SOT106, an investigational antibody-drug conjugate directed against leucine-rich repeat-containing 15 (LRRC15), is moving toward first-in-human testing after receiving four U.S. Food and Drug Administration (FDA) designations across osteosarcoma and soft tissue sarcoma. The program enters clinical development with preclinical data and a prior clinical precedent for LRRC15 targeting from samrotamab vedotin (ABBV-085), but without human safety or efficacy data for SOT106 itself. [1][2][3][17]
Key Takeaways
- The U.S. Food and Drug Administration (FDA) has granted SOT106 Orphan Drug Designation for soft tissue sarcoma (STS) and Fast Track Designation for osteosarcoma. The LRRC15-directed ADC now holds both designations in both indications. No patients have yet received SOT106 in a clinical trial.[1][3]
- SOT106 is a humanized IgG1 antibody with a LALA Fc mutation. MMAE is attached site-specifically to the antibody light chains through a branched, β-glucuronidase-cleavable linker at a drug-to-antibody ratio (DAR) of 4.[7][14]
- The target has a clinical precedent. The first-generation LRRC15-directed ADC samrotamab vedotin (ABBV-085) produced four confirmed partial responses among patients with osteosarcoma and undifferentiated pleomorphic sarcoma (UPS) in a phase 1 study. [17]
- The prevalence of LRRC15 protein on sarcoma cells remains unsettled. SOTIO’s immunohistochemistry dataset reported LRRC15 expression in a substantial proportion of several sarcoma subtypes, while an independent 2026 tissue microarray study found no significant LRRC15 staining across the pediatric, adolescent, and young adult malignancies evaluated. [14][15]
- Osteosarcoma places LRRC15 within pediatric oncology, but no pediatric clinical data have yet been reported for an LRRC15-directed agent. The first LRRC15-directed study to include adolescents is evaluating the radioconjugate LNTH-2403 rather than an ADC. [20][21]
Four FDA Designations, No Clinical Data
SOTIO Biotech announced on September 23, 2026, that the FDA had granted SOT106 Orphan Drug Designation for soft tissue sarcoma and Fast Track Designation for osteosarcoma. The decisions complete a set of four FDA designations for the investigational ADC: Orphan Drug Designation for osteosarcoma, announced in June 2026, and Fast Track Designation for soft tissue sarcoma, announced in August 2026, preceded the latest actions. [1][2][3] The designations apply to a program that has not yet entered human clinical testing. SOTIO expects to initiate the first-in-human study later in 2026. The regulatory designations and the clinical evidence are separate issues. Orphan Drug Designation is available for drugs intended to treat rare diseases or conditions affecting fewer than 200,000 people in the United States. Incentives associated with the designation include tax credits for qualified clinical testing, exemption from certain FDA user fees, and, if approved for the designated indication, seven years of marketing exclusivity.[4]
Fast Track Designation is intended to facilitate development and review of drugs for serious conditions that address an unmet medical need. The designation provides opportunities for more frequent interaction with the FDA and can make the drug eligible for rolling review and, when applicable criteria are met, Priority Review or accelerated approval.[5] Neither designation establishes clinical efficacy or safety. For SOT106, those questions remain to be addressed in human studies.
LRRC15: A Target on Tumor Cells and Tumor Stroma
LRRC15 is a type I transmembrane protein involved in cell-cell and cell-matrix interactions. Investigators at AbbVie described its potential as an ADC target in 2018, when RNA expression profiling identified LRRC15 at high levels in cancer-associated fibroblasts (CAFs) from breast, head and neck, lung, and pancreatic tumors. Expression was also identified directly in subsets of malignant cells of mesenchymal origin, including sarcoma, melanoma, and glioblastoma.[6]
Transforming growth factor-β (TGF-β) induced LRRC15 expression in activated fibroblasts and mesenchymal stem cells. SOTIO’s characterization of the target has reported comparatively limited normal-tissue expression, primarily in placenta and hair follicles, with increased expression in activated fibroblasts during wound healing.[7] The distribution of LRRC15 in both tumor cells and stromal cells has shaped much of the subsequent interest in the target. A 2022 review summarized the biological and therapeutic rationale for LRRC15-directed approaches, including its expression in tumor-associated stroma and selected malignant cells.[8]
Single-cell RNA sequencing studies from Genentech investigators identified the evolution of pancreatic tumor fibroblasts toward a TGF-β-driven LRRC15-positive myofibroblast population. The LRRC15-positive CAF signature was associated with response to anti-PD-L1 therapy across several tumor types.[9] In a subsequent study, genetic depletion of LRRC15-positive myofibroblasts in mouse pancreatic cancer models reduced tumor burden and relieved suppression of CD8-positive T cells.[10] For sarcoma, however, direct expression on malignant cells is particularly relevant.
Investigators at Dana-Farber Cancer Institute and Institut Bergonié evaluated LRRC15 by immunohistochemistry in 711 soft tissue sarcoma specimens. LRRC15 was detected on malignant cells, rather than exclusively within the tumor stroma, across several histologic subtypes. Expression varied substantially between subtypes, and higher expression was associated with higher tumor grade and independently associated with adverse outcome. [11] A separate retrospective study in osteosarcoma also reported an association between LRRC15 expression, aggressive disease, and shorter overall survival.[12]
At the 2026 American Association for Cancer Research’s (AACR) Annual Meeting, held April 17 – 22, 2026, in San Diego, investigators from the National Cancer Institute (NCI) reported an association between LRRC15 and integrin β1 in osteosarcoma cells. The two proteins co-immunoprecipitated, and knockout of either protein produced similar defects in proliferation, migration, and spheroid invasion. [13] These findings provide additional biological context for LRRC15 expression in osteosarcoma but do not establish that LRRC15 itself drives clinical disease or treatment response.
LRRC15 in Sarcoma
One unresolved issue surrounding LRRC15-directed therapy is the prevalence and intensity of protein expression on malignant cells.
SOTIO’s dataset from the 2025 European Society for Medical Oncology’s (ESMO) Sarcoma and Rare Cancers Congress, held in Lugano, Switzerland, used a proprietary diagnostic antibody to evaluate tissue microarrays. The company reported that osteosarcoma had the highest level of tumor-cell expression, with at least 10% LRRC15-positive tumor cells identified in 77% of adult cases and 59% of pediatric cases. Expression was also reported in 58% of chondrosarcomas, 41% of undifferentiated pleomorphic sarcoma (UPS; formerly known as malignant fibrous histiocytoma), 40% of leiomyosarcomas, and 30% of rhabdomyosarcomas. [14]
An independent study presented at the 2026 American Association for Cancer Research’s (AACR) Special Conference on Rare Cancers, held July 16 – 20, 2026, in Vancouver, BC, Canada, produced a different result. The study evaluated membranous expression of six surface targets, including LRRC15, by immunohistochemistry in 342 archival specimens representing 38 pediatric, adolescent, and young adult tumor types. LRRC15 showed no significant staining across the malignancies evaluated. By comparison, B7-H3 staining was diffuse in at least 80% of osteosarcomas in the dataset.[15] These datasets differ in important ways. The studies used different antibodies, scoring criteria, and patient populations. They therefore cannot be treated as directly interchangeable measurements of LRRC15 prevalence.
Transcriptomic data provide another perspective. In an analysis conducted by the Pediatric Preclinical Testing Consortium (PPTC), LRRC15 messenger RNA was detectable in more than 90% of 101 osteosarcoma samples from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database. Expression was substantially higher than in normal tissue. The investigators nevertheless noted that protein-level prevalence in patient samples remained to be established.[16]
SOTIO has developed a diagnostic antibody intended for prospective patient selection in clinical development of SOT106.[7] Whether the assay and its threshold for LRRC15 expression will ultimately identify patients most likely to benefit is a clinical question that will require prospective evaluation.
The ABBV-085 Clinical Precedent
The principal human clinical experience with an LRRC15-directed ADC comes from samrotamab vedotin (ABBV-085). ABBV-085 is a monomethyl auristatin E (MMAE) containing ADC with a DAR of approximately 2. In its first-in-human phase 1 study (NCT02565758), 85 patients with advanced solid tumors received ABBV-085 at doses ranging from 0.3 to 6.0 mg/kg every 14 days. Forty-five patients received the recommended expansion dose of 3.6 mg/kg. This group included 10 patients with osteosarcoma and 10 with UPS.[17]
Across the osteosarcoma and UPS cohorts, the overall response rate was 20%, representing four confirmed partial responses. No objective responses were observed in the other tumor types treated at the recommended expansion dose. The most common treatment-related adverse events included fatigue, nausea, and decreased appetite.[17]
The study established that LRRC15 could be targeted clinically and that objective responses could occur in sarcoma. It did not, however, establish the target as broadly effective across LRRC15-expressing tumors. Preclinical work from the PPTC provides additional context. ABBV-085 was evaluated in seven osteosarcoma patient-derived xenograft (PDX) models. The ADC inhibited tumor growth in six of seven models and extended event-free survival in five compared with an isotype-MMAE control. Two models achieved sustained complete responses. Activity correlated with LRRC15 expression, with the two models having the lowest expression showing no meaningful advantage over the isotype control.[16]
The same study illustrates an important limitation of interpreting targeted ADC activity. In one model with high LRRC15 expression, a non-targeting MMAE conjugate administered at a higher dose produced activity comparable to ABBV-085. This finding illustrates how exposure to a membrane-permeable cytotoxic payload can contribute to target-independent activity when payload concentrations become sufficiently high.[16] The PPTC investigators also observed findings consistent with the known toxicity profile of auristatin-class ADCs, including ocular toxicity and peripheral neuropathy. They did not observe toxicity at sites of normal LRRC15 expression such as skin.[16]
Engineering SOT106
SOT106 combines SOTIO’s humanized anti-LRRC15 antibody with LigaChem Biosciences’ ConjuAll site-specific conjugation platform.[7][14] According to the company’s published characterization, the antibody is based on a humanized IgG1 backbone containing a LALA mutation intended to reduce Fc-mediated effector function. MMAE is attached enzymatically to the antibody light chains through an isoprenoid spacer. A branched linker permits homogeneous, site-specific loading at a DAR of 4. [14] β-glucuronidase, a lysosomal enzyme, cleaves the linker and is overexpressed in several tumor types. The design aims to maintain ADC stability in circulation while allowing intracellular payload release after internalization. [14]
The molecular architecture differs from ABBV-085 in several respects, including the conjugation strategy, linker chemistry, and DAR. Both ADCs use MMAE as the cytotoxic payload. MMAE is membrane-permeable. Consequently, after release from an internalized ADC, the payload can cross the cell membrane and affect neighboring cells. This bystander effect is relevant to LRRC15 because the target is expressed not only by some tumor cells but also by stromal cells, including CAFs. AbbVie investigators previously reported that the bystander activity of ABBV-085 allowed the ADC to kill cancer cells after uptake by LRRC15-positive stromal cells.[6]
Preclinical Activity of SOT106
SOTIO has reported SOT106 data in conference abstracts, posters, and company materials rather than in a peer-reviewed full-length clinical or translational study. [1][7][14] In the LRRC15-positive G-292 osteosarcoma cell line, SOTIO reported an apparent binding affinity of 0.10 nM and an in vitro cytotoxicity value of 40.44 nM. The corresponding values reported for an unnamed clinical benchmark ADC were 0.26 nM and 71.56 nM, respectively. [14]
In mouse models, SOTIO reported complete responses after administering SOT106 at 1 mg/kg. The company described this dose as well tolerated and clinically relevant and reported activity at lower doses and with less frequent dosing than the benchmark ADC. [7]
The company has also reported tumor regression in a pediatric osteosarcoma PDX with low LRRC15 expression, a model in which a first-generation LRRC15-directed ADC was reported to be ineffective. Additional studies included an orthotopic femoral osteosarcoma model and a leiomyosarcoma PDX with high LRRC15 expression.[1][14]
In an exploratory cynomolgus monkey study, SOTIO reported a plasma half-life of approximately 4.5 to 6 days, no premature payload release, and increased plasma stability over 14 days. The reported highest non-severely toxic dose was approximately 10 mg/kg. The company calculated a therapeutic index of approximately 40 using allometric scaling. Dose-limiting toxicities were reported to be consistent with known MMAE-associated effects.[7] These findings remain preclinical. None establishes the safety, pharmacokinetics, pharmacodynamics, or antitumor activity of SOT106 in humans.
LRRC15 Is Becoming a Multimodal Target
SOT106 is one of several investigational approaches directed against LRRC15. Zai Lab presented preclinical data for ZL-6201 at the 2026 AACR Annual Meeting. The ADC uses the company’s TMALIN platform and incorporates C24, a camptothecin-derived topoisomerase I inhibitor, attached through a hydrophilic protease-cleavable linker. The conjugation strategy produces an average DAR of 8. [18] ZL-6201 showed activity in sarcoma PDX models. In models in which LRRC15 expression was restricted to stromal cells, the investigators reported tumor-cell killing following payload release from LRRC15-positive CAFs. Non-human primate studies reported acceptable toxicokinetic findings.[18]
LRRC15 is also being investigated as a target for radiopharmaceutical therapy. Investigators at UCLA and Lund University developed the humanized anti-LRRC15 antibody DUNP19 as a platform for radiolabeling with lutetium-177. In osteosarcoma xenograft models, including an orthotopic tibial model, [177Lu]Lu-DUNP19 inhibited tumor progression and prolonged survival. Activity was also reported in a breast cancer model in which LRRC15 expression was restricted to the tumor stroma, consistent with the crossfire effect produced by β-particle radiation.[19]
The program, now designated LNTH-2403, is being evaluated in a multicenter, open-label phase 1/2 study in patients with relapsed or refractory osteosarcoma (NCT07357519). The study includes dosimetry and dose escalation followed by cohort expansion. [20]
The emergence of these programs means that LRRC15 is no longer being evaluated solely as an ADC target. ADCs, radioconjugates, and other targeted approaches are now being developed against the same antigen. At the same time, other surface targets are moving through clinical development in osteosarcoma. In July 2026, Hansoh Pharma and GSK reported that the B7-H3-directed ADC risvutatug rezetecan (Ris-Rez) met the primary progression-free survival endpoint in the phase 3 ARTEMIS-011 trial in patients with relapsed or refractory osteosarcoma in China.[22]
Pediatric Relevance
Osteosarcoma is the indication that most directly connects LRRC15-directed therapy with pediatric oncology. Despite decades of treatment development, outcomes for patients with localized and metastatic osteosarcoma have changed relatively little since the introduction of multi-agent chemotherapy. The molecular complexity of osteosarcoma has also made it difficult to identify recurrent alterations that can be consistently exploited therapeutically.[16]
LRRC15 is biologically relevant to the mesenchymal lineage. Experimental studies have reported that LRRC15 promotes osteogenic differentiation of mesenchymal stem cells, which are relevant to the cellular biology of osteosarcoma.[23] In SOTIO’s immunohistochemistry dataset, 59% of pediatric osteosarcomas had at least 10% LRRC15-positive tumor cells. [14] Pediatric research has also contributed substantially to the preclinical development of the target. ABBV-085 was evaluated through the Pediatric Preclinical Testing Consortium, an NCI-funded collaborative that evaluates investigational agents across pediatric cancer models. [16]
SOTIO’s preclinical development program includes a pediatric osteosarcoma PDX with low LRRC15 expression, as well as a pediatric model involving femoral implantation.[1][14] The DUNP19 program has also received support from osteosarcoma and childhood cancer foundations. [19] Researchers are investigating other LRRC15-directed approaches in pediatric osteosarcoma. St. Jude Children’s Research Hospital investigators have reported preclinical activity with LRRC15-directed CAR T cells in osteosarcoma models.[24]
However, clinical data remain limited. The completed ABBV-085 phase 1 study enrolled adults. [17] No pediatric clinical data have yet been reported for an LRRC15-directed ADC, CAR T-cell therapy, or radioconjugate. LNTH-2403 is the first LRRC15-directed clinical program to include adolescents. The study generally includes patients aged 12 years and older, although the initial phase is restricted to adults. Patients must weigh at least 30 kg and have received at least one prior chemotherapy regimen. [21]
SOTIO has not yet publicly described the age eligibility criteria for its first-in-human SOT106 study.[1] Uncertainty about LRRC15 expression is particularly relevant in younger patients. An independent tissue microarray study reporting no significant LRRC15 staining specifically evaluated pediatric, adolescent, and young adult sarcomas.[15] By contrast, the PPTC analysis identified LRRC15 messenger RNA in more than 90% of osteosarcoma samples but noted that protein-level prevalence still required confirmation in patient specimens.[16]
These findings underscore the importance of prospective assessment of LRRC15 protein expression as clinical studies begin.
Pediatric Development Requirements
The development of a sarcoma-directed targeted therapy is also subject to the FDA’s pediatric oncology requirements. Under the FDA Reauthorization Act of 2017, certain applications for novel cancer drugs and biologics submitted after August 18, 2020 must include an investigation of the product in pediatric cancer when the product is directed at a molecular target that FDA determines to be substantially relevant to a pediatric cancer. The legislation also removed the previous orphan-drug exemption from pediatric assessment for these products.[25] Orphan Drug Designation for osteosarcoma therefore does not itself constitute a pediatric designation or establish that SOT106 has demonstrated activity in children.
What’s Next
SOTIO expects to initiate the first-in-human study of SOT106 later in 2026. The company confirmed it will post study details on ClinicalTrials.gov and that SOT106 is not currently available through an expanded-access program.[1] The clinical study will provide the first opportunity to determine whether SOT106’s molecular design translates into a meaningful therapeutic profile in patients.
One central question is whether the site-specific conjugation strategy, DAR 4, and β-glucuronidase-cleavable linker produce a different balance of exposure, activity, and toxicity than that observed with ABBV-085. A second question concerns patient selection. The available evidence supports LRRC15 expression in at least some sarcoma cells and tumor-associated stromal populations, but published datasets have produced substantially different estimates of protein-level prevalence.[14][15][16]
That distinction matters because the clinical development strategy for SOT106 depends not simply on whether LRRC15 can be detected, but on identifying patients whose tumors contain sufficient target expression and appropriate target accessibility for an LRRC15-directed ADC.
For now, SOT106 remains a preclinical ADC with a defined molecular design, four FDA designations across osteosarcoma and soft tissue sarcoma, and a target with an initial clinical precedent. The next stage of development will move the LRRC15 question from tissue studies and animal models into patients.
Clinical trials
A Study to Assess Safety and Efficacy of SOT106 in Patients With LRRC15-positive Advanced Unresectable or Metastatic Osteosarcoma or Soft Tissue Sarcoma – ClinicalTrials.gov ID NCT07801222
ABBV-085, an Antibody Drug Conjugate, in Subjects With Advanced Solid Tumors – ClinicalTrials.gov ID NCT02565758
Lu-TARGO (177Lu-TARGeted Osteosarcoma Therapy) – ClinicalTrials.gov ID NCT07357519
Study of HS-20093 Versus Gemcitabine in Combination With Docetaxel in Treatment of Osteosarcoma After Previous Second-line Treatment Failure – ClinicalTrials.gov ID NCT06935409
References
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[20] A phase 1/2, multi-center, open-label study to evaluate the safety, tolerability, pharmacokinetics, radiation dosimetry, and preliminary anti-neoplastic activity of LNTH-2403, a LRRC15-targeted 177Lutetium-labeled monoclonal antibody, in participants with relapsed/refractory osteosarcoma. ClinicalTrials.gov identifier: NCT07357519. Sponsor: Lantheus Medical Imaging. Accessed September 23, 2026. ClinicalTrials.gov: NCT07357519
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Featured image: © 2026 SOTIO-ABBVIE-002. Used with permission.
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