[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 antibody ADCs because they can target multiple cancer cells simultaneously, IntoCell, Inc.’s skepticism stems from the view that their complex structure makes them difficult to design and equally challenging to ensure their efficacy.

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—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 like Bristol-Myers Squibb (BMS) involved, but leading domestic firms such as 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 showcase 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 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, solving 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 obtain 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 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 were not as effective as expected.” He added, “This doesn’t mean that bispecific antibody-drug conjugates (ADCs) won’t work, but we believe the expected return on investment is lower than the input.”

CFO Seo explained, “When two drugs (payloads) are combined, the therapeutic effect tends to be dominated by the stronger of the two, whereas the toxicity—the 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 compromise 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 cytotoxic 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 won) to acquire the rights to commercialize Cystimune’s bispecific antibody-drug conjugate (ADC) technology outside of China. The bispecific antibody ADC therapy developed by BMS and Cystimune, “Izabren” (generic name: izalontamab brengitecan), 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” that recognizes 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 candidates 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 ADC 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

Industry observers note that, as IntoCell, Inc. has pointed out, it is difficult to conclude that bispecific antibody ADCs are inherently more effective. For the efficacy to double simply by combining two antibodies, meticulous structural design is required—a challenge that is difficult to achieve with current technology.

An industry official 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 seems somewhat premature to view bispecific antibody or dual-payload technologies as unconditionally positive.”

However, given that major global pharmaceutical companies are all 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 added, “The technology lies in how to control this, and the challenge is figuring out which combinations to create.” He continued, “This isn’t an area where we can stop development just because we aren’t seeing immediate results. 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 that requires 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.”