In-Depth Analysis of ADC Technology Platforms

Representative ADC Technology Platforms

As a combination drug, any component of an ADC can be replaced or modified.Therefore, the ADC combination technology platform has significant extensibility, allowing for the iterative combination of a rich variety of products.The development history of internationally leading ADC companies is rooted in having a competitive platform.Table 1 lists several representative ADC technology platforms.

In-Depth Analysis of ADC Technology Platforms

Table 1. Summary of Representative ADC Technology Platforms

Domestic ADC Technology Platforms

Currently, most domestic companies optimize and modify based on the ADC technology platform from Daiichi Sankyo, including companies like Hengrui Medicine, Hansoh Pharmaceutical, Baitai Tianheng, Baiyoutai, Chengdu Tianqing, Maiwei Bio, BeiGene, and Yingen Bio, mainly focusing on modifying the toxin DXD and linkers.The optimization of toxins DXD and linkers is primarily aimed at achieving ADC products with good stability, safety, and efficacy.

Modification Based on Daiichi Sankyo’s Technical Route

Daiichi Sankyo has currently developed ADC drugs targeting HER2, TROP2, HER3, and other different targets based on its ADC platform. The main structure of its ADC can be roughly divided into“Antibody-（Mc-GGFG-Dxd）n” structure.

Antibody:Select different antibodies based on different targets, connecting to linkers through exposed sulfhydryl groups after breaking disulfide bonds.
Mc Linker:Maleimido Capronic, as the linker part, can be coupled to the exposed sulfhydryl groups after the disulfide bonds of the antibody are broken.
GGFG Tetrapeptide:Glycine-Glycine-Phenylalanine-Glycine, which can release the free active payload DXd through enzymatic hydrolysis inside the cell.
Toxin Dxd:Topoisomerase camptothecin derivative drugs like irinotecan.
DAR Value n:The ratio of toxin to antibody can be determined as needed.

Figure 1. “Antibody-（Mc-GGFG-Dxd）n” structure

Table 2. Modifications Based on Daiichi Sankyo’s Technical Route

Hengrui Medicine: Modifications Targeting Toxin DXD

Hengrui Medicine’s ADC technology optimizes and modifies the toxin Dxd from the Daiichi Sankyo platform, with a high degree of certainty and maximum retention of efficacy. Currently, ADC products targeting multiple sites such as HER2, TROP2, Claudin18.2, CD79b, Her-3, Nectin-4 have been laid out based on the above technology. The characteristics are as follows:

1) The linker part is Maleimido Capronic Mc linker;

2) The release unit is the GGFG structure;

3) The payload is a derivative of irinotecan, differing in that a group (cyclopropyl) is introduced at the α position of the Dxd amide, enhancing lipophilicity and cleverly increasing appropriate steric hindrance, thus enhancing membrane permeability and cytotoxicity after enzymatic cleavage.

Table 3. Hengrui ADC Product Development Progress

Modifications Based on Seagen Technical Route

Seagen (acquired by Pfizer) has currently developed ADC drugs targeting Nectin-4, CD30, TF, and other different targets based on its ADC platform. The main structure of its ADC can be roughly divided into “Antibody-（Mc-VC-PABC-MMAE）n” structure:

Mc Linker: Maleimido Capronic linker
VC-PABC: i.e., aspartic acid-citrulline-p-aminobenzyl alcohol
Toxin MMAE: A microtubule inhibitor monomethyl auristatin E, a synthetic pentapeptide derived from sea hare toxin-10

Figure 2. “Antibody-（Mc-VC-PABC-MMAE）n” structure

Table4. Modifications Based on Seagen Technical Route

Other ADC Drug Technical Routes

Gilead: Immunomedics (acquired by Gilead) has currently developed ADC drugs targeting TROP2 and other different targets based on its ADC platform. The main structure of its ADC can be roughly divided into “Antibody-（CL2A-SN38）n” structure.

Figure 3. Gilead’s Main ADC Structure

LONZA: Synaffix (acquired by Lonza) has currently developed glyco-conjugation technologies GlycoConnect, HydraSpace, toxSYN, and has completed several external technology authorizations based on the above technology platform, including domestic companies like Innovent Biologics, Lepu Biopharma, etc.

Figure 4. LONZA’s Main ADC Structure

Ambrx: Ambrx has currently developed ADC drugs targeting HER2, PSMA, and other different targets based on its ADC platform. The main structure of its ADC can be roughly divided into “Antibody-（CL2A-MMAF）n” structure with incorporated unnatural para-acetylphenylalanine pAcF.

Figure 5. Ambrx’s Main ADC Structure

Outlook

Although ADC technology is full of hope in cancer treatment, it faces significant challenges that impact its clinical success.The continuous research and innovation of ADC technology aim to overcome these obstacles by enhancing antibody stability, optimizing payload selection, improving linker conjugation methods, and exploring synergies with nanotechnology, deepening our understanding of the challenges and encounters, ultimately driving progress in improving the efficacy and safety of ADCs in the fight against cancer.Although individual components such as linkers, cytotoxins, and antibodies may originate from mature technologies, the development of new ADC platform designs by combining these elements can achieve innovation.This strategy has the potential to advance ADC technology and broaden its practical applications.

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Table 2. Modifications Based on Daiichi Sankyo’s Technical Route

Table 3. Hengrui ADC Product Development Progress

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