[Edaily Reporter KIM SUNG-JIN ] #IntoCell, Inc. has drawn attention by expressing a somewhat skeptical stance toward bivalent antibody-drug conjugates (ADCs), which are garnering global attention as next-generation cancer treatments. While bivalent ADCs are considered a step forward from monoclonal ADCs because they can target multiple cancer cells simultaneously, IntoCell, Inc.’s skepticism stems from the belief that their complex structure makes them difficult to design and ensures efficiency.

However, the industry views bivalent ADCs as a technical challenge that must be overcome for cancer treatment. This is because cancer cells often vary even within the same tumor, making the limitations of existing monovalent ADCs—which target a single antigen—all too clear.

Major domestic and international companies have already jumped into the development of bispecific antibody-drug conjugates (ADCs). Not only are major global pharmaceutical and biotech companies such as Bristol-Myers Squibb (BMS) involved, but leading domestic firms—including Samsung Bioepis, Celltrion(068270), LigaChem Biosciences(141080), and ABL Bio Inc.(298380) —are also accelerating their ADC development efforts.

IntoCell, Inc.: “Low Efficiency Relative to Complexity”

At an event held on the 19th to present the R&D achievements made over the past year since its IPO and to share the company’s vision, IntoCell, Inc. shared its views on bivalent antibody-drug conjugate (ADC) technology. During the Q&A session that day, when asked if the company had plans to develop bispecific antibody ADCs, IntoCell, Inc. CEO Park Tae-kyo said, “In theory, the concept of multi-antibodies and multiple payloads looks promising,” adding, “But that makes me wonder why ADCs utilizing multi-antibodies and multiple payloads haven’t become the mainstream.”

He continued, “Attaching multiple payloads leads to toxicity. While it’s certainly an area worth exploring, resolving this issue takes a lot of time, and combining antibodies with drugs is not easy.”

IntoCell, Inc. revealed that it had conducted its own experiments with multi-antibody ADCs but did not achieve meaningful results. CEO Park explained, “Among various combinations, we tried combining the orlistatin class with the camptothecin class, but there was no synergistic effect, and the approach had its own issues.”

Seo Young-seok, CFO (Vice President) of IntoCell, Inc., said, “The technologies developed by IntoCell, Inc. can be applied to both bispecific antibodies and dual payloads. However, when we tested the dual payload approach, the results did not meet our expectations.” He added, “This does not mean that bispecific antibody-drug conjugates (ADCs) are impossible, but we believe the expected return on investment is lower than anticipated.”

CFO Seo noted, “When two drugs (payloads) are combined, the therapeutic effect tends to be dominated by the stronger of the two, whereas the toxicity—a side effect—is likely to be the sum of both.” Regarding bispecific antibodies, he explained, “When looking at ADCs as a whole, the linker and the drug account for a very small proportion, while the antibody accounts for the majority.” He continued, “However, applying a bispecific antibody increases the size of the antibody, which can diminish its inherent characteristics.”

ADC refers to a technology that attaches a toxic drug to an antibody that targets cancer cells to attack them. It consists of three main components: the antibody that tracks cancer cells, the payload (toxic drug) that attacks the cancer cells, and the linker that connects the antibody and the payload. Since conventional anticancer drugs have severe side effects—attacking not only cancer cells but also healthy cells—ADCs provide a method to precisely target cancer cells with toxic drugs. A bispecific antibody ADC is a technology that connects two antibodies to simultaneously target multiple cancer cells, and research into dual-payload technology—which attaches multiple payloads to a single antibody—is also actively underway.

BMS Takes the Lead… A Race Against Time at Home and Abroad

Major

domestic and international

pharmaceutical and biotech companies view bispecific antibody-drug conjugates (ADCs) as a key technology for securing a foothold in the next-generation cancer treatment market and are accelerating their development efforts.

Leading the pack are the multinational pharmaceutical company BMS and China’s Cystimune. In 2023, BMS paid a staggering $8.4 billion (11.7 trillion Hanwha KRW) to acquire the rights to commercialize Cystimune’s bispecific antibody ADC technology outside of China. The bispecific antibody ADC therapy developed by BMS and Cystimmune is “Izavren” (generic name: isalonumab brengitecan), which received approval in China last June as a “third-line treatment for recurrent or metastatic nasopharyngeal carcinoma.” This marks the first time a new bispecific antibody ADC drug has received marketing approval. On the 19th, the drug also succeeded in a Phase 3 clinical trial in China involving patients with small cell lung cancer, brightening the future outlook for the bispecific antibody ADC market.

Izabren is an ADC that simultaneously targets EGFR and HER3; it is a “bispecific antibody” capable of recognizing two different targets within a single antibody molecule. It is structured with a topoisomerase inhibitor (TOP1)-based payload attached.

In South Korea, ABL Bio Inc. is considered a leading developer of bispecific antibody-drug conjugates. ABL Bio Inc. is currently conducting U.S. Phase 1 clinical trials for its key bispecific ADC pipeline candidates, “ABL206” and “ABL209.” The company completed the first patient dosing for its Phase 1 trials in May and, in July, received approval for a protocol amendment for the Phase 1 trial of “ABL503,” a “PD-L1·4-1BB” dual-antibody being co-developed with the U.S. biotech firm Novabridge Biosciences. ABL Bio Inc. is developing a diverse pipeline of compounds in various preclinical and clinical stages based on its dual-antibody platform “Grabody,” among others.

LigaChem Biosciences is also actively engaged in the development of bispecific antibody-drug conjugates (ADCs). LigaChem Biosciences is developing “LCB36,” a bispecific antibody-drug conjugate that simultaneously targets CD20 and CD22, and plans to begin full-scale clinical trials next year. LigaChem Biosciences’ strength lies in its linker technology for connecting antibodies and payloads, and the company plans to leverage this advantage to develop dual-payload technology that attaches multiple payloads to a single antibody.

Last October, Samsung Bioepis partnered with Chinese biotech firm Frontline Biopharma to develop bispecific antibody-drug conjugates (ADCs). Frontline Biopharma specializes in the development of bispecific antibodies and dual-payload technology, and Samsung Bioepis secured joint development rights for two of Frontline’s pipeline candidates. In 2023, Samsung Bioepis signed an agreement with IntoCell, Inc. to jointly develop a total of five ADCs; of these, the company signed a definitive agreement in July for “SBE303,” a Nectin-4 protein-targeted solid tumor therapy candidate currently undergoing a global Phase 1 clinical trial.

‘Target-Payload’ Combination and Financial Strength Are Key Factors

Industry observers note that, as IntoCell, Inc. has pointed out, it is difficult to conclude that bispecific antibody-drug conjugates (ADCs) are inherently more effective. They argue that simply combining two antibodies does not automatically double the efficacy; it requires meticulous structural design, which is difficult to achieve with current technology.

An industry insider stated, “The most critical aspect of ADCs is how to control toxic drugs; even when considering only single-antibody ADCs, there are still many areas that require further development,” adding, “It therefore seems somewhat premature to view bispecific antibody or dual-payload technologies as unconditionally positive.”

However, given that all major global pharmaceutical companies are entering this market, some argue that domestic companies must also pursue aggressive development to secure competitiveness in the global market.

Another industry insider remarked, “It’s only natural that toxicity increases significantly when you link two antibodies together and attach multiple drugs,” but noted, “The technology lies in how to control this, and the challenge is in creating the right combinations.” He added, “This is not an area where we can stop development just because efficiency hasn’t been achieved yet. It’s a problem we must overcome.”

Ultimately, some analysts suggest that IntoCell, Inc. adopted a strategy of “selection and concentration” because this is a field requiring massive capital investment. Another industry official remarked, “Among the three components that make up an ADC—antibodies, linkers, and payloads—not a single one is unimportant,” adding, “We must create results by combining these three elements in various ways, and that requires a considerable amount of capital.” He also noted, “Alternatively, they would have to acquire existing patented technologies to continue development, but this does not appear to be an easy task for a small company to undertake.”