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Nanobodies Empower Innovative Drugs! First Patient Dosed in Phase III Clinical Trial of JSKN016

Category : Market Insights • Last Updated : 2026-03-27 21:16:49 • Hits : 6

Recently, nanobody applications in oncology have achieved a major breakthrough: JSKN016, a bispecific ADC independently developed by Alphamab Oncology, has dosed its first patient in a Phase III trial. This milestone signifies that nanobody‑enabled innovative drug R&D has entered a critical phase, highlighting the clinical value and application potential of nanobodies.

Nanobodies Empower Innovative Drugs! First Patient Dosed in Phase III Clinical Trial of JSKN016
             As a core innovative drug in the oncology field, the clinical advancement of JSKN016 directly validates the tremendous value of nanobodies. JSKN016 is a bispecific ADC targeting HER3 and TROP2. Compared with existing therapeutic regimens, the core advantages of this innovative drug are inseparable from the empowerment of nanobodies: its HER3-binding domain is designed with a high-affinity nanobody, paired with a low-affinity TROP2-binding domain. This design not only ensures precise tumor targeting but also reduces on-target toxicities such as oral mucositis. Its affinities for HER3 and TROP2 reach 1.233E-9 and 2.854E-9 respectively, demonstrating excellent targeting performance.
           Currently, in addition to the Phase III clinical trial for triple-negative breast cancer (TNBC), JSKN016 is also undergoing multiple Phase II clinical studies for other cancer types including non-small cell lung cancer (NSCLC) and gastric cancer, further expanding the application boundaries of nanobody-empowered ADC drugs.



Target Introduction

TROP2 (Trophoblast Cell Surface Antigen 2)

  • TROP2 is a transmembrane glycoprotein belonging to the family of cell surface antigens. It is expressed at low levels in normal tissues but is highly expressed in various malignant tumors including triple-negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), gastric cancer, and colorectal cancer. Its expression level is closely associated with tumor stage, invasiveness, and patient survival rate.
  • TROP2 regulates tumor cell proliferation, apoptosis, invasion, and metastasis by activating signaling pathways such as PI3K/Akt and MAPK. Meanwhile, it can mediate drug endocytosis, making it an ideal target for antibody-drug conjugate (ADC) therapeutics.
  • Traditional antibodies targeting TROP2 are prone to off-target toxicity. In contrast, nanobodies can precisely recognize TROP2-specific epitopes and efficiently mediate ADC endocytosis upon binding, thereby enhancing tumor-killing efficacy while reducing damage to normal tissues. This has become a core direction for the optimization of TROP2-targeted drugs[1].

Figure 1 Core Role of TROP2 in Oncogenic Signaling Pathways[2]


HER3 (Human Epidermal Growth Factor Receptor 3)

  • It's a member of the epidermal growth factor receptor (EGFR) family and belongs to the transmembrane tyrosine kinase receptors. It is widely expressed in various normal tissues, but exhibits abnormally high expression or activation in multiple malignant tumors including breast cancer, non-small cell lung cancer (NSCLC), gastric cancer, and esophageal cancer.
  • HER3 has weak intrinsic kinase activity and primarily forms heterodimers with other family members such as EGFR and HER2 to activate downstream signaling pathways including PI3K/Akt, thereby promoting tumor cell proliferation, survival, invasion, and metastasis[3], while also participating in the development of resistance to targeted therapy and chemotherapy in tumor cells.
  • Given the pivotal role of HER3 in tumor progression and the correlation between its aberrant expression and poor patient prognosis[4], HER3 has emerged as an important target for precision cancer therapy. With their advantages of high affinity and strong specificity, nanobodies can precisely bind to HER3 antigenic epitopes and block its signal transduction, providing a novel approach for the development of HER3-targeted drugs.


    Figure 2 HER3 Dimerization and Its Signaling Cascade[5]

    Drug Structure and Mechanism of Action

Drug Structure：

JSKN016 is a bispecific antibody targeting TROP2 and HER3 developed using single-domain antibody and bispecific antibody platforms. A homogeneous and stable ADC with a DAR of 4 is obtained via site-specific glycosylation conjugation.


Figure 3 Molecular Structure of JSKN016

Mechanism of Action：

  • Upon binding to receptors on the surface of TROP2- or HER3-positive cancer cells, JSKN016 is internalized into the cells. Following internalization, the drug traffics through early endosomes, late endosomes, and ultimately reaches lysosomes.
  • Owing to the cleavable linker, the linker is cleaved under acidic or enzymatic conditions in lysosomes, releasing the payload (TOPi, a topoisomerase I inhibitor) into the cancer cells. The released TOPi enters the nucleus, inhibits topoisomerase I activity, interferes with DNA replication, and thereby induces apoptosis in positive cancer cells.
  • The TOPi released within TROP2- or HER3-positive cancer cells can penetrate the cell membrane and diffuse into surrounding antigen-negative cancer cells (i.e., cancer cells that do not express TROP2 or HER3). Although these negative cancer cells are not directly targeted by the antibody, they are killed by the diffused toxic payload and undergo apoptosis as well.



    Figure 4 Mechanism of Action of JSKN016



Applications of Nanobodies

Novamab Biopharma: A Trop-2 nanobody inhibitor drug, currently at the drug discovery stage globally with the highest R&D status. Mechanism of action: Trop-2 inhibitor (tumor-associated calcium signal transducer 2 inhibitor). Nanobodies possess advantages such as strong tissue penetration, high internalization efficiency, and low immunogenicity, showing great potential in ADC construction.

HuNbTROP2‑HSA‑MMAE is a Trop-2-targeted nanobody-drug conjugate for the treatment of Trop-2-positive pancreatic cancer. This drug employs an anti-Trop-2 nanobody fused with human serum albumin (HSA) and conjugated to MMAE, with a DAR value of 1. Compared with conventional antibodies, nanobodies confer distinct advantages: high affinity and strong binding specificity to Trop-2; extremely rapid internalization, with efficient uptake into tumor cells within 5 hours; smooth transport to lysosomes for toxin release, inducing apoptosis via the caspase‑3/9 pathway; significant in vivo efficacy: potent tumor inhibition at doses of 0.2 and 1 mg/kg, and tumor eradication at 5 mg/kg. It demonstrates excellent anti-tumor activity in pancreatic cancer models and holds great promise for clinical development[6].

Significance and Prospects

          The R&D progress of JSKN016 and the aforementioned nanobody drugs fully demonstrates that nanobodies are emerging as a core enabler for innovative drug development. Their advantages of high affinity, strong tissue penetration and low toxicity have been powerfully validated in oncology. Furthermore, the technological support from our platform at Novamab Biopharma has accelerated the translation of nanobodies from research tools to clinical applications, injecting new momentum into the development of more innovative drugs and helping break through therapeutic bottlenecks for various diseases.
           With the continuous maturation of nanobody technology and sustained empowerment by platforms such as Novamab Biopharma, more innovative drugs like JSKN016 will advance to the clinic in the future. The drug pipelines targeting TROP2, HER3 and other nanobody-based therapies will also keep expanding, bringing new treatment hopes to patients with tumors and other diseases, and driving the pharmaceutical industry into a new development stage empowered by nanobodies.

References

[1] Xu C, Zhu M, Wang Q, Cui J, Huang Y, Huang X, Huang J, Gai J, Li G, Qiao P, Zeng X, Ju D, Wan Y, Zhang X. TROP2-directed nanobody-drug conjugate elicited potent antitumor effect in pancreatic cancer. J Nanobiotechnology. 2023 Nov 6;21(1):410. doi: 10.1186/s12951-023-02183-9.

[2] Yao L, Chen J and Ma W (2023) Decoding TROP2 in breast cancer: significance, clinical implications, and therapeutic advancements. Front. Oncol. 13:1292211.

[3] Gao L, Zhang Y, Feng M, Shen M, Yang L, Wei B, Zhou Y, Zhang Z. HER3: Updates and current biology function, targeted therapy and pathologic detecting methods. Life Sci. 2024 Nov 15;357:123087.

[4] Muzi A, Arriga R, Bulfaro G, Fata F, Costanzo A, Chiarini V, Cappelletti M, Ferrara FF, Bucci F, Montemiglio LC, Savino C, Marra E, Ciliberto G, Aurisicchio L, Vallone B, Roscilli G. Novel Humanized Anti-HER3 Antibodies: Structural Characterization and Therapeutic Activity. Antibodies (Basel). 2025 Oct 6;14(4):84.

[5] Haikala HM, Jänne PA. Thirty Years of HER3: From Basic Biology to Therapeutic Interventions. Clin Cancer Res. 2021 Jul 1;27(13):3528-3539. doi: 10.1158/1078-0432.CCR-20-4465. Epub 2021 Feb 19.

[6] Xu C, Zhu M, Wang Q, Cui J, Huang Y, Huang X, Huang J, Gai J, Li G, Qiao P, Zeng X, Ju D, Wan Y, Zhang X. TROP2-directed nanobody-drug conjugate elicited potent antitumor effect in pancreatic cancer. J Nanobiotechnology. 2023 Nov 6;21(1):410.




               NBLST is a nanobody industry platform initiated and established by Wuhan Industrial Innovation and Development Institute. It owns an independent laboratory covering 1,400 square meters at the Precision Medicine Industrial Base of Wuhan National Bioindustry Base. Meanwhile, it has set up an alpaca experimental base and a transit base compliant with laboratory animal standards in Zuoling, Wuhan and Tuanfeng, Huanggang respectively. At present, the bases house more than 200 alpacas in total, and can provide alpaca immunization services with "zero immune background" guarantee for research institutions and antibody drug R&D enterprises.


          NBLST focuses on the research, development, engineering and application of nanobodies, and is committed to building an integrated industry-university-research public experimental service platform. The company has established a full-chain technology platform covering antigen preparation (polypeptides, proteins and RNA), antibody discovery and engineering modification, as well as biological function validation and screening. Among these, its RNA antigens include sequence- and structure-optimized RNA products suitable for alpaca immunization.Based on the proprietary NabLib® platform, the company employs the improved pDual bifunctional phage display technology. While retaining the high-efficiency development advantages of traditional phage display, this technology enables seamless connection with high-level expression in mammalian cells, significantly improving the efficiency of eliminating problematic molecules. Its NabLib® mammalian cell display technology not only enhances the developability of antibody molecules, but also allows flexible selection of screening formats, providing reliable support for downstream antibody applications and detection.Through the synergistic complementation of multiple platforms, the company provides flexible and efficient antibody discovery and engineering services for pharmaceutical companies and research institutions, supporting the development of innovative drugs and diagnostic reagents.



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