Synthesis of prodrugs with cleavable linker for targeted tumor therapy (ADC)

Antibody tumor therapies have provided great therapeutic benefit to patients with cancer, autoimmune diseases and other serious medical conditions. However, many antibodies lack sufficient intrinsic anti-tumor activity to be used as first-line therapeutics. Scientists at the University of Göttingen, Germany developed a new and improved synthesis of potent prodrugs (payloads), which can be easily coupled to antibodies (ADC) for a selective antibody tumor therapy.

Challenge

Selective tumor therapy combines the benefits from classical chemotherapy and antibody tumor therapy by providing antibody-drug-conjugates (ADC). These conjugates must provide safe medical application (prodrugs) and extremely high toxicity within the targeted tumor cell (activated and highly potent drug). Thus, there is an unmet need for highly potent drugs/prodrugs, which can be easily linked to antibodies to provide better ADC's.

Our Solution

Scientists at the University of Göttingen developed a new and improved synthesis of potent prodrugs (payloads), which can be easily coupled to antibodies for a selective tumor therapy (ADC). The coupling will not change the high toxicity of the activated drug. The soluble prodrugs are activated into highly cytotoxic drugs (IC50 in the femto-molar range) only in targeted tumor cells.

Advantages

  • New and improved synthesis of our 2nd generation bifunctional prodrugs for easy coupling to antibodies.
  • Coupling of more than one antibody possible – enabling further specificity and efficacy.
  • Antibody linkage does not change the extremely high toxicity of the payload when activated inside the cell.
  • Payload with new MoA: highly toxic non-DNA binding alkylating agent.

New chemical synthesis of heterogenic bifunctional prodrugs allows for direct and easy antibody linkage at the reactive OH-group. Optionally, a second antibody (or even more) can be linked at the sugar moiety. Source: S. Uhle

 

Applications

ADC tumor therapy.

Developmental Status

The new synthesis has been successfully established in the group of Prof. Lutz Tietze.

Patent Status

A European priority patent application has been filed (Applicant: Georg-August-University of Göttingen public law foundation).

References

Tietze et al. Angew. Chem. Int. Ed. 2010, 49(40), 7336-9.
Wirth et al. Angew. Chem. Int. Ed. 2012, 51(12), 2874-7.
Wirth et al. Angew. Chem. Int. Ed. 2013, 125(27), 7059-63.
Chen et al. Mol Pharm. 2013 May 6;10(5):1773-82.
Koch et al. Angew. Chem. Int. Ed. 2015, 54(46), 13550-4.

DE102009051799
WO2017072295

Contact

Dr. Stefan Uhle
Patent Manager Life Science
E-Mail: suhle(at)sciencebridge.de
Tel: +49 551 30724 154
Reference: BioC-2012-SUG

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