Founded in 2018, ProfoundBio originated in Seattle, Washington, USA. The three core founders are Dr. Baiteng Zhao, Dr. Tae H Han, and Dr. Xiao Shang. Dr. Baiteng Zhao graduated from the College of Pharmacy at the University of Texas at Austin and completed his postdoctoral research at the School of Pharmacy, State University of New York at Buffalo. He has previously worked at internationally renowned pharmaceutical companies such as Merck and Seagen.
Their key ADC patent WO2023280227A2 was recently disclosed, with VC as the main linker, preceded by a lysine, extended with multiple PEGs, linked to a sugar chain (glucosamine), increasing hydrophilicity, and the payload using exatecan.
This approach is similar to the previously announced XMT-2056 by Mersana, a HER2-targeted STING Agonist ADC.
Seagen is the earliest ADC company to focus on glycan engineering, and this approach has gradually been adopted by other companies. However, we have yet to see further progress in this area. There are already several designs similar to glycan chain + exatecan, both domestically and internationally.
Based on the efficacy data of PRO1184 (targeting Folate Receptor a), its effects are similar to mAb-deruxtecan (8) (mc-GGFG-DXd).
Some days ago, Multitude Therapeutics published the article “Antibody-exatecan conjugates with a novel self-immolative moiety overcome resistance in colon and lung cancer”. They also enhanced hydrophilicity by adding a polylysine to the self-cleaving PABC structure in the ADC linker.
Nowadays in the ADC field, highly hydrophilic linker has become the main design concept. Currently, only a few companies like Medilink Therapeutics have a bias towards mechanisms, with its platform named Tumor Microenviroment Activable LINker (TMALIN®), as the name suggests, it can release in the tumor microenvironment, rather than purely relying on endocytosis to kill tumor cells in the traditional sense.
The high hydrophilicity of the linker only contributes to the drug-like properties in terms of solving physical and chemical properties, and not much to the biological mechanisms.
It would be ideal if it can be ensured not to drop in the blood but to enter the tumor cells before being cleaved. However, at present, it cannot be determined whether it has specificity.
From numerous cases, it can be seen that isotype ADCs often show some efficacy, but how does this part of the efficacy work? One possibility is that for ADCs with peptide linkers, there are also tissue proteases in the tumor site, leading to the ADC cleaving outside the cell and exerting efficacy. Another reason may be that in the metabolism process of ADCs, there is still overflow of small molecule payloads causing toxicity, which also has certain cytotoxicity to the tumor. The latter is easier to explain. Even for stable ADCs, there is still toxicity from small molecules. According to various literature, ADC drugs that can reach the tumor site only account for about 1%. Of course, the former factor cannot be ruled out either.
ProfoundBio previously introduced synaffix’s sugar site-specific conjugation platform, which has not yet been applied to relevant projects. One possible reason is that the effect is not ideal, and synaffix’s sugar site-specific conjugation platform also has certain limitations. So far, site-specific conjugation has not been practically validated in clinical aspects.
ADCs mainly focus on four directions: antibodies, conjugation methods, linkers, and payloads. In the direction of antibodies, there are fewer discussions on the selection of antibodies. ADCs are an overall concept. If only the linker is considered to solve the hydrophobicity problem, an inadequate antibody will nullify these efforts, and none of the necessary aggregates will be missing. But so far, it is the most labor-saving way to bypass patents by modifying linkers.
Nowadays, the ADC field is starting to consider another issue, drug resistance. From the clinical data of TROP2 DXD, although there is still some efficacy after treatment with camptothecin drugs, it is not outstanding. The effect before camptothecin drug treatment is better, which shows that treated patients still affect the subsequent treatment of similar payloads. This problem has been explained in a paper, which is that mutations in topoisomerases lead to the ineffectiveness of camptothecin drugs.
Therefore, different mechanism payloads still have great potential for modification.
Related highly hydrophilic linkers and ADC services by AxisPharm:
Sugar PEG β-Glucuronide Linker
Antibody drug conjugate linkers
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