Sodium-dependent phosphate transporter 2B (SLC34A2), also known as NaPi-2b, actively transports phosphate into cells via sodium ion cotransport. Mutations in this gene can cause pulmonary alveolar microlithiasis (PAM), characterized by the deposition of calcium phosphate crystals in the alveoli. When SLC34A2 is mutated (e.g., nonsense or frameshift mutations), it leads to defective phosphate transport function in alveolar type II epithelial cells (AT-II), resulting in elevated phosphate levels in the alveolar wall fluid, calcium phosphate stone deposition in the alveoli, and ultimately, pulmonary dysfunction.

(Data source: Jönsson ÅLM, et al. Orphanet J Rare Dis. 2023)

(Data source: Jönsson ÅLM, et al. Eur Respir J. 2020)

SLC34A2 expression distribution

SLC34A2 is primarily expressed in alveolar cells, with limited expression in goblet cells, secretory cells, luminal cells, and germ cells. SLC34A2 is expressed on the surface of various cancer types and is a known fusion partner for ROS1 (ROS proto-oncogene 1, receptor tyrosine kinase) in non-small cell lung cancer. NaPi2b is highly expressed in various malignancies, including high-grade serous ovarian cancer, fallopian tube cancer, primary peritoneal cancer, as well as thyroid cancer, breast cancer, and non-squamous non-small cell lung cancer, while its distribution in normal tissues is limited; therefore, it is considered a promising target for anti-tumor therapy.

(Data source: uniprot)

Structure and mutants of SLC34A2

SLC34A2 is a multi-transmembrane protein composed of 690 amino acids and consisting of 8 transmembrane regions. Its N-terminus and C-terminus are located on the cytoplasmic side, and multiple transmembrane helical segments are connected in the middle to form a complex intracellular and extracellular loop.

(Data source: protter)

SLC34A2 clinical development drug

AP306 is an oral inhibitor that inhibits phosphate transporters NaPi-IIb, PiT-1, and PiT-2. Developed by Alebund, it is the world's first and currently the only pan-inhibitor of sodium-dependent phosphate transporters in clinical development. According to the official announcement from the CDE (Center for Drug Evaluation), the expert panel recognized AP306 as an innovative drug due to its novel mechanism of action. This drug has shown significant clinical improvement in existing treatments. In the completed Phase II clinical trials of AP306 (CTR20230189; NCT05764590), AP306 monotherapy showed a significant decrease in serum phosphate levels after treatment. AP306 is safe and well-tolerated. Compared with existing treatment options, AP306 holds promise for significantly improving serum phosphate control and becoming a new treatment option for patients with hyperphosphatemia.

(Data source: Alebund official website)

LM-2417, an innovative drug independently developed by LaNova Medicines, is a bispecific antibody targeting NaPi2b/4-1BB. Its Phase I clinical trial in China, initiated in September 2025, has successfully enrolled its first patient, marking the official entry of this innovative therapy into the clinical development stage. LM-2417 specifically binds to NaPi2b on the surface of tumor cells and 4-1BB on the surface of immune cells. This mechanism enables precise activation of immune cells in the tumor microenvironment, thereby enhancing anti-tumor effects. Unlike traditional 4-1BB agonists, LM-2417 selectively activates the 4-1BB signaling pathway in a NaPi2b-dependent manner, potentially significantly reducing the risk of toxicity caused by nonspecific immune activation. Preclinical data indicate that LM-2417 not only induces durable anti-tumor immune memory but also exhibits significant synergistic effects when used in combination with other immunotherapies. These characteristics give LM-2417 the potential to become a first-in-class immunotherapy.

YL205 is an antibody-drug conjugate targeting NaPi2b developed by MediLink Therapeutics. It is currently in Phase I clinical trials for the treatment of advanced malignant solid tumors, endometrial cancer, and renal tumors.

(Data source: MediLink Therapeutics official website)

TUB-040 is an antibody-drug conjugate consisting of an IgG1 antibody against NaPi2b and a topoisomerase I inhibitor. It is linked via a cleavable linker system based on the company's proprietary P5 conjugation technology, resulting in a uniform drug-to-antibody ratio (DAR) of 8. TUB-040 has received Fast Track designation from the FDA for the treatment of patients with platinum-resistant ovarian cancer (PROC). This candidate drug is currently being investigated in a multicenter Phase 1/2a study (NAPISTAR 1-01, NCT06303505) to evaluate the safety, tolerability, pharmacokinetics, and efficacy of TUB-040 as monotherapy in patients with PROC or relapsed/refractory non-small cell lung cancer (NSCLC) adenocarcinoma.

In October 2025, Tubulis presented the first clinical data of TUB-040 from the PRO-C1/2a study at the ESMO conference. TUB-040 demonstrated strong clinical activity, good safety and excellent tolerability in PRO-C patients who had not undergone biomarker selection and had received multiple treatments.

(Data source: Tubulis official website)

ARC-201 is a dual-load ADC targeting NaPi2b developed by Araris Biotech. It features good pharmacokinetic properties, high efficiency, and high tolerability. It exhibits high targeting specificity and stronger toxicity compared to DAR4 Exatecan ADC, thus demonstrating a higher Tl value in in vitro experiments.

(Data source: AACR)