Re-Engineering ADCs for Autoimmune and Inflammatory Disease

Key Takeaways

• Antibody–drug conjugates (ADCs) are expanding beyond oncology as developers explore targeted delivery strategies for autoimmune and inflammatory diseases.

• Immunology ADCs differ from oncology ADCs because they often aim to deliver immunomodulatory payloads, reduce systemic toxicity, or selectively deplete pathogenic immune cells rather than kill cancer cells.

• Early programs in rheumatoid arthritis, Crohn’s disease, systemic lupus erythematosus, autoimmune uveitis, and graft-versus-host disease show how ADC design is being re-engineered for immune-mediated disease.

• Targeted glucocorticoid delivery is one of the most active autoimmune ADC concepts, but clinical differentiation remains a major challenge.

• For CDMOs and development partners, immunology ADCs create new demands around linker stability, conjugation control, free payload, potency assays, and immune cell–specific analytics.

Antibody–drug conjugates (ADCs) are best known as cancer therapeutics. Their core design principle is straightforward but technically demanding: an antibody recognizes a target antigen, a linker connects that antibody to a payload, and the resulting conjugate is designed to deliver a potent drug to selected cells while limiting broader exposure. In oncology, that architecture has generally been used to direct highly cytotoxic payloads toward tumor cells, with ongoing innovation focused on antibody selection, linker chemistry, payload choice, drug-to-antibody ratio (DAR), conjugation strategy, and stability.

That same architecture is now being adapted for immune-mediated disease. The emerging immunology story is not a simple extension of oncology ADCs into a new therapeutic category. In autoimmune and inflammatory disorders, the goal is often not maximal cell killing. Instead, developers are exploring whether ADCs can deliver immunomodulatory payloads to disease-relevant immune cells, reduce systemic exposure to drugs with known anti-inflammatory activity, or selectively deplete immune-cell subsets that drive pathology.

This shift matters because autoimmune diseases create a different set of therapeutic expectations. Oncology ADCs often enter settings where high potency and acceptable tolerability must be balanced against advanced disease and limited treatment options. Autoimmune therapies, by contrast, may be used chronically, sometimes in patients who are otherwise medically stable, and often in competitive markets with effective biologics, small molecules, and steroid-sparing strategies already available. As a result, ADCs in immunology must offer more than targeted delivery in theory. They must demonstrate that targeted delivery translates into a practical therapeutic advantage.

The current evidence supports cautious optimism rather than hype. Several programs have reached clinical testing, and multiple preclinical examples show how ADCs can be redesigned around immunology-specific targets and payloads. Still, the field remains early. The strongest conclusion is not that autoimmune ADCs are already a mature pipeline category, but that ADC design is being re-engineered for immunology.

Autoimmune and inflammatory diseases often involve activated immune-cell populations, tissue-localized inflammation, and dysregulated cytokine signaling. These disease features create a logical opening for targeted delivery. If a drug can be concentrated in immune cells that are active in disease while sparing broader tissues from unnecessary exposure, it may be possible to improve the balance between efficacy and safety.

Glucocorticoids illustrate the appeal of that idea. They are among the most powerful anti-inflammatory agents used in medicine, but systemic exposure limits their long-term utility. Chronic or repeated glucocorticoid use can create tolerability and safety challenges, even when the anti-inflammatory biology remains attractive. Immunology ADCs are being explored as one way to preserve local or cell-directed anti-inflammatory effects while reducing systemic payload exposure.^1,2

That concept is elegant, but execution is difficult. A successful immunology ADC must identify the right antigen, demonstrate sufficient binding and internalization, release payload in the intended cellular context, and avoid broad immune suppression or off-target effects. Payload selection also differs from oncology. Many cancer ADCs rely on highly cytotoxic agents, while immunology ADCs may use glucocorticoids, glucocorticoid receptor modulators, or other immunomodulatory payloads designed to alter immune-cell behavior rather than simply kill the target cell.²

The safety standard is also higher in many autoimmune settings. Patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), or other chronic immune-mediated conditions may require years of therapy. A narrow therapeutic window, persistent free payload exposure, or unpredictable immune-cell depletion could limit the practical value of an ADC even if the molecule shows biological activity. This makes the design challenge broader than the usual ADC questions of potency and selectivity. Developers must also show that the product profile is differentiated enough to justify its complexity.

For chemistry, manufacturing, and controls (CMC), that creates an important implication. Immunology ADCs will likely require especially careful control of conjugation consistency, DAR, free payload, linker stability, aggregation, and potency assays. Those attributes are important for oncology ADCs as well, but in chronic immune-mediated diseases, they may become central to demonstrating that the proposed targeting strategy can produce a reliable and clinically meaningful safety margin.

The most clinically developed example of ADC design moving into immune-mediated disease is AbbVie’s tumor necrosis factor (TNF)-targeted glucocorticoid receptor modulator program. ABBV-3373 was described as an investigational ADC composed of anti-TNF targeting and a proprietary glucocorticoid receptor modulator payload, intended to direct anti-inflammatory activity to activated immune cells while limiting systemic glucocorticoid-associated effects.³

The rationale was clear. TNF is already a validated target in autoimmune disease, and anti-TNF biologics have an established place in the treatment of inflammatory conditions. By linking anti-TNF targeting to a glucocorticoid receptor modulator payload, the program attempted to combine antibody-mediated immune-cell targeting with intracellular anti-inflammatory activity. AbbVie reported phase IIa data in rheumatoid arthritis, including improvement in disease activity in patients treated with ABBV-3373.^3,4

ABBV-154 extended the same broader concept into other immune-mediated diseases. In Crohn’s disease, ABBV-154 was evaluated in a phase IIb randomized, double-blind, placebo-controlled trial in patients with moderately to severely active disease who had an inadequate response to or intolerance of prior biologic therapy.⁵ The study reported that ABBV-154 was well tolerated and showed proof-of-concept efficacy during the initial 12-week period, including higher observed endoscopic response rates in ABBV-154 induction groups than in the placebo group.

The same program also illustrates the high bar for autoimmune ADCs. The Crohn’s disease trial was voluntarily terminated early, and interpretation was limited by reduced sample size and shorter exposure duration.5 More importantly, the ABBV-154 program was discontinued after review of available phase II data from Crohn’s disease, RA, and polymyalgia rheumatica because the evidence did not support a sufficiently differentiated benefit-risk profile compared with existing therapies.

That outcome should not be read as a failure of the entire immunology ADC concept. It is better understood as an important translational lesson. ABBV-3373 and ABBV-154 showed that ADCs can be engineered for immune-mediated disease and advanced into meaningful clinical testing. They also showed that biological activity and targeted-delivery rationale are not enough. In chronic inflammatory disease, an ADC must compete against established treatment options and must demonstrate a clear advantage in efficacy, safety, durability, dosing, patient selection, or steroid-sparing potential.

For future immunology ADCs, the AbbVie experience may be especially instructive. It suggests that target selection and payload design cannot be evaluated separately from real-world differentiation. A technically successful conjugate still needs a clinical profile strong enough to justify the manufacturing complexity, cost, development burden, and long-term safety expectations associated with chronic immune-mediated conditions.

Not all immunology ADCs are built around glucocorticoid delivery. Some are being explored as tools to selectively eliminate immune-cell populations that contribute to disease. This approach is closer to oncology ADC logic in one sense, because it can involve killing selected cells, but the therapeutic goal is different. Instead of targeting malignant cells, the intent is to reduce pathogenic immune activity while preserving enough normal immune function to maintain safety.

A CD6-targeted ADC offers one example. CD6 is expressed on T cells, and the CD6 ADC was designed to eliminate activated, proliferating pathogenic T cells. In preclinical work, the ADC selectively killed activated proliferating human T cells and antigen-specific mouse T cells in vitro. It also treated two autoimmune uveitis models and one graft-versus-host disease model in vivo, while the same dose had no significant detrimental effect on normal T cells in naïve CD6-humanized mice.⁶

This model expands the immunology ADC design space. Rather than using an antibody to deliver a broadly anti-inflammatory payload, the CD6 ADC approach uses antibody targeting to focus immune-cell depletion on activated disease-relevant populations. The distinction matters. Autoimmune disease often involves pathogenic immune cells that are difficult to suppress without also affecting protective immunity. A targeted depletion strategy could be valuable if it can separate harmful immune activation from normal immune surveillance.

A CD19-directed triptolide conjugate provides a B cell–focused example in systemic lupus erythematosus. The study developed a CD19 monoclonal antibody (mAb)–triptolide conjugate, named ADC-TP, for lupus. The conjugate selectively depleted B-cell subsets in vitro and in vivo, alleviated disease symptoms in mouse lupus models, and showed enhanced therapeutic efficacy compared with CD19 monoclonal antibody, with fewer side effects than triptolide in the reported models.⁷

The CD19 example is notable because triptolide has potent biological activity but is constrained by toxicity concerns. By conjugating it to an antibody directed at B cells, the study explored whether a powerful payload could be redirected toward a disease-relevant immune-cell compartment. Like the CD6 work, this remains preclinical, but it reinforces a broader point: immunology ADCs may be useful not only for delivering conventional anti-inflammatory drugs more selectively, but also for revisiting payloads whose systemic use would otherwise be difficult.

These approaches will still face demanding translational questions. Immune-cell depletion must be precise enough to avoid unacceptable immunosuppression, durable enough to matter clinically, and controllable enough for chronic or relapsing diseases. Still, CD6 and CD19 ADC strategies show that the field is not limited to steroid-targeting concepts. ADCs may become a platform for selective immune-cell editing through depletion, suppression, or intracellular payload delivery.

Targeted glucocorticoid delivery remains one of the most active immunology ADC concepts. The appeal is clear: glucocorticoids are potent anti-inflammatory agents, but systemic exposure is a major limitation. ADC delivery offers a way to test whether glucocorticoid activity can be redirected to immune cells or inflammatory compartments while reducing broader toxicity.

A CD74-targeted budesonide ADC provides one lupus-focused example. CD74 is expressed on several immune-cell types relevant to systemic lupus erythematosus, including B cells, dendritic cells, plasmacytoid dendritic cells, and macrophages.⁸ The CD74 Bud-ADC study reported rapid CD74 internalization and showed that the conjugate had immunosuppressive activity in vitro and in vivo. In murine lupus models, the CD74-targeted Bud-ADC showed superior efficacy compared with free budesonide.

This example reflects one of the central immunology ADC hypotheses: a familiar anti-inflammatory payload may behave differently if its exposure is shifted toward relevant immune cells. The goal is not to discover a new anti-inflammatory mechanism, but to alter the delivery context of an existing one. For diseases such as lupus, where multiple immune-cell compartments contribute to pathology, that targeting question becomes especially important.

LFD-200 represents a more current early clinical example of targeted glucocorticoid delivery. ClinicalTrials.gov lists a phase I study of LFD-200 in healthy adults and participants with moderate-to-severe RA.⁹ Company-presented ACR 2025 material describes LFD-200 as an ADC designed to selectively deliver a glucocorticoid payload to immune cells and states that a first-in-human study evaluating safety, pharmacokinetics, and pharmacodynamics had been initiated.¹⁰

Other early work points in the same direction. A Simcere ACR abstract described a TNF-targeted glucocorticoid ADC using an anti-TNFα antibody and cleavable linker. The abstract reported antigen-dependent release of glucocorticoid payload and activity in functional assays and mouse models, including contact hypersensitivity and collagen antibody-induced arthritis models.¹¹ As with LFD-200, this is early evidence and should not be overstated. But it reinforces the pattern: multiple groups are exploring whether ADC architecture can make glucocorticoid biology more targeted and tolerable.

The important point is not that targeted glucocorticoid ADCs have already succeeded clinically. The AbbVie experience argues for caution. The more accurate takeaway is that glucocorticoid ADCs remain a plausible and actively explored design strategy, but one that must prove clear differentiation against existing therapies and against the known risks of systemic immunosuppression.

The movement of ADCs beyond oncology is not limited to autoimmune therapy. CD45-targeted ADC conditioning illustrates a related use of ADC design: selective manipulation of hematopoietic and immune-cell populations before gene therapy or stem cell transplant. This is not the same as treating rheumatoid arthritis or lupus, but it belongs in the broader story of ADCs becoming tools for immune-system engineering.

A 2024 study reported development of anti-human CD45 ADCs using pyrrolobenzodiazepine payloads as targeted conditioning agents for gene therapy and stem cell transplant. The ADCs internalized to lysosomes and produced potent and specific killing of human CD45-positive cells in vitro. In humanized mice, they ablated human hematopoietic stem cells without toxicity to non-hematopoietic tissues and enabled engraftment of gene-modified autologous and allogeneic human hematopoietic stem cells.¹²

The relevance of this example is conceptual. It shows that ADCs can be used to direct potent biological effects toward immune or hematopoietic compartments outside the cancer setting. In conditioning, the goal is to replace broad, toxic preparative regimens with more selective cell depletion. In autoimmune disease, the goal may be to suppress or deplete pathogenic immune activity with greater precision. The indications and clinical objectives differ, but both applications rely on the same core premise: antibody-guided delivery can reshape the distribution and effect of potent payloads.

This broader immune-system engineering lens may become increasingly important as ADC technology matures. The platform is no longer defined only by the delivery of cytotoxins to tumors. It is becoming a set of design tools for directing pharmacology toward selected cell populations. That evolution could support autoimmune therapy, transplant conditioning, gene therapy preparation, and other applications where selective immune or hematopoietic targeting is valuable.

Immunology ADCs share many technical requirements with oncology ADCs, but the development priorities can differ. Antigen selection remains foundational. A target must be expressed on disease-relevant cells, internalize efficiently enough to support payload release, and provide adequate selectivity over cells whose depletion or modulation would create safety concerns. In autoimmune disease, this is particularly difficult because the same immune-cell markers that identify pathogenic populations may also appear on normal immune cells.

Linker design is equally important. Premature release can increase systemic exposure and undermine the rationale for targeted delivery. Insufficient release can reduce pharmacodynamic activity in the target cell. The optimal balance depends on the payload, target biology, internalization pathway, and intended therapeutic effect. Immunosuppressive ADCs therefore require careful alignment between antigen behavior, linker stability, and intracellular payload activation.

Payload selection may be the most important distinction from oncology. Many cancer ADCs use cytotoxic agents selected for their ability to kill rapidly dividing or antigen-expressing cells. Immunology ADCs may instead use glucocorticoids, glucocorticoid receptor modulators, or other anti-inflammatory payloads. In selective depletion strategies, cytotoxic payloads may still be relevant, but the acceptable exposure and depletion profile may be narrower than in many oncology settings. The payload must be potent enough to produce a meaningful effect but controlled enough to support chronic or repeated dosing.

These design requirements flow directly into CMC. DAR, conjugation-site distribution, aggregation, free payload, residual impurities, and stability can all shape both product quality and clinical behavior. Small differences in conjugation or release characteristics may matter if the therapeutic hypothesis depends on minimizing systemic payload exposure. Potency assays may also need to evolve. For immunology ADCs, traditional tumor-cell cytotoxicity assays may be insufficient. Developers may need assays that capture immune-cell binding, internalization, payload release, cytokine suppression, selective depletion, or disease-relevant pharmacodynamic activity.

For contract development and manufacturing organizations (CDMOs), this creates both opportunity and complexity. Manufacturing partners with ADC experience already understand the challenges of handling potent payloads, controlling conjugation, developing robust purification strategies, and supporting analytical characterization. Immunology ADCs may add a further layer: the need to connect molecular attributes to a therapeutic window suitable for chronic inflammatory disease. That connection will likely require close collaboration among discovery, process development, analytical, toxicology, and clinical teams.

The clinical bar for immunology ADCs is high because autoimmune and inflammatory diseases are often chronic, heterogeneous, and already served by multiple treatment classes. A new ADC must demonstrate not only that it can engage a target or deliver a payload but that it can improve the therapeutic equation for patients and clinicians. That improvement might come through better efficacy, lower systemic toxicity, steroid sparing, less frequent dosing, activity in refractory populations, or more precise use in biomarker-defined subgroups.

The ABBV-154 experience is the clearest cautionary example. In Crohn’s disease, the study reported proof-of-concept efficacy and tolerability during the initial treatment period, but the program was discontinued because the available phase II data did not support a sufficiently differentiated benefit-risk profile compared with existing treatments.⁵ That distinction is critical. A drug can show activity and still fall short if it does not offer enough advantage over available options.

This may be one of the defining challenges for the field. In oncology, ADCs often compete in settings where incremental activity can be meaningful, particularly for patients with advanced disease or limited alternatives. In autoimmune disease, patients may have long treatment horizons, and physicians may be reluctant to adopt a complex targeted-delivery product unless the clinical benefit is clear. Safety concerns may also be viewed differently when therapy is intended for chronic use.

Future programs may therefore need sharper development strategies from the outset. Patient selection could become important if an ADC’s target is especially relevant in a defined disease subset. Pharmacodynamic biomarkers may help show that targeted delivery is working as intended. Comparative studies may be necessary to demonstrate that an ADC offers a meaningful advantage over biologics, targeted small molecules, or conventional immunosuppressive agents. Without that differentiation, the scientific sophistication of the platform may not be enough.

This is also where development strategy intersects with manufacturing. A candidate cannot be clinically differentiated if its product attributes are difficult to control, if free payload exposure varies, or if analytical methods cannot convincingly link product quality to targeted pharmacology. For autoimmune ADCs, CMC rigor is not only a regulatory requirement. It is part of the clinical value proposition.

As ADCs move into immunology, developers will need partners that understand both established ADC manufacturing and the special demands of chronic immune-mediated disease. Core capabilities remain essential: antibody production, linker and payload synthesis, conjugation, purification, analytical characterization, containment, and fill–finish. However, immunology ADCs may place additional pressure on consistency, release testing, and assays that reflect immune-cell activity rather than tumor-cell killing alone.

The payload issue is especially important. Glucocorticoids and other immunomodulatory payloads may not require the same handling assumptions as the most potent oncology cytotoxins, but they still demand precise control of conjugation, release, free payload, and impurity profiles. Selective depletion strategies may use more potent payloads, creating additional containment and safety considerations. In either case, developers will need manufacturing processes that preserve the intended relationship among antibody targeting, linker behavior, payload release, and pharmacodynamic effect.

Analytical development may become a major differentiator. Immunology ADCs may require assays that measure binding to activated immune cells, antigen-dependent internalization, intracellular payload release, cytokine suppression, or selective depletion of defined immune-cell subsets. These methods may be more complex than standard cytotoxicity assays and may need to be tailored to the biology of each program. A CDMO that can help build those assays early may contribute more than manufacturing execution; it can help define whether the candidate’s mechanism is measurable and reproducible.

Process development decisions may also affect clinical strategy. If an ADC is intended to reduce systemic payload exposure, then control of free payload and linker stability becomes central to the program’s rationale. If a candidate is intended for repeated dosing in chronic disease, then batch-to-batch consistency and long-term stability become especially important. If the goal is selective immune-cell depletion, potency assays must distinguish desired activity from broader immune toxicity.

For CDMOs, immunology ADCs could therefore represent a natural extension of existing ADC capabilities, but not a simple one. The opportunity lies in helping developers translate a targeted-delivery concept into a product profile that can survive clinical comparison with established therapies. That requires early integration of manufacturability, analytics, toxicology, and clinical positioning.

The future of immunology ADCs will not be determined by whether they can borrow the prestige of oncology ADCs. It will depend on whether they can solve a different and arguably harder problem: delivering potent immune-modulating activity with enough precision to matter in chronic disease. Autoimmune and inflammatory disorders do not simply need stronger suppression. They need therapies that can intervene more selectively, spare patients from cumulative toxicity and create room for durable disease control without broadly compromising immune function.

That is what makes the early movement of ADCs into immunology so compelling. TNF-targeted glucocorticoid receptor modulator ADCs, VISTA-directed glucocorticoid delivery, CD6-mediated pathogenic T cell elimination, CD19–triptolide delivery and CD74-targeted glucocorticoid delivery all point toward the same larger ambition: using antibody-guided delivery to reshape where potent pharmacology goes, how long it acts and which immune cells are most affected.

The field is still early, and the AbbVie experience shows why caution is warranted. A targeted delivery concept must still become a differentiated therapy. In autoimmune disease, that means showing not only biological activity, but a clearer therapeutic window than existing biologics, small molecules or conventional immunosuppressive regimens can provide. The strongest candidates will likely be those that match the right antigen, payload, linker and patient population closely enough to produce a benefit that is clinically visible, not just mechanistically elegant.

For developers and CDMOs, that raises the stakes for every part of ADC design and execution. Antibody selection, linker stability, payload release, conjugation control, free payload, potency assays and pharmacodynamic readouts are not isolated technical details. They are the machinery through which a targeted immunology concept either becomes a viable therapy or fails to distinguish itself from simpler alternatives.

The next chapter for ADCs beyond oncology will therefore be measured less by how many autoimmune programs enter the pipeline than by whether any can prove that targeted immune modulation changes the treatment equation. If they can, ADCs may evolve from cancer-cell killing platforms into a broader architecture for precision immunopharmacology, opening a new way to treat diseases where the central challenge has always been how to calm the immune system without silencing it altogether.

1. Han, Amy, et al. “Development of Novel Glucocorticoids for Use in Antibody–Drug Conjugates for the Treatment of Inflammatory Diseases.” Journal of Medicinal Chemistry. 64: 11958–11971 (2021).

2. Yaseen, Aiman A, and L Nathan Tumey. “Advances and Challenges in Immunosuppressive Antibody Drug Conjugates.” European Journal of Medicinal Chemistry. 291: 117576 (2025).

3. Novel Antibody Drug Conjugate ABBV-3373 Shows Improvement in Disease Activity in Phase 2a Study of Patients with Rheumatoid Arthritis. AbbVie. 10 Jun. 2020.

4. Buttgereit, Frank, et al. “Efficacy and Safety of ABBV-3373, a Novel Anti–Tumor Necrosis Factor Glucocorticoid Receptor Modulator Antibody–Drug Conjugate, in Adults with Moderate-to-Severe Rheumatoid Arthritis Despite Methotrexate Therapy: A Randomized, Double-Blind, Active-Controlled Proof-of-Concept Phase IIa Trial.” Arthritis & Rheumatology. 75: 879–889 (2023).

5. Reinisch, Walter, et al. “Efficacy and Safety of ABBV-154 in Patients with Moderately to Severely Active Crohn’s Disease: A Phase 2b, Randomized, Double-Blind, Placebo-Controlled Trial.” Crohn’s & Colitis. 360 8: otag014 (2026).

6. Zhang, Lingjun, et al. “A CD6-Targeted Antibody-Drug Conjugate as a Potential Therapy for T Cell–Mediated Disorders.” JCI Insight. 8: e172914 (2023).

7. Wang, Lai, et al. “A Rationally Designed CD19 Monoclonal Antibody-Triptolide Conjugate for the Treatment of Systemic Lupus Erythematosus.” Acta Pharmaceutica Sinica B. 14: 4560–4576 (2024).

8. Du, Qizhen, et al. “CD74-Targeting Antibody–Drug Conjugate Enhances Immunosuppression of Glucocorticoid in Systemic Lupus Erythematosus.” International Journal of Molecular Sciences. 26: 11761 (2025).

9. “NCT07207954: A Phase 1 Study of LFD-200 in Healthy Adults and Participants With Moderate to Severe Rheumatoid Arthritis.” ClinicalTrials.gov. (2026).

10. McClure, Matt, et al. “LFD-200, an Antibody Drug Conjugate that Selectively Delivers a Glucocorticoid Payload to Immune Cells, Provides Sustained Anti-Inflammatory Effects Without Systemic Toxicity in Non-Human Primates.” Arthritis & Rheumatology. 77: suppl. 9 (2025).

11. Chai, Xiaojuan, et al. “Development of Novel Glucocorticoid as Immunology Antibody-Drug Conjugate Payload for the Treatment of Autoimmune and Inflammatory Diseases.” Arthritis & Rheumatology. 74: suppl. 9 (2022).

12. Yeung, Jenny, et al. “Anti-CD45 PBD-Based Antibody-Drug Conjugates Are Effective Targeted Conditioning Agents for Gene Therapy and Stem Cell Transplant.” Molecular Therapy. 32: 1672–1686 (2024).