A track better than double-antibody and ADC? Overseas pioneers were frustrated, and several domestic pharmaceutical companies laughed

Recently, Zymeworks, a U.

At present, it is still in the stage of exploration and verification, and whether it can be finally made into a drug still needs to be verified
.

01 Better than monoclonal antibody ADCs? Why are dual-anti-ADCs emerging frontier technologies?

As Darwin said in Evolution: "Natural selection, survival of the fittest
.

The reason why cancer treatment drugs continue to evolve lies in the limitations
of drugs.

The reason why cancer treatment drugs continue to evolve lies in the limitations
of drugs.

But even third-generation ADC drugs still have drawbacks
.

But even third-generation ADC drugs still have drawbacks
.

Therefore, acting on ADC drugs, the double antibody can not only achieve better intracytosis than monoclonal antibody, but also reduce the off-target toxicity that may lead to off-target toxicity because it is not endocytosized, and the double antibody ADC has a higher amount of toxin accumulation than monoclonal antibody ADC, stronger cytotoxicity, and can kill tumor cells
more effectively.

In theory, the efficacy is more significant and can circumvent homogenization of double-anti-ADCs,

02 Double-antibody ADCs are still in the early stages of exploration, and HER2 double-antibody ADCs dominate

02 Double-antibody ADCs are still in the early stages of exploration, and HER2 double-antibody ADCs dominate

Since the field of dual-antibody ADCs is still in the early stage of exploration, there are fewer products under research at present, and most of them are in the preclinical stage
.

At present, the drugs under research for double-anti-ADCs are mainly based on HER2 double-anti-ADCs
.

This combination therapy method is superior to monotherapy in terms of therapeutic effect, and the HER2 double-antibody ADC developed on this basis is expected to have a good therapeutic effect
on patients who are resistant to ADC drugs such as trastuzumab, pattuzumab, and even TDM-1.

Unfortunately, however, Zymeworks recently released the news that the
Phase I clinical data of ZW49 for the treatment of solid tumors did not meet expectations.

(Preliminary results of the Phase I study of ZW49 Source: ESMO 2022 abstract)

In addition, AstraZeneca's biepitope quadrivalent HER2 ADC drug MEDI4276, although it has shown good efficacy for trastuzumab, pattuzumab and T-DM1 resistance models, MEDI4276 was terminated
due to adverse events leading to discontinuation of treatment and dose-limiting toxicity 。 Overall, in addition to HER2 double-anti-ADCs, there are also regenerative cMet/cMet double-anti-ADCs (REGN5093-M114) that target two different binding epitopes of the same antigen, which are currently in phase I/II clinical trials
.

There are two different binding epitope pathways for double-anti-ADC drugs that target the same antigen, and there are also research and development pathways
that target 2 different antigens on the same cancer cell.

03 Corning Jerry and Biosetto compete on the double-anti-ADC track

As can be seen from the above, whether it is the research and development of the first three generations of ADC drugs or the new generation of double-anti-ADC drugs, it has always been inseparable from solving the problems
of toxicity and safety.

In fact, it is essentially to solve the problem of ADC structure design, that is, how to find the balance between the three components of antibodies, cytotoxins and hymen
.

For example, Corning Jereh's double-anti-ADC drug JSKN003 is developed
on the basis of its Fc-based heterodimer bispecific antibody development platform, that is, charge rejection induced bispecificity (CRIB) platform and multifunctional immunomodulatory antibody technology (including BADC, etc.
).
Although Corning Jereh is doing the mature target HER2, unlike other pharmaceutical companies are doing new targets, the company uses cutting-edge technology to integrate and build a fixed-point coupling platform, relying on the self-developed antibody coupling technology, and benchmarking DS-8201
with its unique glycosylation fixed-point coupling method.
According to preclinical studies, JSKN003 has been shown to have better stability and comparable tumor suppressive activity
.
In July 2022, JSKN003's IND application was submitted to the State Food and Drug Administration and accepted for the treatment of solid tumors, which is also the first double-anti-ADC drug
in China to apply for clinical trials.
In addition, Biosetto has also developed two double-anti-ADC drugs based on the company's RenLite full-human antibody mouse platform, namely TROP2/HER2 double-anti-ADC drug YH012 and MET/EGFR double-anti-ADC drug YH013, which are planned for the treatment of solid tumors and are currently in the development stage
.
Moreover, BIOSETT can also use this dual-antibody ADC R&D platform to achieve high-throughput screening and development of dual-antibody ADC combinations, resulting in a steady stream of highly differentiated and innovative dual-antibody ADC molecules
.

However, the fixed-point coupling platform integrated and built by the company using cutting-edge technology relies on the self-developed antibody coupling technology and benchmarks DS-8201
with its unique glycosylation fixed-point coupling method.

(Based on RenLite platform high-throughput real estate out of the double antibody ADC Source: BIOSETT official website)

Conclusion: On the whole, whether there is an independent research and development platform is undoubtedly crucial
for the research and development of dual-anti-ADC drugs that test the comprehensive research and development strength and structural design.
After all, we can strive for the lowest cost of trial and error at an early stage of exploration and improve the success rate
of research and development.
It depends on whether domestic pharmaceutical companies such as Corning Jereh and Biosetto can successfully succeed
.

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