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News & Press release


Kolmar Korea’s recognition of ProEn’s secret: A single platform that creates powerful CAR, ADC, and RPT(Mar 25, 2024)

25 Mar 2024
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THEBIO


[Interview] Lee Il-han, CEO of ProEn Therapeutics

[by Lee, Young Sung] The concept that emerged while verifying antibody characteristics proved pivotal in establishing the core platform technology of ProEn Therapeutics (hereinafter referred to as ProEn).

ProEn's challenge was to develop a novel drug that would mitigate the drawbacks and improve the efficacy of existing ADCs (antibody-drug conjugate), RPTs (radiopharmaceuticals), and CARs (chimeric antigen receptor). This is through the ArtBody platform technology, which involves the artificial creation of antibodies. The name itself carries a dual connotation, implying an antibody that reaches artistic excellence. When healthy cells transform into cancerous ones, there’s a notable increase in the density of specific antigens. Currently, a patent application is underway for the technology derived from experimental validation and quantification of the phenomenon indicating significantly enhanced binding force when both arms of the antibody are attached to the antigen, as opposed to just one arm.

This phenomenon, known as antibody avidity, significantly increases the binding force when both arms of an antibody bind to a target concurrently, compared to when only one arm is involved. However, its significance is deemed considerable as its underlying principle or magnitude remains undisclosed.

This technology received attention earlier this month after Kolmar Korea Holdings made a strategic investment in ProEn. Additionally, as part of open innovation cooperation, ProEn inked a contract with HK inno.N, a subsidiary of Kolmar Korea Holdings, to co-develop CAR-T therapies for solid cancer treatment. Going forward, ProEn aims to co-develop new ADCs, RPTs, and CAR drugs using diverse platforms with various partners.

Lee Il-han, CEO of ProEn, stated in a recent interview with at the company’s headquarters in Seongnam, Gyeonggi Province, "ArtBody serves as a functional recombinant protein platform with notable scalability advantages." He further added, saying, “We intend to use this platform to co-develop new drugs such as ADC, RPT and CAR therapies with various partners.”

ArtBody, a ‘pseudoantibody’, resembles Toll-like receptors (TLR) in structure, possessing two shapes for recognizing foreign substances. It is engineered via genetic recombination to target specific antigens. Approximately one-third smaller than a genuine antibody, ArtBody features connected arms for antigen recognition, but lacks the Fc domain present in antibodies. While the absence of an Fc region eliminates potential side effects associated with immune cell interactions, it also results in a shorter half-life compared to antibodies. However, it has been confirmed that ArtBody drugs persist for extended periods within tumor tissue after administration.

◇"Simultaneous dual target binding action... Prevents attack on healthy cells with low antigen density"

Typically, therapeutic antibodies feature both arms attached to the body (Fc) region. Upon encountering an antigen, the antibody may bind to it using one arm or both arms. When an antibody arm binds to an antigen, multiple body Fc regions are brought together. This triggers a series of immune responses, like the recruitment of natural killer (NK) cells capable of killing, complement immune responses, or an overall increase in the body's immune activity.

This is the standard antibody immune response. ‘Tumor-Associated Antigens (TAAs)’, which are overexpressed when healthy cells change into cancer cells, serve as targets for antibodies. Examples include antigens like 'EGFR' and 'TROP2', which are focal points of anticancer drug development companies around the world. EGFR functions as a TAA in lung, breast, and stomach cancers, while TROP2 serves as a TAA in ovarian, pancreatic, prostate, and breast cancers.

However, these antigens are not exclusive to cancer cells; healthy cells also have them, albeit at lower levels. Therefore, there is the potential for antibody drugs to inadvertently attack healthy cells, resulting in side effects.

"ProEn’s internal experiments have validated that antibodies detach more easily when bound with one arm to the antigen, whereas they exhibit prolonged adherence when bound with both arms. This phenomenon was observed when antibodies were sprayed onto a specific chip. Of particular note was the appearance of significant antibody accumulation and the induction of a 'follow-on immune response' when the density of the target (antigen) was high,” explained Lee.

Hence, ProEn's ArtBody platform features a double-arm structure akin to antibodies.

ArtBody is structured in two forms: a 'homo-dimer' configuration where both arms identify and bind to a single antigen, and a 'hetero-dimer' configuration where each arm attaches to different antigens. Given the potential for cancer cells to have elevated levels of specific antigens, and the propensity for individual cancer cells to express multiple antigens, ArtBody’s design facilitates total recognition of these targets, whether they exhibit high concentrations of a single antigen or multiple antigens simultaneously.

Nevertheless, it was engineered in such a way that only one arm identifies the antigen and can be easily detached upon binding. Lee elucidates that, due to the low density of antigens in normal cells and their heightened presence only in cancer cells, ArtBody exhibits excellent selectivity, predominantly targeting cancer cells while minimally affecting healthy cells. The attachment of a payload (drug) to each arm of ArtBody serves as a linker, causing a strong anti-cancer reaction. Attachment of a chemically toxic payload transforms it into an ADC, while attachment of a radioactive isotope converts it into an RPT.

“We named this mechanism of action ‘dual target simultaneous binding.’ There is no payload attack on healthy cells, and we have engineered it to exclusively target cancer cells,” Lee remarked.

Specifically, Lee stated, "In most cases of double antibodies, either one or both antibodies attach to an antigen. However, ProEn's ArtBody detaches easily when only one antibody binds to an antigen, but for effectiveness, both antibodies must simultaneously attach to the antigen.” He further emphasized, saying, “This underscores a fundamental difference from conventional double antibodies. For instance, ArtBody possesses the capability to attack cancer cells by simultaneously recognizing EGFR, even in cases where the expression level of HER2 is minimal.” Consequently, it may hold an advantage in developing treatments effective even in cancers with low HER2 expression levels.

◇"Reevaluation required for discontinued ADC development pipeline"

ProEn recognized the importance of leveraging the attributes of its platform and re-evaluating its ADC development pipeline, which had been halted globally due to side effects. The rationale was to accelerate progress by using targets that have been sufficiently explored, rather than pursuing entirely new "noble targets", through a mechanism that significantly reduces side effects and increases efficacy beyond that of traditional double antibodies.

“We will accelerate the development of ADC in the future. ArtBody stands as an optimal platform not only for the development of novel CAR drugs, but also for the development of drugs that disappear quickly from the blood and only work on cancer cells, akin to RPTs,” explained Lee.

Currently, within ProEn's pipelines, the development of 'PRN201', an EGFR (homodimer ArtBody) ADC candidate, progresses at the fastest pace. It targets patients with metastatic colorectal cancer and KRAS mutations, with phase 1 clinical trials slated to commence in 2026.

PRN222, the EGFR x c-MET bispecific (heterodimer ArtBody) ADC designed for lung cancer recurrence after first-line treatment, and the EGFR x HER2 bispecific (heterodimer ArtBody) ADC, 'PRN211,' intended for breast and gastric cancer, are presently undergoing non-clinical trials. Cancer cell killing is contingent upon the simultaneous combination of both target types.

ProEn secured KRW 7 billion (approximately USD 5.2 million) in investment through Series A funding in August 2020, with participation from LSK Investment, Aju IB Investment, MEP-Partners, and Hyundai Investment Partners. Series B funding is scheduled for the second half of this year. Both the Technology Innovation Program for Society (TIPS) and Post-TIPS phases have been successfully completed, and the National New Drug Development Project is currently underway.

“Following the Series B investment in the second half of this year, we aim to initiate phase 1 clinical trials for PRN201 in 2026 and pursue technological evaluation,” Lee expressed. “Our strategy includes planning for an Initial Public Offering (IPO) along with the launch of phase 2a clinical trial for PRN201 in 2027, facilitating ongoing advancements through technology transfer agreements in Korea and overseas starting next year,” he added.


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