Sudocetaxel zendusortide, also known as TH1902, is as novel, investigational peptide-drug conjugate (PDC) candidate being developed by Canadian biotech Theratechnologies as single agent and in combination with other anticancer therapies. The drug targets tumors that express the sortilin (SORT1) receptor.

The normal role of sortilin is to act as a cellular shuttle system,  In this role, it moves proteins across the cell membrane via the endosomal/lysosomal pathway.  However, the sortilin receptor is preferentially expressed on cancer cells compared to healthy tissue.

Peptide–drug conjugates are the next generation of targeted therapeutics drug after antibody–drug conjugates (ADCs).  Considered novel format conjugates, these agents offer core benefits of enhanced cellular permeability, improved drug selectivity and and reduced toxicity for the efficient treatment of cancers. [1]

This Immunotherapies have significantly improved the treatment of cancer. Researchers continue to explore the power of the body’s own immune system to find and destroy cancer cells. ‘Hot’ tumors show signs of inflammation, meaning the tumor has already been infiltrated by immune cells rushing to fight the cancerous cells. Only a few types of cancers are considered to be hot. In contrast, ‘cold’ tumors have not yet been infiltrated with T-cells. This signals that the immune response is not working, making it difficult to provoke an immune response with immunotherapies.

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Most cancers of breast, ovary, prostate, pancreas and brain (Glioblastoma/GBM) are considered cold tumors, and, as a result, they are generally treated with traditional therapies like radiation and chemotherapy. To understand how to ‘turn cold tumors hot,’ researchers are investigating how reversing the suppressive microenvironment surrounding cold tumors and attracting more of the right anti-tumor lymphocytes can improve the potential for immunotherapies.

Turning cold to hot
Data presented in poster sessions at the annual meeting of the American Association for Cancer Research (AACR), held April 14-19, 2023 at the Orange County Convention Center in Orlando, Florida suggests that sudocetaxel zendusortide can induce immune cell infiltration in ‘cold’ tumors and increased anti-cancer efficacy in combination with programmed cell death-ligand 1 (PD-L1) checkpoint inhibitor therapy in a melanoma mouse model. [2]

Additional in vivo data demonstrates significant activity of sudocetaxel zendusortide against SORT1+ triple-negative (TNBC) and HER2+ breast cancers, resulting in complete tumor regression.

The data supports the rationale for targeted therapy with sudocetaxel zendusortide in solid tumors with a high expression of SORT1.

Furthermore, sudocetaxel zendusortide generated superior activity in comparison to a combination of trastuzumab (Herceptin®; Genentech/Roche) and docetaxel (Taxotere®; Sanofi) in the HER2+ trastuzumab-resistant tumor model. A third poster showed high expression of SORT1 in multiple tumor types, compared to healthy tissues, bolstering the rationale for SORT1 inhibition as a potential therapeutic approach.

SORT1 in melanoma
“It’s particularly exciting to see in the melanoma animal model that using the SORT1 receptor with sudocetaxel zendusortide in combination with immunotherapy shows greater tumor inhibition and longer survival compared to immunotherapyalone,” said Christian Marsolais, Ph.D., Senior Vice President and Chief Medical Officer of Theratechnologies.

“Collectively our three AACR poster presentations reinforce the potential of sudocetaxel zendusortide, on its own and in combination, to enable targeted delivery of anticancer therapy. We look forward to further characterizing this novel investigational agent as we seek partners and advance our clinical development program.”

Inducing immune cell infiltration
In the first AACR poster, researchers reported that sudocetaxel zendusortide induces immune cell infiltration and potentiates the anti-tumoral activity of anti-PD-L1 therapy in a melanoma mouse model.

Surprisingly, in this non-immunogenic, or ‘cold,’ tumor type, immunohistochemistry (IHC) analysis showed a net increase in total leukocyte infiltration within sudocetaxel zendusortide-treated tumors compared with docetaxel-treated tumors, especially with regard to marked increases in tumor-infiltrating lymphocytes and tumor-associated macrophages. Researchers also observed elevated cytotoxic T and natural killer cells in the sudocetaxel zendusortide-treated tumors.

Next, the researchers halved the doses of sudocetaxel zendusortide and docetaxel and combined each agent with an anti-PD-L1 checkpoint inhibitor. Notably, sudocetaxel zendusortide alone showed greater tumor growth inhibition than docetaxel, anti-PD-L1 or anti-PD-L1/docetaxel combination. In addition, the sudocetaxel zendusortide/anti-PD-L1 combination significantly increased tumor growth inhibition and median survival over either anti-PD-L1 or sudocetaxel zendusortide as single agents (21 days compared to 2.5 and 12.5 days, respectively). The investigators attributed the superior anticancer activity of sudocetaxel zendusortide over docetaxel, in part, to the modulation of infiltrating immune cells within the tumor microenvironment.

“Our data are the first to demonstrate that immune cell infiltration patterns could play a pivotal role in the sudocetaxel zendusortide-associated anti-tumoral response,” Marsolais added.

“Given that preclinical results showed a statistically significant improvement in the efficacy of an anti-PD-L1 inhibitor for tumors treated with sudocetaxel zendusortide in contrast to docetaxel, we are hopeful that further research with combination therapy may also lead to improved clinical outcomes.”

Breast cancer
The second AACR poster reported high expression of SORT1 in several TNBC and HER2-positive breast cancer cell lines as well as in more than 60-75% of cases from commercial breast cancer tissue microarrays.

Researchers further observed that SORT1 is involved for both cell surface recognition and internalization of the peptide, TH19P01, without payload. Fluorescence microscopy showed rapid uptake and co-localization of both TH19P01 and sudocetaxel zendusortide in the late endosomal and lysosomal compartments at the perinuclear region, indicating that both compounds are internalized through a receptor-mediated endocytosis (a cellular process in which substances are brought into the cell) pathway. [2]

In a murine MDA-MB-231 TNBC tumor model, weekly administration of sudocetaxel zendusortide at a dose (35 mg/kg) equivalent to the maximally tolerated dose (MTD) of docetaxel (15 mg/kg) led to complete and sustained tumor regression, while docetaxel only inhibited tumor growth by half.

In vitro, while the TH19P01 peptide itself did not exert any antiproliferative or apoptotic effects, the docetaxel-TH19P01 conjugate (TH1902) exerted potent antiproliferative and antimigratory activities when tested on TNBC-derived MDA-MB-231 cells. TH1902 triggered faster and more potent apoptotic cell death than did unconjugated docetaxel.

Furthermore, in mice bearing HER2-positive breast tumor tissue grafts, sudocetaxel zendusortide induced complete tumor regression, unlike docetaxel, Herceptin and Herceptin/docetaxel combination.

Based on the demonstrated high anticancer properties of sudocetaxel zendusortide against SORT1-positive TNBC and Herceptin-resistant HER2-positive breast cancer models, as well as its higher tolerability compared to docetaxel, the researchers concluded that sudocetaxel zendusortide can be a promising avenue for further evaluation in the treatment of patients with SORT1-positive breast cancers.

SORT1 receptor
The SORT1 receptor plays a significant role in protein internalization, sorting and trafficking. It is highly expressed in cancer cells compared to healthy tissue, which makes SORT1 an attractive target for cancer drug development.

Expression of SORT1 is associated with aggressive disease, poor prognosis and decreased survival. It is estimated that the SORT1 receptor is expressed in 40% to 90% of cases of endometrial, ovarian, colorectal, triple-negative breast and pancreatic cancers.

To better understand SORT1 expression, the research team used IHC to screen 19 cancer tissue microarrays with 1394 evaluable cancer cores. They scored each cancer core using an H-score ranging from 0 to 300, whereby a score of 0 indicates no cell staining for SORT1 and a score of 300 corresponds to strong SORT1 staining in all cells.

 

The results of the presentations validate and build upon previous reports on the pattern and prevalence of SORT1 expression in common tumor types, underscoring the promise of SORT1 as a target for the delivery and internalization of anticancer therapeutic agents.

Development program
The U.S. Good and Drug Administration (FDA) granted fast track designation to TH1902 as a single agent for the treatment of all sortilin-positive recurrent advanced solid tumors that are refractory to standard therapy.

Sudocetaxel zendusortide is currently being evaluated in a Phase 1 clinical trial, although patient recruitment was voluntarily paused on December 1, 2022. In alignment with this decision, the FDA placed the trial on partial clinical hold.The Company is currently preparing a protocol amendment, which includes recommendations from the Scientific Advisory Committee meeting held in March 2023.

Clinical trials
TH1902 in Patients With Advanced Solid Tumors – NCT04706962

Highlights of prescribing information
Docetaxel (Taxotere®; Sanofi)[Prescribing Information]
Trastuzumab (Herceptin®; Genentech/Roche)[Prescribing Information]

Reference
[1] Chavda VP, Solanki HK, Davidson M, Apostolopoulos V, Bojarska J. Peptide-Drug Conjugates: A New Hope for Cancer Management. Molecules. 2022 Oct 25;27(21):7232. doi: 10.3390/molecules27217232. PMID: 36364057; PMCID: PMC9658517.
[2] Demeule M, Currie JC, Charfi C, Zgheib A, Cousineau I, Béliveau R, Marsolais C, Annabi B. The peptide-drug conjugate sudocetaxel zendusortide (TH1902) potentiates anti-tumoral activity of the anti-PD-L1 checkpoint inhibitor and induces immune cell infiltration in a B16-F10 syngeneic melanoma mode. In: Proceedings of the 114th Annual Meeting of the American Association for Cancer Research; 2023 April 14-19; Orlando, FL. Philadelphia (PA): AACR; 2023. Abstract nr 4499 / 24
[3] Charfi C, Demeule M, Currie JC, Zgheib A, Danalache BA, Béliveau R, Marsolais C, Annabi B. Sudocetaxel Zendusortide (TH1902), a peptide-drug conjugate for the treatment of sortilin-positive (SORT1+) TNBC and HER2-positive breast cancers. In: Proceedings of the 114th Annual Meeting of the American Association for Cancer Research; 2023 April 14-19; Orlando, FL. Philadelphia (PA): AACR; 2023. Abstract nr 4493.

Featured image: The AACR 2015 Annual Meeting. Photo courtesy: © 2018 – 2023 AACR/Todd Buchanan. Used with permission.

This article was first published in Onco’Zine on April 20, 2023

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