Self Interest: Autoimmune Disease Pipeline and Deal-Making in 2026

The Landscape

Autoimmune disease results from biological mutiny: the normally protective, self-regulating immune system turns on its host, driving debilitating, chronic, and incurable conditions estimated to afflict 5-10% of the global population. There are somewhere between 80 and 150 distinct autoimmune diseases, those of highest prevalence in Western countries being rheumatoid arthritis, Type 1 diabetes, psoriasis, celiac disease, and Hashimoto's thyroiditis. Causation is far from understood, with genetics, environmental factors, infection, lifestyle, and gender (women bear a greater autoimmune burden than men) being known contributors.

Whether organ-specific (as in Type 1 diabetes or multiple sclerosis) or systemic (as in rheumatoid arthritis or lupus), autoimmune pathology is driven by aberrant T and B cell responses: autoreactive T cells that directly damage tissue or release pro-inflammatory cytokines, and autoreactive antibodies that trigger complement-mediated destruction and inflammation. Both arms of the adaptive immune system are now the focus of intensive drug development and deal-making activity.

From Corticosteroids to Cytokine Blockade

Pharmacologic management of autoimmune conditions was once limited to non-steroidal and corticosteroid anti-inflammatories, disease-modifying anti-rheumatic agents such as methotrexate and leflunomide, and broadly acting immunosuppressants such as hydroxychloroquine and sulfasalazine. Autoimmune disease treatment, along with biopharmaceutical industry earnings, was revolutionized in the late 1990s with the introduction of cytokine-neutralizing biologic agents, which gained rapid label expansion to encompass rheumatoid arthritis, inflammatory bowel disease, and psoriasis indications. At peak, the anti-tumor necrosis factor (TNF) antibodies infliximab (Remicade®) and adalimumab (Humira®), and the fusion protein etanercept (Enbrel®), generated annual revenues of $8 billion, $21.2 billion, and $8 billion respectively before the onset of biosimilar competition.

Newer anti-cytokine agents such as ustekinumab (Stelara®), a dual IL-12/IL-23 inhibitor; risankizumab (Skyrizi®), an anti-IL-23 inhibitor; secukinumab (Cosentyx®), an IL-17A inhibitor; and vedolizumab (Entyvio®), which targets the α4β7 integrin present on gut-homing T helper cells, have all returned recent annual sales in the $5 billion to $10 billion range. Small molecule oral Janus kinase (JAK) inhibitors such as tofacitinib (Xeljanz®), upadacitinib (Rinvoq®), and filgotinib (Jyseleca®), which act by inhibiting cytokine signaling, currently generate multibillion-dollar sales across autoimmune disease indications.

While these therapies have vastly improved the quality of life of millions of patients, substantial scope remains for improvements in response and adverse event rates: no current autoimmune treatment is curative. Deeper understanding of immune surveillance, checkpoint regulation, and cytokine signaling has transformed cancer treatment, and biopharma is looking to bring about a comparable revolution in autoimmunity through a focus on new targets and modalities that may offer the prospect of functional cure for some conditions. Autoimmune drug development interest has led to a surge in deal-making over the past two years, with established players forming partnerships with, or acquiring, specialty companies offering biologic, small molecule, and cell therapy assets and enabling technologies.

Betting on B Cell Depletion

B cells play a central role in autoimmunity, principally through autoantibody production but also by promoting T cell involvement through antigen presentation and cytokine secretion. Rituximab (Rituxan®), a therapeutic antibody specific for CD20, a B cell marker, has been used therapeutically as a B cell-depleting agent in refractory rheumatoid arthritis for close to two decades. The more recently approved anti-CD20 antibodies ocrelizumab (Ocrevus®) and ofatumumab (Kesimpta®) are indicated in the treatment of multiple sclerosis.

CAR-T Cell Therapy: From Oncology to Autoimmunity

Potentially more effective B cell depletion treatments are in the works. Chimeric antigen receptor T (CAR-T) cell therapy, originally developed for the treatment of refractory B cell hematologic malignancies, is highly effective in achieving complete B cell depletion and can root out B cells in antibody-inaccessible tissue compartments. Investigational use of CAR-T cells specific for the B cell markers CD19 or BCMA in autoimmune conditions including systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and myasthenia gravis has generated impressive outcomes.

Clinical-stage candidates include CD19 NEX-T (BMS-986353; Bristol Myers Squibb), which has completed Phase I evaluation in patients with refractory systemic sclerosis, systemic lupus erythematosus, and idiopathic inflammatory myopathies: 94% of study subjects were able to discontinue chronic immunosuppressive treatment. Other autologous CD19-specific CAR-T candidates include KYV-101 (Kyverna Therapeutics), in Phase II evaluation in Stiff Person syndrome and myasthenia gravis; and rese-cel (CABA-201; Cabaletta Bio), in Phase I/II evaluation in systemic lupus erythematosus and other conditions. Descartes-08 (Cartesian Therapeutics), currently in Phase III development in generalized myasthenia gravis, eschews viral vector T cell transformation and uses mRNA encoding a CAR targeting BCMA.

Allogeneic and In Vivo Alternatives

Allogeneic cell therapy has caught the eye of global biopharma companies. AstraZeneca acquired EsoBiotec to access the company's Engineered NanoBody Lentiviral T cell engineering platform for up to $1 billion. Capstan Therapeutics was acquired by AbbVie for a headline value of $2.1 billion on belief in its early clinical lead asset, CPTX2309 (now designated ABBV-619), a lipid nanoparticle-formulated mRNA encoding CD19 for delivery to CD8+ T cells, and the CellSeeker enabling technology. Eli Lilly entered CD19-targeting in vivo cell therapy development with the acquisition of Orna Therapeutics for its preclinical candidate, ORN-252, and the company's LNP-delivered circular RNA technology, for up to $2.4 billion. BMS acquired a similar technology through the purchase of Orbital Therapeutics, along with preclinical candidate OTX-201.

T Cell Engagers for Scalable B Cell Depletion

T cell engagers also offer the advantage of scalable, off-the-shelf B cell depletion. The bispecific antibodies blinatumomab (Blincyto®; CD19×CD3) and teclistamab (Tecvayli®; BCMA×CD3) are approved for hematologic cancer indications and both have shown efficacy in the treatment of refractory autoimmune conditions, including rheumatoid arthritis, systemic sclerosis, and Sjögren's syndrome, in investigational studies.

CLN-978 (Cullinan Therapeutics) is an extended half-life CD19×CD3 bispecific in early clinical development in rheumatoid arthritis, systemic lupus erythematosus, and Sjögren's syndrome. Antengene's preclinical CD19×CD3 bispecific ATG-201 incorporates steric blocking of the CD3 to reduce off-target T cell activation; global rights were acquired by UCB for approximately $1.2 billion ($80 million upfront and near-term, plus more than $1.1 billion in milestones). Prolium Bioscience is betting on CD20 targeting, and PRO-203, a CD20×CD3 bispecific, will shortly enter clinical development in systemic sclerosis.

Candid Therapeutics holds two preclinical trispecific T cell engagers (one licensed from WuXi Biologics): CND319 (CD19×CD20×CD3) and CND460 (BCMA×CD19×CD3), in addition to two early clinical-stage bispecific candidates. Cizutamig (BCMA×CD3) and CND261 (CD20×CD3) have both shown promise across several autoimmune conditions. Boehringer Ingelheim acquired the rights to CDR-111, a preclinical trispecific (CD19×BCMA×CD3) T cell engager, a product of CDR-Life's M-gager antibody fragment technology, in a deal worth up to $570 million.

Zenas Biopharma has taken a different approach with obexelimab, a CD19×FcγRIIb bispecific that results in reversible B cell inhibition rather than depletion. Obexelimab is in a Phase III immunoglobulin G4-related disease study. Japanese rights have been acquired by BMS for an upfront of $50 million, and the company struck a deal with Royalty Pharma on the strength of future obexelimab sales to secure $300 million for late-stage clinical development.

Restoring Immune Tolerance

In health, the immune system maintains a state of tolerance. Self-recognizing ("autoreactive") T and B cells are purged or rendered harmless through central tolerance (in the thymus and bone marrow) and through regulatory T and B cell (peripheral tolerance) mechanisms. Immune policing is imperfect: escaped autoreactive cells can mount inflammatory responses leading to a self-propagating cascade of immune cell recruitment and tissue destruction.

The restoration of tolerance has the potential to ameliorate autoimmune disease while avoiding broad immunosuppression. One means of achieving this may be through tolerogenic or "inverse" vaccines, which present disease-relevant antigens in such a way as to inactivate immune effector cell memory while inducing or expanding regulatory T cells (Treg) to maintain lasting immune tolerance.

Translational studies suggest that strategies including liver targeting, mRNA, and nanoparticle delivery can achieve tolerance in autoimmune disease model systems. Eli Lilly and BMS have both entered into deals with Repertoire Immune Medicines in the hope that the company's DECODE platform for disease-relevant, HLA Class II-specific antigen identification, coupled with mRNA autoantigen delivery, can restore tolerance across a range of autoimmune conditions.

Clinical Validation of Tolerogenic Approaches

Clinical validation of tolerogenic vaccination is limited. Retogatein (rhGAD65; Diamyd Medical), a recombinant GAD65 protein formulated with alum and delivered directly into lymph nodes, is in Phase III development in Type 1 diabetes with the objective of preserving insulin production, although utility is restricted to those carrying the HLA DR3-DQ2 gene. Reduction in celiac disease symptoms have been reported in a Phase II study of KAN-101 (Anokion), an intravenously administered liver-targeting deaminated gliadin peptide conjugate; and from a Phase II study of TPM502 (Topas Therapeutics), a nanoparticle-antigen conjugate which, like retogatein, is restricted to those of particular HLA genotypes.

HLA restriction is a significant commercial constraint for tolerogenic approaches. Because each vaccine candidate targets specific HLA class II alleles, the addressable patient population for any single product is a fraction of the total disease population. This contrasts with B cell depletion strategies, which are HLA-agnostic and can in principle serve broader populations across multiple autoimmune indications.

Regulatory T Cell Therapies

Another route to restoration of immune tolerance is through Treg cell therapy using polyclonal ex vivo expanded donor cells, by reprogramming of T cells to a Treg phenotype, or through T cell receptor and CAR engineering. Companies actively developing Treg solutions for autoimmune conditions include Sonoma Therapeutics (autologous CAR candidate SBT777101 in a rheumatoid arthritis Phase Ib study); PolTREG (autologous ex vivo expanded therapy PGT-007 in Type 1 diabetes Phase I); GentiBio (autologous TCR-engineered therapy GNTI-122 in Type 1 diabetes Phase I); and Quell Therapeutics (autologous CAR-engineered therapy QEL-005 in rheumatoid arthritis and systemic sclerosis Phase I/II). Quell's preclinical candidates QEL-002 (Type 1 diabetes) and QEL-003 (inflammatory bowel disease) are partnered with AstraZeneca.

Beyond Cytokine Blockade: New Targets and Modalities

Growing understanding of the signaling pathways that contribute to immune activation and drive inflammation has led to new therapeutic strategies that may offer better standards of care and the ability to address unmet needs across the spectrum of autoimmune conditions.

TL1A: A High-Conviction Target

TL1A (TNF-like ligand 1A) is highly expressed in inflammatory bowel disease and other autoimmune conditions. AbbVie acquired rights to FutureGen's preclinical anti-TL1A antibody FG-M701 for up to $1.6 billion, hoping it might eventually compete with Merck's tulisokibart (acquired along with Prometheus Bioscience and now in Phase III), Sanofi/Teva's duvakitug (Phase III), and Roche's RVT-3101 (afimkibart), with rights acquired along with Telavant (also Phase III).

Caldera Therapeutics was launched largely on the potential of CLD-423, an early clinical-stage bispecific antibody (IL-23p19×TL1A). Boehringer Ingelheim also sees promise in dual IL-23p19×TL1A targeting and licensed the preclinical bispecific SIM0709 from Simcere Pharmaceutical for up to $1.08 billion. Sanofi's TL1A interest also encompasses the bispecific candidates HXN-1002 (α4β7×TL1A) and HXN-1003 (IL-23×TL1A), aimed at inflammatory bowel disease, with rights acquired from Earendil Labs for $1.8 billion. The companies entered into a second deal for future Earendil Labs AI-designed autoimmune assets worth up to $2.6 billion.

Dual Pathway Inhibitors and Novel Mechanisms

Biogen has initiated a Phase III IgA nephropathy study of felzartamab, a plasma cell-depleting CD38 antibody originally developed by MorphoSys, with rights acquired on acquisition of Human Immunology Biosciences for $1.85 billion. Dianthus Therapeutics is taking two approaches to generalized myasthenia gravis: claseprubart, a subcutaneously delivered antibody specific for C1s, is in Phase III; and DNTH212 is a fusion protein dual inhibitor of BDCA2 that reduces IFN-1 expression while simultaneously inhibiting BAFF/APRIL. Biogen's BDCA2 antibody itifilimab recently received FDA Breakthrough Therapy Designation for cutaneous lupus erythematosus.

Small Molecules and Emerging Platforms

Small molecule autoimmune drug development is not entirely neglected. Lilly hopes that integrin α4β7 can be successfully inhibited by MORF-057, a Phase II oral small molecule inhibitor acquired along with Morphic for up to $3.2 billion. Another early clinical oral small molecule asset, MRT-6160, a molecular glue degrader of VAV1, is the subject of a licensing agreement between Monte Rosa Therapeutics and Novartis worth up to $2.1 billion.

AstraZeneca sees promise in macrocyclic peptides in autoimmune and chronic conditions, gaining development and commercial rights from Syneron Bio for up to $3.4 billion. Takeda is betting on chemoproteomics to produce new therapies for autoimmune and neurological diseases, acquiring rights to discoveries from BridGene's IMTAC platforms for close to $1 billion. Boehringer Ingelheim is pursuing drugs that act on immune cell metabolism through a partnership with Sitryx, paying up to $0.5 billion for rights to a portfolio of small molecule inhibitors.

Autoimmune Disease: The New Oncology?

Several dynamics will shape autoimmune drug development over the coming years. The race to deliver scalable, off-the-shelf alternatives to autologous CAR-T therapy is arguably the highest-stakes competition in the field, with in vivo approaches, allogeneic cell therapies, and T cell engagers all vying to demonstrate equivalent efficacy with greater manufacturing practicality. TL1A has rapidly emerged as a high-conviction target in inflammatory bowel disease, and the Phase III data readouts for tulisokibart, duvakitug, and afimkibart will be closely watched. Dual- and tri-specific antibody formats are proliferating, with more than a dozen candidates now in clinical or advanced preclinical development. Meanwhile, tolerogenic vaccines and Treg cell therapies remain earlier-stage bets on the possibility of functional cure, though the scientific rationale is compelling.

Competitive density varies significantly across modalities and indications. B cell depletion is the most contested space, with autologous CAR-T, allogeneic cell therapies, in vivo approaches, and T cell engagers (bispecific and trispecific) competing on efficacy, scalability, and cost. TL1A inhibition in inflammatory bowel disease is similarly crowded, with three anti-TL1A antibodies in Phase III and multiple bispecific candidates entering development. By contrast, tolerogenic vaccination and Treg cell therapy remain relatively uncrowded, partly because they are scientifically earlier-stage but also because they face the additional challenge of HLA-restricted addressable populations. Outside the most common indications (SLE, RA, IBD, myasthenia gravis), rarer autoimmune conditions such as systemic sclerosis, Stiff Person syndrome, and IgA nephropathy are attracting growing attention as competitive pressure pushes development programs into less contested territory.

The convergence of oncology-derived modalities, target biology, and deal-making momentum has created an autoimmune pipeline of unprecedented breadth and ambition. While the prospect of immune reset through cell therapy, tolerogenic vaccination, or other modality lies somewhere in the future, the current pipeline holds real promise for the many patients burdened by currently untreatable conditions.

Selected Deals and Transactions

Deal values represent maximum potential consideration including upfront payments, milestones, and royalties where disclosed. Combined headline deal value across all 29 transactions: approximately $48 billion. Sources: company press releases and public filings.