SOT-102: A Comprehensive Analysis of a Discontinued CLDN18.2-Targeted Antibody-Drug Conjugate and its Strategic Implications

Executive Summary

This report provides a comprehensive analysis of SOT-102, an investigational antibody-drug conjugate (ADC) developed by SOTIO Biotech for the treatment of CLDN18.2-positive solid tumors, primarily gastric and pancreatic adenocarcinoma. SOT-102 was engineered with a distinct molecular architecture, combining a proprietary, high-affinity monoclonal antibody targeting the tumor-associated antigen Claudin 18.2 (CLDN18.2) with a highly potent topoisomerase II inhibitor payload, PNU-159682. The construct utilized a site-specific, non-cleavable linker technology, reflecting a design philosophy heavily focused on maximizing stability and tolerability.

The preclinical data for SOT-102 were exceptionally promising, demonstrating complete tumor responses in all tested patient-derived xenograft models, including those with low target expression, suggesting a potentially wide therapeutic window and broad patient applicability. This compelling preclinical package supported the initiation of the Phase 1/2 CLAUDIO-01 clinical trial in April 2022. The trial was designed to efficiently evaluate SOT-102 as both a monotherapy and in combination with standard-of-care regimens in patients with advanced gastric and pancreatic cancer.

Despite positive early updates, including a company statement in October 2023 that no dose-limiting toxicities had been observed, SOTIO Biotech terminated the CLAUDIO-01 trial and discontinued the SOT-102 program in January 2025. The stated reason was a "benefit-risk reassessment." While specific clinical data have not been disclosed, this analysis posits that the decision was driven not by acute toxicity but by a failure to meet the increasingly high efficacy bar set by a crowded and rapidly advancing field of CLDN18.2-targeted competitors. The approval of the naked antibody zolbetuximab and the strong clinical data emerging from other ADCs, particularly those utilizing topoisomerase I inhibitor payloads, created a competitive landscape where only a best-in-class profile would be viable.

The discontinuation of SOT-102 does not represent a failure of SOTIO's ADC strategy but rather a strategic pivot. The company has since redeployed its resources into a diversified pipeline of next-generation ADCs, leveraging multiple advanced technology platforms and pursuing novel, less-crowded targets such as LRRC15 and CDH17. This move demonstrates an agile and sophisticated approach to portfolio management. The story of SOT-102 thus serves as an important case study on the challenges of preclinical-to-clinical translation, the critical importance of competitive positioning in modern oncology drug development, and the rational decision-making required to navigate a dynamic therapeutic landscape.

SOT-102: Molecular Architecture and Therapeutic Rationale

Profile of an Investigational Agent: SOT-102

SOT-102 is an investigational antibody-drug conjugate (ADC) developed by the Czech Republic-based SOTIO Biotech, a subsidiary of the PPF Group.[1] The drug was being evaluated for the treatment of advanced solid tumors, with a primary focus on gastric adenocarcinoma, gastroesophageal junction (GEJ) adenocarcinoma, and pancreatic adenocarcinoma.[3] Throughout its development, the asset has been referred to by several names, including its clinical designation SOT-102 and its earlier code name SO-N102, as well as more descriptive synonyms like ADC SOT102 and anti-Claudin 18.2/PNU ADC SOT102.[5] As an ADC, SOT-102 is classified as a biologic therapeutic and was designed for intravenous administration.[1]

The Target: Scientific and Clinical Rationale for Claudin 18.2 (CLDN18.2)

The therapeutic strategy behind SOT-102 is centered on its highly specific targeting of Claudin 18.2 (CLDN18.2), a transmembrane protein that has emerged as a premier target in oncology. CLDN18.2 is an isoform of Claudin-18, a protein family that forms the backbone of tight junctions—the specialized cell-to-cell adhesion complexes that regulate the barrier function of epithelial and endothelial tissues.[5]

The scientific rationale for targeting CLDN18.2 is rooted in its unique and highly differentiated expression profile between healthy and malignant tissues. In normal physiology, CLDN18.2 expression is strictly limited to the differentiated epithelial cells of the gastric mucosa.[5] Critically, within these healthy cells, the protein's extracellular domains—the epitopes that an antibody could bind to—are sequestered within the tight junction complex, making them inaccessible to circulating therapeutic agents.[8]

This dynamic changes dramatically during malignant transformation. In a range of cancers—most notably gastric, GEJ, and pancreatic adenocarcinomas, but also esophageal, lung, ovarian, and others—the loss of normal cell polarity and the disruption of tight junction architecture exposes the CLDN18.2 epitopes on the tumor cell surface.[5] This cancer-specific "unmasking" transforms CLDN18.2 into an ideal tumor-associated antigen (TAA). It is not an oncogenic driver itself, meaning its presence does not directly cause the cancer to grow faster, but rather serves as a highly specific surface marker that distinguishes cancer cells from their healthy counterparts.[11] This characteristic provides a powerful opportunity for targeted therapies like ADCs to selectively deliver a cytotoxic payload to the tumor while largely sparing healthy tissues, thereby creating a potentially wide therapeutic window.

Further bolstering its credentials as a drug target, the protein sequence of the specific extracellular loop targeted by SOT-102 is 100% identical among humans, cynomolgus monkeys, and rodents.[9] This high degree of conservation is a significant advantage in drug development, as it allows for preclinical toxicology and efficacy studies in relevant animal models to be more predictive of the drug's behavior in humans.

Deconstruction of the SOT-102 Antibody-Drug Conjugate

SOT-102 is a complex, tripartite molecule, meticulously engineered with three core components: a targeting antibody, a cytotoxic payload, and a linker system connecting them.[3] Each component was selected to create a differentiated therapeutic profile.

The Targeting Moiety: A Proprietary Anti-CLDN18.2 IgG1 Antibody

The backbone of SOT-102 is a proprietary, humanized immunoglobulin G1 (IgG1) monoclonal antibody (mAb) developed in-house by SOTIO to bind with high specificity and affinity to CLDN18.2.[5] Preclinical characterization demonstrated a high target affinity, with a half-maximal effective concentration (

EC50​) in the range of 2-4 nM on both CLDN18.2-transfected and endogenously expressing cell lines.[9] This strong binding is followed by rapid and efficient internalization into target-expressing cells, a prerequisite for an ADC to deliver its payload. Studies showed that over 60% of bound SOT-102 was internalized within the first 12 hours.[9]

A particularly sophisticated feature of the antibody's design was the modification of its Fc region. The antibody's effector functions were engineered to decrease its interaction with Fc-gamma receptors (FcRγ) while preserving its ability to bind to the neonatal Fc receptor (FcRn).[9] This represents a critical strategic choice. A standard IgG1 antibody would normally engage FcRγ on immune cells like natural killer (NK) cells to trigger antibody-dependent cellular cytotoxicity (ADCC), an independent mechanism of tumor killing. By intentionally "silencing" this function, SOTIO aimed to rely exclusively on the cytotoxic payload for therapeutic effect. This design minimizes the risk of on-target, off-tumor toxicity, where ADCC could be triggered against the healthy gastric mucosal cells that express CLDN18.2, potentially causing severe gastrointestinal side effects. By focusing the killing mechanism on payload delivery

after internalization, the toxicity is theoretically restricted only to the cells that internalize the ADC. Concurrently, maintaining FcRn binding is essential for prolonging the antibody's circulating half-life, giving it more time to locate and accumulate within the tumor. This design demonstrates a clear prioritization of safety and tolerability.

The Cytotoxic Warhead: PNU-159682, a Highly Potent Topoisomerase II Inhibitor

The cytotoxic payload, or "warhead," attached to the antibody is PNU-159682, a potent derivative of the anthracycline antibiotic nemorubicin.[3] PNU-159682 is a major metabolite of nemorubicin, formed in the liver by the cytochrome P450 enzyme CYP3A4.[14] Its mechanism of action is as a DNA topoisomerase II (TOP2) inhibitor.[1] Upon release inside the cancer cell, it intercalates into the DNA and inhibits topoisomerase II, which disrupts DNA replication and repair and halts RNA and protein synthesis, ultimately leading to apoptotic cell death.[5]

The choice of PNU-159682 was a key point of differentiation for SOT-102. The payload is exceptionally potent, reported to be thousands of times more cytotoxic than the conventional anthracycline doxorubicin, and is considered a more potent and better-tolerated ADC cytotoxin.[17] This mechanism contrasts with the payloads used in the majority of competing CLDN18.2 ADCs, which predominantly employ either microtubule inhibitors like monomethyl auristatin E (MMAE) or topoisomerase I (TOP1) inhibitors such as exatecan derivatives.[20] The use of a TOP2 inhibitor could have provided a therapeutic advantage against tumors resistant to other common classes of chemotherapy. However, the extreme potency of PNU-159682 is a double-edged sword. While it holds the promise of profound efficacy, it places immense pressure on the stability of the entire ADC construct. Any premature release of the payload in systemic circulation could lead to severe off-target toxicity, making the design of the linker and conjugation technology paramount.

The Conjugation Platform: Site-Specific, Non-Cleavable Linker Technology (SMAC)

To connect the antibody and payload, SOT-102 utilized a state-of-the-art conjugation platform licensed from NBE-Therapeutics. This platform features two key elements: site-specific conjugation and a non-cleavable linker.[1]

The technology, known as Sortase-Mediated Antibody Coupling (SMAC), ensures that the payload is attached to a precise location on the antibody.[1] This site-specific conjugation overcomes a major limitation of earlier ADC technologies, which resulted in a heterogeneous mixture of molecules with varying numbers of payloads attached at random sites. The SMAC technology yields a highly homogenous product with a consistent and defined drug-to-antibody ratio (DAR) of 2.[7] A low and uniform DAR is generally associated with a more favorable pharmacokinetic profile and improved tolerability compared to ADCs with higher or variable DARs.[22]

The linker itself is described as a stable, non-cleavable amide/peptide linker.[5] Non-cleavable linkers are designed to be highly stable in the bloodstream and only release their payload after the entire ADC has been internalized by the target cell and the antibody component is degraded within the lysosome.[13] This contrasts with cleavable linkers, which are designed to be broken by specific conditions within the tumor microenvironment or inside the cell, but which can sometimes be cleaved prematurely in circulation, leading to off-target toxicity.

The combination of a silenced Fc region, a low and homogenous DAR of 2, and a highly stable non-cleavable linker paints a clear picture of SOTIO's design strategy: to create an exceptionally stable and tolerable ADC. This conservative, safety-focused approach was almost certainly a deliberate effort to manage and contain the extreme potency of the PNU-159682 payload. This very design, however, creates a central question that is critical to understanding the drug's ultimate fate. While intended to maximize the therapeutic window, this safety-first architecture may have inadvertently compromised efficacy if the non-cleavable linker was too stable to allow for efficient payload release inside the tumor cell, a possibility that must be considered in the context of its eventual discontinuation.

Preclinical and Clinical Development History

Preclinical Evaluation: A Profile of Potency and Specificity

Prior to entering the clinic, SOT-102 established a compelling preclinical profile, with key data presented at the American Association for Cancer Research (AACR) Annual Meeting in 2021.[9] The results from these studies generated significant optimism for the program, highlighting its potent anti-tumor activity and favorable pharmacological properties.

In a series of studies using patient-derived xenograft (PDX) models—which are considered more representative of human disease than standard cell-line xenografts—SOT-102 demonstrated remarkable single-agent efficacy. Across 10 different PDX models of gastric, pancreatic, liver, colon, and lung adenocarcinomas, SOT-102 induced complete tumor responses in all of them.[9] This 100% complete response rate is an exceptionally strong preclinical signal.

Perhaps more importantly, this profound efficacy was observed to be independent of the level of CLDN18.2 expression on the tumors. Complete responses were achieved in models with expression levels ranging from low (immunohistochemistry [IHC] score 1+) to high (IHC 3+).[9] This finding was particularly significant, as it suggested that SOT-102 could be effective in a much broader patient population than therapies requiring high target expression for activity. The potency was further underscored by the low minimum effective doses required to achieve these responses, which ranged from 0.2 mg/kg to 0.6 mg/kg.[9]

The preclinical safety and pharmacokinetic (PK) profile was equally encouraging. Preliminary toxicology studies in mice, rats, and cynomolgus monkeys indicated an acceptable tolerability profile, with a maximum tolerated dose (MTD) established at 10 mg/kg in mice and 1 mg/kg in monkeys.[9] The ADC exhibited a favorable PK profile with long circulating half-lives of approximately 8 days in cynomolgus monkeys and 13 days in rats.[9] Biodistribution studies using radioactively labeled SOT-102 confirmed its specificity, showing effective accumulation in tumors with limited binding to healthy stomach tissue.[9] Furthermore, the construct demonstrated excellent stability both

in vitro and in vivo, with no significant premature loss of the PNU-159682 payload.[9]

This collection of preclinical data was exceptionally robust, suggesting that SOT-102 had the potential to be a highly effective and well-tolerated therapy with a wide therapeutic index. The impressive results, particularly the complete responses in low-expressing models, set a very high bar of expectation for the drug's clinical performance. This makes the eventual outcome of the program a stark example of the "preclinical-to-clinical translation gap" that frequently challenges oncology drug development, where outstanding results in animal models do not always predict success in human trials.

The CLAUDIO-01 Clinical Program (NCT05525286 / EudraCT 2021-005873-25)

Buoyed by the strong preclinical data, SOTIO initiated the Phase 1/2 CLAUDIO-01 clinical trial in April 2022, marking the first-in-human evaluation of SOT-102.[4]

Study Design, Endpoints, and Patient Population

CLAUDIO-01 was an open-label, multicenter trial designed to enroll up to 109 patients with advanced or metastatic gastric/GEJ adenocarcinoma and pancreatic adenocarcinoma at sites across the United States and Europe, including Belgium, the Czech Republic, France, and Spain.[4]

The study was structured with a multi-part, adaptive design to efficiently gather data on safety, efficacy, and dosing in various settings:

• Primary Objectives: For the initial dose-escalation portions of the trial (Parts A and B), the primary objectives were to determine the maximum tolerated dose (MTD) and to establish the recommended Phase 2 dose (RP2D) of SOT-102.[24] For the subsequent dose-expansion portions (Parts C and D), the primary objective was to assess the anti-tumor efficacy of SOT-102, as measured by the objective response rate (ORR) according to RECIST 1.1 criteria.[3]
• Secondary Objectives: A comprehensive set of secondary objectives included assessing the overall safety and tolerability profile, characterizing the pharmacokinetic profile of the ADC and its metabolites, and evaluating further efficacy measures such as duration of response (DoR), progression-free survival (PFS), and overall survival (OS).[3]

Monotherapy and Combination-Therapy Cohorts

The trial's design was ambitious, aiming to test SOT-102 both as a single agent and in combination with standard-of-care (SoC) therapies across different lines of treatment.[25] The specific cohorts were:

• Part A (Monotherapy Dose Escalation): Patients with advanced gastric or pancreatic cancer who had exhausted standard treatment options received escalating doses of SOT-102 monotherapy. This arm was CLDN18.2-agnostic, meaning patients were enrolled regardless of their tumor's CLDN18.2 expression level.
• Part B (Combination Dose Escalation): This first-line treatment arm evaluated SOT-102 in combination with SoC chemotherapy. For pancreatic cancer, the combination was with nab-paclitaxel and gemcitabine. For gastric cancer, it was with mFOLFOX (folinic acid, fluorouracil, oxaliplatin) and the checkpoint inhibitor nivolumab. This arm was also CLDN18.2-agnostic.[25]
• Part C (Monotherapy Expansion): Following determination of the RP2D, this cohort was planned to enroll patients with CLDN18.2-positive tumors who had received at least one prior line of systemic therapy (i.e., second-line or later) to receive SOT-102 monotherapy.
• Part D (Combination Expansion): This cohort was planned to enroll first-line patients with CLDN18.2-positive tumors to receive SOT-102 at the RP2D in combination with the relevant SoC chemotherapy regimen.

SOT-102 was administered as a 45-minute intravenous infusion every 14 days, with a starting dose of 0.032 mg/kg, to be escalated based on a modified Fibonacci scheme.[3] Patients were premedicated with dexamethasone to manage potential side effects.[3]

As of October 2023, SOTIO issued a press release announcing that the first patients had been dosed in the combination therapy arms (Part B).[31] In this same announcement, the company made a critically important statement: "To date the trial has reported no dose-limiting toxicities".[31] This update, coming more than a year into the trial, suggested that the program was progressing as planned and that the drug was well-tolerated at the dose levels tested up to that point. The short timeframe between this positive-sounding update and the subsequent termination of the program is a key factor in analyzing the reasons for its discontinuation.

The End of the Line: Termination of the CLAUDIO-01 Trial and Program Discontinuation

Despite the promising preclinical data and the seemingly smooth initial progress of the clinical trial, SOTIO abruptly halted the development of SOT-102 in early 2025.

Multiple industry data sources confirm that the CLAUDIO-01 trial (NCT05525286) was terminated.[6] A report from Adis Insight, updated on January 10, 2025, specified that SOTIO had terminated the trial "based on benefit-risk reassessment".[34] This was corroborated by a report from the industry publication ApexOnco, which stated that the trial was terminated in January and that SOTIO had confirmed to them that "this molecule has been discontinued".[35]

SOTIO has not publicly released any specific clinical safety or efficacy data that precipitated this decision. The use of the broad term "benefit-risk reassessment" is common in such situations and deliberately avoids specifics. However, it is highly informative. It implies that the totality of the emerging clinical data—encompassing both safety (risk) and efficacy (benefit)—did not support a viable path forward for the drug. This type of reasoning differs from a discontinuation due to a clear, acute safety signal (which is often disclosed to regulatory bodies and the public) or a complete lack of biological activity. It suggests a more nuanced, multifactorial decision, likely driven by a calculation that the drug's clinical profile would not be competitive or commercially viable in the evolving therapeutic landscape. The absence of reported DLTs as of late 2023 further suggests the "risk" component may have manifested as an accumulation of lower-grade, chronic toxicities, or that the observed "benefit" was simply insufficient to justify any level of risk in the face of superior competitor data.

The Competitive Landscape for CLDN18.2-Targeted Therapies

The decision to discontinue SOT-102 cannot be understood in a vacuum. It was made within the context of one of the most dynamic and competitive target spaces in modern oncology. The clinical and commercial success of the first CLDN18.2-targeted agent, coupled with a crowded pipeline of next-generation ADCs, created an environment where only candidates with a clear best-in-class or highly differentiated profile could hope to succeed.

The Commercial Benchmark: Analysis of Zolbetuximab (Vyloy)

The benchmark for all CLDN18.2-targeted therapies was set by zolbetuximab (Vyloy, formerly IMAB362), a first-in-class chimeric IgG1 monoclonal antibody developed by Astellas.[8] Unlike an ADC, zolbetuximab is a "naked" antibody that does not carry a cytotoxic payload. Its mechanism of action relies on binding to CLDN18.2 on the surface of tumor cells and recruiting the patient's own immune system to attack the cancer through two primary mechanisms: antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).[36]

Zolbetuximab achieved regulatory success based on two large, randomized Phase 3 trials, SPOTLIGHT and GLOW.

• The SPOTLIGHT trial evaluated zolbetuximab in combination with the mFOLFOX6 chemotherapy regimen. It met its primary endpoint, demonstrating a statistically significant improvement in progression-free survival (PFS) (median 10.6 vs. 8.7 months; Hazard Ratio 0.75) and a key secondary endpoint of overall survival (OS) (median 18.2 vs. 15.5 months; HR 0.75) compared to placebo plus chemotherapy.[10]
• The GLOW trial evaluated zolbetuximab with the CAPOX chemotherapy regimen and similarly met its endpoints, showing improved PFS (median 8.2 vs. 6.8 months; HR 0.69) and OS (median 14.4 vs. 12.2 months; HR 0.77).[10]

Based on these results, zolbetuximab received regulatory approval in Japan (March 2024), the European Union (September 2024), and the United States (October 2024) for the first-line treatment of patients with locally advanced unresectable or metastatic, HER2-negative, CLDN18.2-positive gastric or GEJ adenocarcinoma.[10]

A critical aspect of zolbetuximab's approval is its reliance on a companion diagnostic test, the VENTANA CLDN18 (43-14A) Assay, and a stringent biomarker cutoff. To be eligible for treatment, a patient's tumor must exhibit moderate-to-strong membranous CLDN18.2 staining in ≥75% of tumor cells.[8] This high level of expression is found in approximately 38% of screened patients with gastric cancer, limiting the eligible patient population.[43]

The approval of zolbetuximab established a clear, albeit modest, clinical benchmark. Any new CLDN18.2-targeted agent, particularly a potent ADC like SOT-102, would need to demonstrate a compelling advantage. This could be achieved through significantly superior efficacy (a higher ORR or a greater magnitude of PFS/OS benefit), a more favorable safety profile (zolbetuximab is associated with significant nausea and vomiting), or, crucially, efficacy in a broader patient population—such as those with the low-to-moderate CLDN18.2 expression who are ineligible for zolbetuximab. SOT-102's preclinical data specifically suggested potential in this low-expressing population, which would have been a powerful differentiator. Its failure to advance implies this advantage did not translate into the clinic.

The Antibody-Drug Conjugate Arena: A Comparative Assessment

The field of CLDN18.2-targeted ADCs is intensely competitive, with numerous companies advancing candidates built with diverse technological approaches.[20] The progress of these competitors provides the most critical context for understanding the high bar SOT-102 failed to clear.

The discontinuation of SOT-102 was not an isolated event. In March 2025, Elevation Oncology announced it was discontinuing its own CLDN18.2 ADC, EO-3021.[50] EO-3021, which used an MMAE payload and a cleavable linker, was halted after demonstrating an ORR of only 22.2% in its Phase 1 trial. The company explicitly stated this was "insufficient to provide patients a competitive benefit-risk profile compared to other Claudin 18.2 ADCs in development".[50] This decision provides a valuable benchmark for what is considered a non-competitive efficacy signal in this space.

It is highly probable that the emerging clinical data for SOT-102 showed an efficacy profile in a similar, non-competitive range. Faced with a rapidly advancing field where competitors were posting superior results, SOTIO likely concluded that SOT-102's benefit-risk profile was unfavorable. The decision to terminate was therefore a rational, data-driven choice based on the high probability that the asset would not be clinically or commercially viable.

Table 1 provides a comparative overview of SOT-102 and its key competitors, highlighting the different technological strategies being pursued.

Table 1: Comparative Landscape of Key CLDN18.2-Targeted Antibody-Drug Conjugates

Drug Name	Developer(s)	Payload	Payload MOA	Linker	DAR	Highest Phase	Status / Key Data
SOT-102	SOTIO Biotech / NBE-Therapeutics	PNU-159682	Topo II Inhibitor	Non-cleavable	2	Phase 1/2	Discontinued (Jan 2025) based on benefit-risk reassessment.34
Zolbetuximab (Vyloy)	Astellas	None (Naked mAb)	ADCC / CDC	N/A	N/A	Approved	First-in-class approved agent. Modest PFS/OS benefit in high-expressers (≥75%).42
IBI-343	Innovent Biologics / Synaffix	Exatecan	Topo I Inhibitor	Cleavable (toxSYN®)	4	Phase 3	Strong data in 2L+ pancreatic cancer (cORR 22.7%, mPFS 5.4 mo). FDA Fast Track & NMPA BTD.51
AZD0901 (CMG901)	AstraZeneca / Keymed Biosciences	MMAE	Tubulin Inhibitor	Cleavable	~4	Phase 3	Promising efficacy in gastric cancer (ORR 48% at 2.2 mg/kg), but notable toxicity (55% Grade ≥3 TRAEs).55
RC118	RemeGen	MMAE	Tubulin Inhibitor	Cleavable (vc-PAB)	TBD	Phase 1/2	Early data (Dec 2022) showed favorable safety and tolerability with no DLTs.20
EO-3021 (SYSA1801)	Elevation Oncology / CSPC Pharma	MMAE	Tubulin Inhibitor	Cleavable	2	Phase 1	Discontinued (Mar 2025) due to insufficient efficacy (ORR 22.2%).10

MOA: Mechanism of Action; Topo: Topoisomerase; ADCC: Antibody-Dependent Cellular Cytotoxicity; CDC: Complement-Dependent Cytotoxicity; DAR: Drug-to-Antibody Ratio; MMAE: Monomethyl Auristatin E; ORR: Objective Response Rate; PFS: Progression-Free Survival; BTD: Breakthrough Therapy Designation.

The data in Table 1 clearly illustrates the intense competition and the variety of technologies being deployed. The success of topoisomerase I inhibitor-based ADCs like IBI-343 (and the broader success of this payload class in other oncology settings, e.g., Enhertu) may indicate a superior therapeutic window for this payload class compared to MMAE or, in the case of SOT-102, the ultra-potent PNU-159682.

Strategic Analysis and Expert Perspective

A Critical Analysis of SOT-102's Discontinuation: Synthesizing Potential Factors

The discontinuation of SOT-102, a program backed by exceptionally strong preclinical data and a rational, safety-focused design, can be attributed to a confluence of factors that underscore the brutal realities of modern oncology drug development. The decision was likely not based on a single catastrophic failure but on a holistic "benefit-risk reassessment" in a fiercely competitive environment.[34]

1. Insurmountable Competitive Pressures and a Rising Efficacy Bar: The primary driver for the discontinuation was almost certainly the rapidly evolving competitive landscape. As detailed in the previous section, the approval of zolbetuximab and, more critically, the impressive early clinical data from other ADCs like AZD0901 (48% ORR) and IBI-343 (22.7% cORR in difficult-to-treat pancreatic cancer) set an extremely high bar for clinical success.[52] The subsequent discontinuation of a peer ADC, EO-3021, due to a 22.2% ORR being deemed "insufficient to provide a competitive benefit-risk profile," provides a tangible benchmark for failure.[50] It is the most plausible hypothesis that SOTIO's internal, unblinded data from the CLAUDIO-01 dose-escalation cohorts revealed an efficacy signal (e.g., ORR) that was in this non-competitive range. For a company to continue investing hundreds of millions of dollars into late-stage development, it needs to see a clear path for its asset to be, at minimum, competitive, if not best-in-class. The emerging data likely showed that SOT-102 was not on that path.

2. The Preclinical-to-Clinical Translation Gap: The stark contrast between the 100% complete response rate in preclinical models and the presumed lackluster clinical efficacy necessitates an examination of why the translation failed. There are two primary, non-mutually exclusive possibilities related to SOT-102's unique design:

• Unforeseen Payload Toxicity: While the company reported "no DLTs" in late 2023, this does not preclude the emergence of a pattern of cumulative, lower-grade toxicities that could have narrowed the therapeutic window in humans. The PNU-159682 payload is exceptionally potent.[17] It is possible that chronic, on-target toxicities (e.g., in the GI tract) or other off-target effects became apparent with continued dosing in humans, in a way that was not captured in shorter-term animal toxicology studies. This could have limited dose escalation, preventing the drug from reaching a concentration needed for robust efficacy.
• Suboptimal Efficacy Due to a Safety-Focused Design: The alternative, and perhaps more likely, explanation is that the design choices made to ensure safety inadvertently blunted efficacy. The combination of a silenced Fc region, a low DAR of 2, and a highly stable, non-cleavable linker was engineered to prevent premature payload release.[5] However, this very stability may have been its downfall. If the non-cleavable linker was not efficiently processed within the lysosomes of human cancer cells, it would lead to insufficient release of the PNU-159682 warhead at the site of action. This would result in a lower-than-expected level of tumor cell killing, leading to the modest efficacy profile that could not compete with ADCs using more optimized, cleavable linker-payload systems.

3. Rational Strategic Portfolio Prioritization: Ultimately, the decision was a strategic one about resource allocation. SOTIO is a privately-funded, clinical-stage biotech that must make calculated bets to maximize its return on investment. Continuing to pour capital and personnel into a high-risk program in an over-crowded field, especially when its clinical profile is showing signs of being non-competitive, is a poor use of resources. The rational business decision was to terminate the SOT-102 program and pivot those resources to other assets in the pipeline where the company perceives a greater probability of success and a clearer competitive advantage.

SOTIO Biotech's Evolving Pipeline Strategy: A Post-Mortem Pivot

SOTIO's corporate strategy following the discontinuation of SOT-102 is highly instructive. The company did not retreat from the ADC space; instead, it executed a sophisticated pivot, demonstrating a commitment to the modality while evolving its technological approach and strategic focus. This pivot is characterized by diversification in technology, targets, and complexity.

Technology Diversification: SOTIO has moved from a primary reliance on the NBE-Therapeutics platform used for SOT-102 to a multi-platform strategy, in-licensing technologies from several leading ADC specialists.[61] This includes partnerships with:

• LegoChem Biosciences: Licensing the ConjuALL™ platform, which utilizes a cleavable linker, for the development of SOT106.[35]
• Synaffix (a Lonza company): Licensing the GlycoConnect™ site-specific conjugation and toxSYN® linker-payload platforms. This technology is notably used for SOT109, which employs a topoisomerase I inhibitor (exatecan) payload—the same class used by the successful competitor IBI-343—and for its new bispecific ADC programs.[35]
• Biocytogen: Licensing access to the RenLite® platform to generate fully human monoclonal and bispecific antibodies, providing high-quality targeting moieties for its next-generation ADC programs.[63]

Target and Complexity Diversification: SOTIO has strategically moved away from the hyper-competitive CLDN18.2 target. Its new lead ADC assets are aimed at novel targets where it has a greater opportunity to establish a first-in-class or best-in-class position:

• SOT106: Targets Leucine-rich repeat-containing protein 15 (LRRC15), a protein overexpressed in mesenchymal malignancies like sarcomas.[65]
• SOT109: Targets Cadherin-17 (CDH17), a protein highly and homogenously expressed in colorectal cancer and other GI cancers.[68]
• SOT112 and SOT113: These are preclinical bispecific ADCs, representing a move toward more complex therapeutics designed to address challenges like tumor heterogeneity. SOT113 is being developed for prostate cancer, while SOT112 has potential applicability in several major cancer indications.[66]

This strategic evolution demonstrates that SOTIO is a mature and agile organization. The company learned from the market dynamics surrounding SOT-102, made the difficult but correct decision to avoid investing further in a non-competitive asset, and redeployed its capital into a diversified portfolio. This new portfolio is built on what are now considered more clinically validated technologies (e.g., Topo1i payloads, Synaffix's platform) and is aimed at less-crowded, high-potential targets. This is the hallmark of sophisticated, modern R&D portfolio management.

Concluding Perspective: The Future of CLDN18.2 as a Target and Lessons for ADC Development

The development and subsequent discontinuation of SOT-102 offers several critical lessons for the field of oncology drug development, particularly for antibody-drug conjugates.

First, CLDN18.2 remains a clinically validated and commercially significant therapeutic target. The regulatory approvals of zolbetuximab have firmly established its importance, and the intense industry focus, with dozens of companies pursuing the target with various modalities, attests to its perceived value.[11] The market for these therapies is substantial, driven by the high prevalence of gastric and pancreatic cancers.[80]

Second, the story of SOT-102 is a powerful cautionary tale about the gap between preclinical promise and clinical reality. Even an outstanding preclinical data package, as SOT-102 possessed, is no guarantee of clinical success. The complexities of human biology, metabolism, and toxicology can reveal liabilities that are not apparent in animal models.

Third, in a highly competitive therapeutic area, being "good" is often not good enough. A new therapeutic agent must demonstrate a clear and compelling advantage over both the existing standard of care and the emerging competition. SOT-102 was discontinued not necessarily because it was a "bad" drug, but because it was unlikely to be a "better" drug in a field where the bar for success was rising rapidly.

Finally, the SOT-102 program highlights the exquisite balancing act required in ADC design. The interplay between the antibody, linker, and payload determines the therapeutic window. SOTIO's safety-focused design, intended to contain a highly potent payload, appears to have resulted in a suboptimal clinical profile. This underscores that every component of an ADC must be co-optimized not just for stability, but for effective payload delivery and release within the target cell. The ultimate lesson from SOT-102 is one of strategic agility. SOTIO's willingness to terminate a program that was not meeting a high competitive standard and pivot its resources to a new generation of assets is a model of rational portfolio management in the high-stakes, fast-moving world of cancer drug development.

Appendices

Detailed Parameters of the CLAUDIO-01 Clinical Trial (NCT05525286 / EudraCT 2021-005873-25)

The CLAUDIO-01 trial was a Phase 1/2, first-in-human, open-label, multicenter study designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of SOT-102 in patients with advanced gastric/GEJ and pancreatic adenocarcinoma.[21] The trial was conducted at sites in the USA, Belgium, Czech Republic, France, and Spain.[4]

Table 2: Overview of the CLAUDIO-01 (NCT05525286) Study Design

Part	Patient Population	Biomarker Status	Intervention	Primary Objective
A	Advanced Gastric/Pancreatic Cancer (Last-line)	CLDN18.2 Agnostic	SOT102 Monotherapy (Dose Escalation)	Determine MTD and RP2D
B	Advanced Gastric/Pancreatic Cancer (First-line)	CLDN18.2 Agnostic	SOT102 (Dose Escalation) + SoC Chemotherapy*	Determine MTD and RP2D
C	Advanced Gastric/Pancreatic Cancer (≥2nd-line)	CLDN18.2 Positive	SOT102 Monotherapy (at RP2D)	Assess Objective Response Rate (ORR)
D	Advanced Gastric/Pancreatic Cancer (First-line)	CLDN18.2 Positive	SOT102 (at RP2D) + SoC Chemotherapy*	Assess Objective Response Rate (ORR)

SoC (Standard of Care) Chemotherapy: For pancreatic cancer, nab-paclitaxel + gemcitabine. For gastric cancer, mFOLFOX + nivolumab.[25]

Key Inclusion Criteria [25]:

• Age ≥18 years.
• Histological or cytological evidence of advanced, inoperable, or metastatic adenocarcinoma of the stomach, GEJ, or pancreas.
• ECOG performance status of 0 or 1.
• Life expectancy of ≥3 months.
• Adequate organ function (hematologic, hepatic, and renal).
• For Part C/D, confirmed CLDN18.2-positive tumor status.
• For Part A, patients must have had no better treatment option available.
• For Part C, patients must have received at least one (pancreas) or two (gastric) prior systemic therapies for advanced disease.

Key Exclusion Criteria [25]:

• Prior therapy with any agent directed at CLDN18.2.
• Symptomatic central nervous system (CNS) metastases.
• History of interstitial pneumonitis or pulmonary fibrosis.
• Peripheral sensory neuropathy of Grade ≥2.
• Active, uncontrolled infection.
• Significant cardiovascular conditions, including history of major ventricular arrhythmias or NYHA class ≥3 heart failure.
• Severe preexisting medical conditions, such as active gastric ulcers with bleeding.

Key Data Points from Preclinical Studies

The following table summarizes key quantitative data from the preclinical evaluation of SOT-102, primarily from the poster presented at the AACR 2021 Annual Meeting.[9]

Parameter	Finding	Species/Model
Target Affinity (EC50​)	2-4 nM	CLDN18.2-expressing cell lines
Internalization Rate	>60% within 12 hours	Target-expressing cells
In Vitro Cytotoxicity (EC50​)	10 pM	HEK293_CLDN18.2 cells
In Vivo Efficacy	Complete responses in 10/10 models	PDX models (gastric, pancreatic, etc.)
Minimum Effective Dose	0.2 - 0.6 mg/kg	PDX models
Maximum Tolerated Dose (MTD)	10 mg/kg (single dose)	Mouse
Maximum Tolerated Dose (MTD)	1 mg/kg (single dose)	Cynomolgus Monkey
Pharmacokinetic Half-life (t1/2​)	~8 days	Cynomolgus Monkey
Pharmacokinetic Half-life (t1/2​)	~13 days	Rat

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