A unique cancer therapy combining antibody fragments with molecularly engineered nanoparticles permanently eradicated gastric cancer in mice, a multi-institutional team of researchers reports.
“I’ve seen beautiful results before, but I’ve never seen something that eradicates a tumor like this,”
said Dr. Michelle Bradbury, co-lead author and professor of radiology at Weill Cornell Medicine.
The “hit and run” drug delivery system resulted from a five-year collaboration between Cornell, the Memorial Sloan Kettering Cancer Center (MSKCC), and the biopharmaceutical company AstraZeneca.
Cornell Prime Dots Evolved
Due to each therapy’s limitations, targeted cancer treatments such as antibody and nanoparticle therapies have seen limited clinical application. However, the new therapeutic — an evolution of what the researchers call Cornell prime dots, or C’ dots — combines the best characteristics of both therapies into an ultrasmall, highly effective system.
A) 3D rendering of complete target/immune-drug particle complex with ERBB2 extracellular domain (ECD, red) and scFvs (VL and VH regions blue and green, respectively) with PEG-Cy5-C′ dot (white/red space-filled) and SG4015 with linker (yellow).
B) Rotated space-filling model depicting contact sites between the ERBB2 ECD (maroon) and scFvs directed to ERBB2 ECD with four sites of nnAA integration (red; N-Term, LC100, HC44, and C-Term, inset). Sites were rationally designed to be distal to the antigen-binding domains and surface-exposed to enable efficient conjugation.
C) Structure of topoisomerases inhibitor (SG4015) payload. D) Conjugate characterization: (top) FCS correlation curve with fit; (bottom, left) UV–vis spectrum showing clear fingerprints of DFO (≈250 nm), DBCO (double peak ≈300 nm), drug (≈350–400 nm), and Cy5 dye (Abs. max ≈650 nm); (bottom, right) TEM of the final particle (scale bar 20 nm).
Credit: Adv. Therap. 2023, 6, 2200209 CC-BY
Once injected into the body, C’ dots, which are composed of silica nanoparticles measuring just 6 nanometers in diameter, are small enough to penetrate tumors and safely pass through organs. Wiesner first created them more than 15 years ago, and in 2018, he and Bradbury published a study demonstrating that an antibody fragment-nanoparticle hybrid is particularly effective at locating tumors.
This collaboration with AstraZeneca initiated the search for a molecularly engineered therapeutic variant of this immuno-conjugate. AstraZeneca “site engineered” antibody fragments to effectively attach to the C’ dots and target HER2 proteins (human epithelial growth factor receptor 2) associated with gastric cancer.
Hit and Run Therapeutic
Using AstraZeneca’s specialized inhibitor drugs, the team optimized fragment conjugation to the C’ dot surface. This allowed nanoparticles to transport approximately five times more drugs than antibodies.
A) Longitudinal analysis of coronal and axial tomographic PET images acquired at 3-, 24-, 48-, 72-, 144- and 192-h post i.v. injection of radiolabeled particle immunoconjugates in NCI-N87 tumor-bearing mice (n = 6 for each group) as follows—targeted group: 89Zr-DFO-scFv-SG4015-PEG-Cy5-C′ dots (top panel) and isotype control group: 89Zr-DFO-Ctr/scFv-SG4015-PEG-Cy5-C′ dots (bottom panel). For each group, maximum intensity projection (MIP) images were also acquired at 72 h p.i. (right panels). Tumors were marked with white and red arrows for the targeted and control groups, respectively. B) Biodistribution profiles for both groups at 192 h p.i. ***p < 0.0001. The two degrees-of-freedom F-test was followed by pairwise t-tests that were adjusted for multiple comparisons using the Holm method. Each data point represents the mean ± s.e.m of six replicates. C,D) Time-activity curves showing major organ uptake of 89Zr-labeled nanoparticles in NCI-N87 tumor bearing-mice injected with a targeted: 89Zr-DFO-scFv-SG4015-PEG-Cy5-C′ dots (C) or isotype control: 89Zr-Ctr/scFv-SG4015-PEG-Cy5-C′ dots (D). E) Comparison of tumor uptake between groups. F–H) Comparison of tumor-to-blood (F), tumor-to-liver (G), and tumor-to-muscle (H) ratios for both groups. n = 6 animals per group, ***p < 0.001, **p < 0.01, *p < 0.05.
Credit: Adv. Therap. 2023, 6, 2200209 CC-BY
According to the researchers, the final product was a version of C’ dots equipped with cancer-targeting antibody fragments and a large drug payload packed into a sub-7-nanometer, drug-immune conjugate therapy.
“We describe the mode of action as ‘hit and run,'”
Wiesner said.
Why hit and run? Due to their small size, C’ dots either target the tumor microenvironment and kill tumor cells or are safely eliminated from the body via renal clearance, minimizing off-target accumulation and associated side effects and toxicity.
No Tumor Recurrence
The therapeutic was administered in three doses to mice with gastric cancer. Not only did the treatment eradicate the disease in every mouse, but after nearly 200 days there was no evidence of tumor recurrence.
“Usually you’d have to couple the treatment with other therapies to see those kind of long-term results,” Bradbury said. “It showed that the very detailed, careful work of this team, the years spent on the stoichiometry and the surface chemical developments, it paid off.”
Bradbury emphasized the versatility of the C’ dots platform and stated that she does not envision it as a replacement for antibody therapies, but rather as a complementary tool that can be adapted to various types of cancer and other patient-specific needs.
“‘C’ dots have become unusually efficacious and safe in treating cancer. They completely obliterated the tumor, even at the cellular level,” said Wiesner. “This is what we ultimately had hoped for and it further supports our earlier decision to bet on therapeutic C’ dot applications.”
Elucida Oncology, a startup company Wiesner and Bradbury founded to help commercialize the technology, will continue the research behind the new C’ dot therapeutic, according to Wiesner and Bradbury. Although Elucida is not using antibody fragments in its current clinical trial of C’ dots, the work will assist the company in developing new conjugates that can potentially be used in future trials.
Reference:
- Zhang, L., Aragon-Sanabria, V., Aditya, A., Marelli, M., Cao, T., Chen, F., Yoo, B., Ma, K., Zhuang, L., Cailleau, T., Masterson, L., Turker, M. Z., Lee, R., DeLeon, G., Monette, S., Colombo, R., Christie, R. J., Zanzonico, P.,Wiesner, U., Subramony, J. A., Bradbury, M. S. Engineered Ultrasmall Nanoparticle Drug-Immune Conjugates with “Hit and Run” Tumor Delivery to Eradicate Gastric Cancer. Adv. Therap. 2023, 6, 2200209.
Last Updated on September 20, 2023