Pioneering the next frontier in targeted cancer therapy, the Elucida Oncology confirmed that it has submitted an Investigational New Drug Application (IND) to the U.S. Food and Drug Administration (FDA) for a Phase 1/2 clinical trial of ELU-001 for the treatment of cancers overexpressing folate receptor alpha(FRα).
ELU-001 is a targeted therapy C’Dot Drug Conjugate (CDC). These CDCs are composed of a silica core, in which Cy5, a far–red dye is covalently encapsulated. The silica core is covalently coated with a layer of polyethylene glycol which is then functionalized with targeting moieties and payloads.
The C’Dot technology platform, which forms the basis of CDCs, is more flexible compared to other nanoparticle delivery platforms. specific ligands prevent attack from the body’s defenses while targeting groups cause C’Dot’s to specifically bind with tumor cells.
C’Dots, originally called Cornell dots (and referred to as CU-dots), are ultra–small nanoparticles consisting of a core of about 2.2 nanometers (nm) in diameter containing several dye molecules, surrounded by a protective silica shell, making the entire particle about 25 nm in diameter. They were created in the lab of Uli Wiesner, the Spencer T. Olin Professor of Engineering in the Department of Materials Science and Engineering.
Preclinical development
In preclinical animal models CDCs have demonstrated faster tumor targeting and deeper tumor penetration than antibody-drug conjugates (ADC), targeting tumors in the brain and pancreas that are difficult to access while exhibiting limited exposure to normal (healthy) tissues due to their efficient renal elimination.[1]
Elucida’s ELU001 is functionalized with ~20 molecules of the topoisomerase–1 inhibitor exatecan linked via a proteolytic cleavable linker as a payload and ~15 folic acids to provide targeting to FRa overexpressing cancers. The investigational drug is rapidly internalized into FRa expressing cells and is trafficked to the lysosome where exatecan is released from the CDC.[1]
ELU001 exhibits potency in the low single-digit nanomolar to sub-nanomolar range against cancer cells that express 3+ (KB, IGROV-1) and 2+ (SK-OV-3, HCC827, and OVCAR-3) levels of FRa after a 6-hr exposure in a 7-day viability study.[1]
In contrast, an anti-FRa ADC based upon mirvetuximab soravtansine (ImmunoGen) exhibits lower potency (>100 nM IC50) against SK-OV – 3 and HCC827 cells and 40 nM IC50 against OVCAR-3 cells.[1]
Researchers observed that ELU001 exhibits potent efficacy against established s.c. KB human cervical tumor xenografts in immunodeficient mice with significantly better efficacy and safety than free exatecan payload. It is also effective in treating established SK – >OV – 3 tumors with lower (2+) FRa expression, a setting where the ADC is again less effective.[1]
Significant improvement
Geno Germano, a 30-year veteran of the pharmaceutical and Life Sciences industry and Elucida’s President and Chief Executive Officer, explained that the company’s CDC platform technology ‘enables a significant improvement over antibody-drug conjugates (ADC) due to a simpler, less expensive, and less time-consuming manufacturing process.’
The CDC platform technology is designed to increase the concentration of cytotoxic drugs inside difficult-to-treat tumors with reduced systemic exposure. In addition to its folate receptor-targeted topoisomerase 1 inhibitor CDC being developed as a treatment for patients with advanced, recurrent, or refractory platinum-resistant ovarian cancer, Elucida has a CDC for primary glioma and other brain cancers in pre-clinical development. CDCs are also being investigated in lung cancer as a potential drug to effectively manage the disease and minimize off-target effects at a fraction of the native drug dose and prostate cancer. [2][3]
“This is a tremendous accomplishment for our team, and a great step forward in developing newer, potentially more effective, and better-tolerated therapies for patients with cancer. This first C’Dot-Drug-Conjugate, using the innovative C’Dot platform, could pave the way to an entirely new frontier in precision cancer therapy,” Germano said.
“We are extremely excited about advancing ELU-001 into the clinical phase of development. Our preclinical studies have generated compelling data that suggests this novel targeted therapy can overcome many of the limitations associated with currently available cancer therapeutics. CDCs are designed to enable precise tumor targeting, deep solid tumor penetration, and delivery of high levels of drug payload, which distinguish this platform from others, including antibody-drug-conjugates. We anticipate beginning our Phase 1/2 trial as soon as possible after FDA review,” noted Gregory Adams, Ph.D., Chief Scientific Officer of Elucida Oncology.
Clinical trial
The open-label, a multi-center clinical trial has two parts: Part 1 Dose Escalation Safety Study to identify the maximum tolerated dose (MTD) and/or the recommended phase 2 dose (RP2D), and Part 2 Tumor Group Expansion Cohort(s) where specific cancer types will be evaluated for efficacy and safety at the RP2D. Part 1 will enroll a basket of patients with advanced cancers known to overexpress FRα, including ovarian cancer, endometrial cancer, colorectal cancer, gastric cancer, gastroesophageal junction cancer, triple-negative breast cancer, non-small cell lung cancer, or cholangiocarcinoma. The most promising tumor types will proceed to investigation in Part 2.
Elucida was founded in 2014 and co-founders include Wiesner, Kai Ma, Ph.D. ’15, and Dr. Michelle Bradbury, director of intraoperative imaging at Memorial Sloan Kettering Cancer Center and professor of radiology at Weill Cornell Medicine.
Reference
[1] Adams GP, Ma K, Venkatesan A, Chen F, Wu F, Turker M, Gardinier T, Chen P, Patel V, Bayever E, Rudick P, Germano G.ELU001, a targeted C’Dot-drug conjugate (CDC) for the treatment of folate receptor alpha (FRα) overexpressing cancers.
[2] Madajewski B, Chen F, Yoo B, Turker MZ, Ma K, Zhang L, Chen PM, Juthani R, Aragon-Sanabria V, Gonen M, Rudin CM, Wiesner U, Bradbury MS, Brennan C. Molecular Engineering of Ultrasmall Silica Nanoparticle-Drug Conjugates as Lung Cancer Therapeutics. Clin Cancer Res. 2020 Oct 15;26(20):5424-5437. doi: 10.1158/1078-0432.CCR-20-0851. Epub 2020 Jul 28. PMID: 32723835; PMCID: PMC7686858.
[3] Chen F, Ma K, Zhang L, Madajewski B, Turker MZ, Gallazzi F, Cruickshank K, Zhang X, Jenjitranant P, Touijer KA, Quinn TP, Zanzonico P, Wiesner U, Bradbury MS. Ultrasmall Renally Clearable Silica Nanoparticles Target Prostate Cancer. ACS Appl Mater Interfaces. 2019 Nov 27;11(47):43879-43887. doi: 10.1021/acsami.9b15195. Epub 2019 Nov 13. PMID: 31675204; PMCID: PMC7199444.
Featured image: A rendering of the molecular structure of a Cornell dot, which is smaller than 10 nanometers.
