A first patient has been dosed in a Phase 1 clinical study (NCT06440005) with AGX101, a novel TM4SF1-directed Nuclear-Delivered Antibody-Drug Conjugate™ (ND-ADC) therapy for the treatment of solid tumors. AGX101, which is being developed by privately held biotech startup Angiex, is based on a new, groundbreaking ADC technology platform with a unique mechanisms of action.
The Phase 1 study for AGX101 is an open-label, dose-escalation, and expansion study designed to assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary anti-tumor activity of AGX101 monotherapy. The dose escalation portion of the study is designed to assess doses up 10 mg/kg in an all-comers, solid tumor patient population. The dose expansion portion of the study is designed to evaluate treatment at the Recommended Phase 2 Dose in multiple indications.
The target
A number of studies have found that Transmembrane-4 L Six Family member 1 (TM4SF1) belongs to a family of integral membrane proteins. TM4SF1 is specific to endothelial cells, the cells lining the walls of blood vessels, where it enables new blood vessels to grow.[1][2]
However, TM4SF1 also promotes and regulates the migration and tumor cell invasion by inducing epithelial-mesenchymal transition, self-renewal and cell growth, tumor angiogenesis, the formation of invadopodia (which is associated with associated with degradation of the extracellular matrix in cancer invasiveness and metastasis), and the related signaling pathways. [3]
Ongoing studies have further shown that TM4SF1 is overexpressed in many malignant tumors, including gliomas, melanomas, and liver, prostate, breast, pancreatic, bladder, colon, lung, gastric, ovarian, and thyroid cancers, and is an independent prognostic indicator and biomarker in several cancers. TM4SF1 also promotes drug resistance, which is a major cause of therapeutic failure. Combined, these characteristics make TM4SF1 an attractive target for antibody-based immunotherapy.[3][4]
Glioma
In an study, unrelated to the development of AGX101, researchers at the second affiliated hospital of Soochow University, Suzhou, Jiangsu, China, investigated the role of TM4SF1 in glioma, the most common and aggressive malignant brain tumor in adults. The outcome of the study demonstrated that TM4SF1 was highly expressed in glioma tumor tissues and cell lines. The scientists also noted that expression levels of TM4SF1 were negatively correlated to the survival rate of patients. In contrast, their study demonstrated that silencing TM4SF1 by RNA interference, inhibited the proliferation, migration, and invasion of glioma cells, while, at the same time, TM4SF1 silencing induced glioma cell cycle arrest and early apoptosis.[1]
In contrast, overexpression of TM4SF1 in glioma cells exhibited the opposite effects.[1]
The scientists found that, mechanistically, the loss of TM4SF1 reduced phospho-ATK, Cyclin D1, Bcl-2, and MMP-9 levels in glioma cells. Based on these outcomes they concluded that, taken together, their findings provide novel insights into glioma pathogenesis and suggest that TM4SF1 represent a novel target for glioma intervention.[1]
Ovarian Cancer
Another study, conducted by researchers from the department of gynecologic oncology affiliated with the tumor hospital of the Guangxi Medical University, in Nanning, China, showed that a positive expression of TM4SF1 in epithelial ovarian cancer tissues was higher than that in benign ovarian tumor tissues (90.90% vs 65.22%), which, in turn, was higher than the expression of TM4SF1 in normal ovarian epithelial tissues (31.25%), with both differences considered significant (P < 0.05).[2]
Pancreatic Cancer
Other researchers, including a team of scientists from the department of cancer biology at the University of Texas MD Anderson Cancer Center in Houston, Tx, found that TM4SF1 is overexpressed in pancreatic ductal adenocarcinoma (PDAC), affecting the development of this cancer. In their study, the team noticed that TM4SF1 is highly expressed in pancreatic cancer cells and increases the chemoresistance to gemcitabine (Gemzar®; Eli Lilly & Co). Hence, they concluded that TM4SF1 may be a promising target to overcome the chemoresistance of pancreatic cancer. [4]
Mechanism of action
AGX101 utilizing its unique target as a Trojan Horse to carry a chemotherapeutic payloads to the nucleus of cells in the tumor. By doing so, it targets the cancer cells and the tumor vasculature and eliminates tumor blood vessels, kills tumor cells capable of invasion and metastasis, and directs the immune system to attack the cancer.
In preclinical studies AGX101 demonstrates exceptional tumor selectivity and therapeutic margin by specifically killing tumor cells and tumor vascular endothelial cells.
By attacking the tumor’s endothelial cells, AGX101 cuts off the tumor’s blood supply, starving it of oxygen and nutrients. This leads to apoptosis (or cancer cell death), a mechanism which has been established as an anti-cancer defense. This approach to therapy has, according to the team at Angiex, no known resistance mechanism and may overcome the limitations of existing therapies, providing new hope for patients with hard-to-treat cancers.
“TM4SF1 is an emerging cancer target with exciting features: expression in two compartments of the tumor, tumor cells and the tumor vasculature; broad expression in malignant cancers, but limited expression in normal tissue; and a novel internalization pathway enabling delivery of chemotherapeutic payloads directly to the nucleus of cells in the tumor environment,” explained Paul Jaminet, co-founder and Chief Executive Office of Angiex.
“Building upon 20 years of biological research and through 12 years of drug development, Angiex has tailored AGX101 design to TM4SF1 biology. Preclinical studies have supported AGX101’s ability to attack cancers by multiple mechanisms of action, and demonstrated a broad therapeutic margin in animals. We believe AGX101 has potential to help clinical cancer patients, especially in indications with high unmet need. We are excited to announce that the first patient has been dosed in this first-in-human study of our novel TM4SF1 ADC, AGX101,” Jaminet added.
“Antibody-drug conjugates are an exciting drug modality that seek to improve the safety and efficacy of chemotherapies by targeting the therapies to tumors and keeping them away from normal tissue,” noted Ildefonso Ismael Rodriguez Rivera, MD, site principal investigator for the study at NEXT Oncology in San Antonino, Tx.
First-in-class
“AGX101 with its novel and differentiated mechanisms of action represents a first-in-class drug with potential to address high unmet medical needs. We look forward to evaluating AGX101 in this trial,” Rodriguez further noted.
The Phase 1 study is an open-label, dose-escalation and expansion study designed to assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary anti-tumor activity of AGX101 monotherapy. The dose escalation portion of the study is designed to assess doses up 10 mg/kg in an all-comers, solid tumor patient population. The dose expansion portion of the study is designed to evaluate treatment at the Recommended Phase 2 Dose in multiple indications.
Partnering with a CDMO
In developing AGX101, Angiex has partnered with Abzena, a CDMO developing complex biologics and bioconjugates, to support the development, manufacture and supply of clinical trial material for the phase 1 study. Abzena supports the Angiex with an integrated program that includes linker-payload design and synthesis, bioconjugation, process development, and cGMP manufacturing for the investigational agent
“The Abzena team is incredibly proud to helped Angiex achieve this significant milestone,” said Matt Stober, Chief Eecutive Officer of Abzena.
“Our unique ability to support Angiex with a fully integrated approach allowed us to de-risk and rapidly progress AGX101 into the clinic for patient dosing. We will continue supporting Angiex with our extensive ADC expertise and integrated capabilities to accelerate the development timeline of AGX101, and ultimately get this life-changing treatment to cancer patients faster.”
Transforming treatment
Angiex’s Phase 1 trial represents a major milestone in the development of this promising new therapy. AGX101 has the potential to transform the treatment landscape for solid tumors by targeting a fundamental vulnerability of cancer – its dependence on blood supply.
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Clinical trials
A Study to Evaluate Safety, Tolerability and Preliminary Activity of AGX101 in Participants With Advanced Solid Tumors – ClinicalTrials.gov ID NCT06440005
References
[1] Zheng YW, Wang M, Zhong ZM, Wu GQ, Zhang T, Chen LL, Li M. TM4SF1 promotes glioma malignancy through multiple mechanisms. Neoplasma. 2022 Jul;69(4):859-867. doi: 10.4149/neo_2022_211009N1427. Epub 2022 May 9. PMID: 35532297.
[2] Gao C, Yao H, Liu H, Feng Y, Yang Z. TM4SF1 is a potential target for anti-invasion and metastasis in ovarian cancer. BMC Cancer. 2019 Mar 15;19(1):237. doi: 10.1186/s12885-019-5417-7. PMID: 30876464; PMCID: PMC6419813.
[3] Fu F, Yang X, Zheng M, Zhao Q, Zhang K, Li Z, Zhang H, Zhang S. Role of Transmembrane 4 L Six Family 1 in the Development and Progression of Cancer. Front Mol Biosci. 2020 Aug 18;7:202. doi: 10.3389/fmolb.2020.00202. PMID: 33015133; PMCID: PMC7461813.
[4] Cao J, Yang J, Ramachandran V, Arumugam T, Deng D, Li Z, Xu L, Logsdon CD. TM4SF1 Promotes Gemcitabine Resistance of Pancreatic Cancer In Vitro and In Vivo. PLoS One. 2015 Dec 28;10(12):e0144969. doi: 10.1371/journal.pone.0144969. PMID: 26709920; PMCID: PMC4692438.
Featured image courtesy © 2020 – 2024 Abzena. Used with permission.
DOI 10.14229/jadc.2024.08.08.001
