Given the heterogeneity of ovarian cancer, identification of a biomarker that is subtype-agnostic and stably expressed over time is of particular clinical interest. One such target is sodium-dependent phosphate transport protein 2b (NaPi2b), which may serve as a lineage biomarker and therapeutic gateway for innovative antibody-drug conjugates (ADCs).
“Platinum-resistant ovarian cancer has a higher need because we don’t have sufficiently active treatments,” Antonio Gonzalez-Martin, MD, stated in an interview with OncLive®. “One of the most important strategies today is to explore the concept of ADCs [for gynecologic malignancies.] NaPi2b is a very interesting target [for ADC development], because it’s a cell surface transporter that is highly expressed in ovarian cancer.” Gonzalez-Martin serves as director of the Department of Medical Oncology and the Cancer Center Clinica Universidad de Navarra in Pamplona, Spain, as well as a principal investigator of the Translational Oncology group.
Prior research has suggested that dysregulation of phosphate transport through NaPi2b contributes to tumorigenesis in ovarian, lung, and breast cancers. Moreover, both preclinical and early clinical studies have shown that NaPi2b is highly expressed in high-grade serous epithelial ovarian, fallopian tube, and primary peritoneal cancers, with limited expression in normal tissues. Expression has also been observed in thyroid, breast, and nonsquamous non–small cell lung cancers (NSCLC), underscoring its relevance across tumor types.
Additional preclinical data have shown that antibodies directed against NaPi2b have successfully been used for tumor mapping and targeted cytotoxic delivery. Collectively, these findings support NaPi2b as a viable target for drug development.
Mixed Results Arise With Earlier NaPi2b-Targeted Agents
Although NaPi2b is not an oncogene and thus not suitable for targeted inhibition, its selective expression in ovarian tumor tissue offers a unique opportunity for ADC-mediated drug delivery.
To date, 2 NaPi2b-targeting ADCs—lifastuzumab vedotin (LIFA) and upifitamab rilsodotin (UpRi; XMT-1536)—have been evaluated in early-phase studies in ovarian cancer:
Lifastuzumab Vedotin
LIFA, an ADC comprising a humanized anti-NaPi2b monoclonal antibody conjugated to monomethyl auristatin E, was evaluated in a phase 2 study (NCT01991210) of patients with platinum-resistant ovarian cancer. Findings from the study showed that patients experienced a median progression-free survival (PFS) of 5.3 months with LIFA (n = 47) vs 3.1 months with pegylated liposomal doxorubicin (n = 48; HR, 0.78; 95% CI, 0.46-1.31; P = .343) in the overall population.2 Among those with high NaPi2b expression by H-score immunohistochemistry, the median PFS was 5.3 vs 3.4 months (HR, 0.71; 95% CI, 0.40-1.26; P = .243), respectively; objective response rates (ORR) with these respective regimens were 36% (95% CI, 22%- 52%) vs 14% (95% CI, 6%-27%; P = .02).
Although these results suggested a potential clinical benefit with LIFA, the difference in PFS between the 2 arms was not statistically significant. However, 93% of study participants were classified as high expressors of NaPi2b, potentially indicating that the diagnostic assay used in this study was not optimized to identify true responders vs nonresponders.1
The agent was later evaluated alongside carboplatin with or without bevacizumab (Avastin) in patients with platinum-sensitive ovarian cancer in an open-label, multicenter phase 1b study (NCT01363947), where it demonstrated safety and initial activity.3 Among efficacy-evaluable patients (n = 41), the confirmed ORR (cORR) was 59%, and the median PFS was 10.7 months (95% CI, 8.54-13.86) across all cohorts. At the recommended phase 2 dose of 2.4 mg/kg of LIFA with carboplatin AUC6, the median PFS was 8.5 months (95% CI, 5.78, 13.80) without 15 mg of bevacizumab and 13.9 months (95% CI, 12.32-20.96) with bevacizumab. No dose-limiting toxicities were observed in this study.
Based on findings from the phase 2 evaluation, the development of this agent was later discontinued.
Upifitamab Rilsodotin
UpRi, a first-in-class NaPi2b-directed ADC, was developed using a novel Dolasynthen platform enabling a high drug-to-antibody ratio of 10:1. Its auristatin F-HPA payload was engineered to produce a controlled bystander effect and minimize off-target toxicity. Early data from a phase 1/1b study of 97 patients with high-grade serous ovarian cancer demonstrated encouraging antitumor activity and a favorable safety profile with this agent.4
However, results from the subsequent phase 1/2 UPLIFT trial (NCT03319628) were far more modest. Among patients with NaPi2b-positive platinum-resistant high-grade serous ovarian cancer (n = 141), the ORR was 15.6% (95% CI, 10.0%-22.7%), falling short of the prespecified efficacy threshold.5 ORRs were 10.2% (95% CI, 5.6%-16.9%) in the NaPi2b-low group (n = 127) and 13.1% (95% CI, 9.3%-17.7%) in the intention-to-treat population. These findings suggested that NaPi2b expression alone was not predictive of response.
As a result, the development of UpRi was discontinued by Mersana Therapeutics in July 2023.6 However, in December 2022, the European Commission granted UpRi orphan drug designation for ovarian cancer, underscoring ongoing interest in NaPi2b as a therapeutic target.7
TUB-040 Renews Interest in ADCs as an Effective Avenue for Targeting NaPi2b in Ovarian Cancer
Although prior ADCs such as LIFA and UpRi demonstrated feasibility but limited efficacy, promising early activity with the next-generation ADC TUB-040 has renewed interest in NaPi2b-targeted approaches.
TUB-040 consists of an Fc-silenced IgG1 antibody directed against NaPi2b, conjugated via a P5 peptide-cleavable linker to the cytotoxic topoisomerase I inhibitor exatecan, with a drug-to-antibody ratio of 8:1.8 The design aims to enhance tumor penetration, improve tolerability, and maintain potency.
“TUB-040 is a nice ADC because of the design of the molecule,” Gonzalez-Martin explained.“It makes the payload extremely stable to the linker. That could make the difference [not only] in terms of safety, but also in terms of [bystander] activity.”
The agent is currently under evaluation in the phase 1/2a NAPISTAR1-01 trial (NCT06303505), a proof-of-concept dose escalation study in patients with platinum-resistant, high-grade serous ovarian cancer and NSCLC.8
At the 2025 ESMO Congress, initial findings from 46 patients in the ovarian cancer cohort were presented. In this patient population, the cORR was 50% and a disease control rate (DCR) of 96% across dose levels ranging from 1.67 mg/kg to 3.3 mg/kg. At a median follow-up of 7.8 months (range, 1.0-9.2), cORRs of 40%, 58%, 58%, and 42% were observed at the 1.67-mg/kg, 2.1-mg/kg, 2.5-mg/kg, and 3.3-mg/kg doses, respectively. Of note, 1 patient achieved a complete response at the 2.5 mg/kg level. The CA125 response rate was 81%, and the drug’s activity was observed across both high and low folate receptor alpha expression groups.
“It’s important [to note] that this was a heavily-pretreated patient population, and patients have already received the current standard of care,” Gonzalez-Martin noted. “Interestingly, we started to see responses [starting] from the 1.67-mg/kg dose. ORRs for these 4 doses range from [40% to 60%], indicating that this drug produces a high response rate, even at lower doses.”
NAPISTAR-01 enrolled a total of 67 patients with ovarian cancer across dose levels ranging from 0.5 mg/kg to 5.3 mg/kg. Across all dose cohorts, the median age was 62 years (range, 34.0-81.0) and the time from first diagnosis was a median of 5.3 years. The median number of prior lines of therapy was 4 (range, 1-7); most patients were previously exposed to bevacizumab (83.6%) or a PARP inhibitor (76.1%), and 13.4% had previously been treated with mirvetuximab soravtansine-gynx (Elahere). The median NaPi2b H-score was 175 (range, 95-295). The median exposure to TUB-040 was 161 days. In total, 22% of patients discontinued treatment due to disease progression (n = 13) and adverse effects (n = 2).
Treatment-emergent adverse effects (TEAEs) occurred in all patients. Grade 3 or higher TEAEs were reported in 35% of those in the 1.67-mg/kg to 3.3-mg/kg dose range and 49% across the full ovarian cancer cohort. The most common TEAEs were nausea (78.3%), fatigue (47.8%), neutropenia (41.3%), anemia (34.8%), and diarrhea (32.6%), which were predominantly grade 1/2. Dose-limiting toxicity was observed at 5.3 mg/kg, establishing a maximum tolerated dose of 4.4 mg/kg for subsequent evaluation in the phase 2a portion of the study.
“We are now starting the dose optimization [part of the] study, which is important just to select the best dose for our patients,” Gonzalez-Martin noted. “We are obviously in the early process of development for TUB-040, but our initial data—the response rate, the safety, the suggested durability of responses—look extremely promising.”
In June 2024, the FDA granted fast track designation to TUB-040 for the treatment of patients with platinum-resistant ovarian cancer based on its early clinical activity and manageable safety profile.9
As data from NAPISTAR1-01 continue to mature, efforts to leverage NaPi2b as a therapeutic target may finally bear fruit for ovarian cancer and other related malignancies.
“There are a lot of opportunities for the development [of TUB-040 and other ADCs] in ovarian cancer, not only in the platinum-resistant setting. We are waiting for the data from the lung cancer cohort, [which will tell us if] this approach will also [have activity] in NSCLC. This could be something [that is] very good for our patients in the future,” Gonzalez-Martin concluded.
References
- Banerjee S, Drapkin R, Richardson DL, et al. Targeting NaPi2b in ovarian cancer. Cancer Treat Rev. 2023;112:102489. doi:10.1016/j.ctrv.2022.102489
- Banerjee S, Oza AM, Birrer MJ, et al. Anti-NaPi2b antibody-drug conjugate lifastuzumab vedotin (DNIB0600A) compared with pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer in a randomized, open-label, phase II study. Ann Oncol. 2018;29(4):917-923. doi:10.1093/annonc/mdy023
- Moore KN, Birrer MJ, Marsters J, et al. Phase 1b study of anti-NaPi2b antibody-drug conjugate lifastuzumab vedotin (DNIB0600A) in patients with platinum-sensitive recurrent ovarian cancer. Gynecol Oncol. 2020;158(3):631-639. doi:10.1016/j.ygyno.2020.05.039
- Richardson D, Hamilton E, Barve M, et al. Updated results from the phase 1 expansion study of upifitamab rilsodotin (UpRi; XMT-1536), a NaPi2b-directed dolaflexin antibody drug conjugate (ADC) in ovarian cancer (076). Gynecol Oncol. 2022;166(suppl 1):S48. doi:10.1016/S0090-8258(22)01294-X
- Richardson DL, Concin N, Hays JL, et al. UPLIFT (ENGOT-OV67/GOG-3048): Results from the phase II trial of upifitamab rilsodotin (UpRi; XMT-1536), a NaPi2b-directed dolaflexin antibody-drug conjugate in platinum-resistant ovarian cancer. Presented at the 2024 SGO Annual Meeting on Women’s Cancer; San Diego, CA; March 16-18, 2024.
- Mersana Therapeutics announces topline data from UPLIFT clinical trial in patients with platinum-resistant ovarian cancer and strategic reprioritization. News Release. Mersana Therapeutics, Inc. July 27, 2023. Accessed November 12, 2025 https://ir.mersana.com/news-releases/news-release-details/mersana-therapeutics-announces-topline-data-uplift-clinical
- European Commission designates UpRi as an orphan medicinal product for the treatment of ovarian cancer. News Release. Mersana. December 14, 2022. Accessed November 12, 2025. https://ir.mersana.com/news-releases/news-release-details/european-commission-designates-upri-orphan-medicinal-product
- González-Martín A, Sehouli J, Braicu EI, et al. NAPISTAR 1-01: A phase I dose escalation study of TUB-040, a novel NaPi2b-targeting exatecan antibody-drug conjugate (ADC) in patients with platinum-resistant ovarian (PROC) high grade serous carcinoma (HGSC). Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA43.
- Tubulis receives FDA fast track designation for antibody-drug conjugate candidate TUB-040 in platinum-resistant ovarian cancer. News release. Tubulis. June 27, 2024. Accessed November 12, 2025. https://tubulis.com/news/tubulis-receives-fda-fast-track-designation-for-antibody-drug-conjugate-candidate-tub-040-in-platinum-resistant-ovarian-cancer/
