein engineering combined with targeted drug delivery to create molecular platforms with tunable kinetics, with a focus on ‘tuning’ molecules for mucosal delivery.

Significant progress in inflammatory bowel disease (IBD) over the last two decades has yielded approved biologic and small-molecule therapies targeting inflammatory cytokines (TNF-alpha, IL-23) and leukocyte trafficking. Despite this, the majority of IBD patients fail to achieve long-term durable remission in response to therapy and predictive biomarkers are lacking. Patients are often diagnosed at a young age, and achieving personalized medicine and a definitive cure remains the primary goal. 

Despite new options for long-term management of autoimmune disease, there is significant unmet need for treating acute crisis and flares. IgG proteases can bridge short term crisis management with long term reduction of autoantibody levels. IgG proteases rapidly (in minutes) and deeply (>99% reduction) deplete IgG at catalytic doses that are ideal for convenient subcutaneous administration, including degradation of autoantibodies already bound to antigen. CYR212 is an engineered IgG protease of bacterial origin, modified using AI tools and rational design, for best-in-class potential. Long PK-PD, low immunogenicity, and fast recovery from antibody-mediated disease are demonstrated in in vivo models.

Accurately predicting treatment response to biologics in rheumatoid arthritis is essential for improving outcomes and reducing trial-and-error prescribing. This talk will review recent advances in multi-omics profiling, machine-learning models, and clinical biomarkers that enable earlier identification of likely responders. Case studies will illustrate how integrating molecular signatures with real-world data can refine patient stratification and guide development of next-generation targeted therapies for RA.

S-4321 is a novel dual-cell bidirectional agonist that selectively binds and signals through the inhibitory receptors PD-1 and FcβRIIb at the synapse between a T cell and an antigen-presenting cell. Unlike first-generation PD-1 depleters, S-4321 has the potential to restore immune homeostasis without causing loss of PD-1 expression on T cells, induction of pro-inflammatory cytokines, or depletion of PD-1+ Tregs.

In Type 1 diabetes (T1D) oxidised insulin (oxPTM-INS) can be detected even before the clinical onset. Antibody response to oxPTM-INS neoepitope peptides (oxPTM-INSPs) and stimulate humoral and T cell responses in T1D. Biased human antibody library from T1D donors raised specific oxPTM-INS antibodies. Selected mAbs bind specifically to inflamed islet and may have a significant impact on the treatment of T1D.

Autoimmune diseases often involve a repertoire of autoantigens as drivers of disease. However, a single autoantigen or small subset can drive immune responses, particularly at early stages of disease. Autoantigen-drug conjugates aim to selectively cull or re-educate the offending autoimmune cells. Our approaches to link autoantigen to various drugs will be presented and our work in Type 1 Diabetes will be emphasized.

Xencor is advancing a portfolio of bispecific antibodies designed to restore immune balance in autoimmune disease. We will share translational data from XmAb657 (CD19xCD3), which achieves potent, sustained depletion of B-lineage cells in tissues after a single dose, plamotamab (CD20xCD3) transitioning from oncology to autoimmunity, and a novel IL2RG-directed bispecific that modulates γc cytokine pathways to temper autoreactive T-cell activity. Together, these programs highlight versatile engineering approaches to immune modulation.

Regulatory T cells (Tregs) can modulate the immune system with antigen specificity in transplant rejection and autoimmunity. Yet, antigen-specific Tregs are vanishingly rare and the key antigens are often unknown. Synthetic biology can impart any desired specificity to Tregs. Human pluripotent stem cells (hPSCs) can be differentiated into every cell type in our body. We are co-engineering hPSCs and Tregs such that chimeric antigen receptor (CAR) Tregs protect CAR target-expressing hPSC-derived beta cells from immune attack in humanized mice. Moreover, we modified Tregs with a chimeric anti-HLA antibody receptor (CHAR) to specifically inhibit alloreactive B cells in HLA pre-sensitized patients.