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Genmab announced that it will acquire the privately owned biotech ProfoundBio for $1.8 billion in cash. ProfoundBio’s most mature candidate is rinatabart sesutecan (Rina-S， PRO1184), a potentially best-in-class ADC that works by targeting folate receptor alpha (FRα).Rina-S is comprised of a FRα-directed antibody conjugated to sesutecan,ProfoundBio's novel, proprietary hydrophilic Exatecan-based linker-drug, at a homogeneous drug-to-antibody ratio (DAR) of 8. The linker component of sesutecan is a highly hydrophilic, stable, cleavable linker designed to mask the hydrophobicity of Exatecan, enabling high DAR and efficient delivery of the Exatecan payload to tumors while maintaining favorable physicochemical and pharmacokinetic properties of the ADC.

Fig.1 Structure of PRO1184

Exatecan is a highly potent, membrane permeable topoisomerase-1 inhibitor with strong bystander effect, but its use as an ADC payload has been limited because of its hydrophobicity and challenging biophysical properties, which appear to be strongly caused by the steric hindrance around the stereo-defined primary amine^[1].This issue was solved by Daiichi Sankyo scientists by using a slightly modified glycolic acid derivative of Exatecan, named DXd.Which retained Exatecan potency, while enabling the successful bioconjugation of up to 8 DXd molecules per antibody without significant aggregation^[2].

Therefore, circumventing the hydrophobic and pro-aggregation characteristics of the ADCs and improving the therapeutic window of Exatecan have become hot topics. The synergistic combination of ProfoundBio's novel hydrophilic linker and Exatecan will help Exatecan ADC drugs reach a new heights.

ChemExpress can provide GMP Exatecan mesylate,and non-GMP Exatecan and intermediates in multiple kilograms in stock, dedicated to achieving the goal of synthesizing Exatecan economically and efficiently. Get ADC Product Brochure, Please Contact

Tel: (+86) 021-58950125             E-mail: [email protected]

Challenges

Originator's Patent Route

(WO2019044946A1)

Fig.2 RoS of Key Intermediate and Exatecan

-WO2019044946A1/ US11318212B2/ AU2018327170B2

■ Usage of noble metals (Pd), making the process expensive for scaling-up

■ High pressure hydrogenation, making the process risky

■ 10 steps, 5.3% overall yield

Solutions

ChemExpress's Patent Route

(WO2022000868A1)

Fig.3 Chemexpress RoS of Key Intermediate and Exatecan

-WO2022000868A1/ US20230257392A1 / CN111875517A

Compared with the prior art, the beneficial effects of the present invention are:

✔ Innovative synthesis of intermediate A , avoiding infringing existing patents

✔ Only 4 steps are required to obtain the key intermediate from inexpensive commercial SM and thetotal yield reach to 54%

✔ No noble metal catalyzed coupling reaction or high-pressure hydrogenation is needed, making the synthesis process less expensive and suitable for large scale manufacturing

✔ 8 steps, 15% overall yield

ChemExpress Exatecan Production Capacity

✔ Kilogram-scale GMP production meets commercial production requirements

✔ 3 sec-DMFs (DMF code: MF036708, MF037931, MF037930）

✔ The robust process can manufacture kilogram scale Exatecan in a single batch with ≥99.5% purity, >99.8% ee and >99.8% de

Reference:

[1] Pharmaceuticals (Basel). 2021 Mar 9;14(3):247.

[2] J Hematol Oncol. 2023 Jan 17;16(1):3.