SN38 is an inhibitor of topoisomerase I that blocks DNA replication and transcription. On April 7, 2021, the FDA approved sacituzumab govitecan (Trodelvy, Immunomedics, Inc.)—an ADC that consists of SN-38 linked with a humanized anti-TROP-2 IgG antibody—for patients with metastatic triple-negative breast cancer (mTNBC) after at least two prior therapies. TROP-2, a cell-surface glycoprotein, is expressed in over 90% of TNBCs. Unlike highly toxic payloads such as DM1 or MMAE, ADCs using chemotherapeutic agents often require higher drug loading to achieve efficacy. However, SN38 is a highly hydrophobic, and traditional linkers can cuase aggregation and precipitation. The super-hydrophilic, water-soluble, and charge neutral AqT linker greatly enhances SN38's solubility by forming extensive hydrogen bonds with water, preventing SN38 stacking and protecting the antibody from enzymatic degradation. This result in a high loaded, stable ADC with minimal aggregation. Preliminary in vitro data shows that SN38 with AqT linker often shows much toxic effect on the target with similar loading.
AqT-SN38 (CM81301) drug asset is currently available for partner evaluation. After AqT-ADC reaches the target, AqT linker can be separated from SN38 via its releasable ester bond. This tactic (traceless release) allows: 1) efficient transportation of the ADC in the biological media with minimum aggregation and toxicity, 2) preservation of the bystander killer effect of SN38.
Key Features of AqT-SN38 Asset
- Proprietary super-hydrophilic and water-soluble linkage
- High loading with average 5 to 7 SN38 per antibody with minimal added aggregation
- Sugar alcohol-based AqT linker preserves the properties of the antibody
- Releasable linkage with fully released SN38 (traceless release) to maximize the efficacy
Comparison of ADCs made by CM81301 and CM11408 (with SN38 Acid)
|
|
ADC by CM81301 (AqT-SN38) |
ADC by CM11408 (Ab SN38 Conjugation Kit with Classical Linker) |
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Proprietary |
Yes (composition of matter protected by AqT® technology) |
No, if your antibody is generic |
|
Linker Properties |
Proprietary super-hydrophilic and water soluble AqT® linker |
Classic hydrophobic ethylene-type linker |
|
Spacer |
Long spacer |
Short spacer (4 atoms) |
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Releasable Chemistry |
Same (ester bond) |
Same (ester bond) |
|
Loading |
High: 5−7 SN38 per antibody |
Low: 2−4 SN38 per antibody |
|
Hydrophobicity |
Slight changes in hydrophobicity |
Dramatically increases hydrophobicity |
|
Aggregation by SEC |
No or less than 2% added aggregation |
Average 10−50% added aggregation |
|
Heterogenicity by HIC |
Less heterogenicity |
Highly heterogenous product |
|
Stability |
Stable even with high loading: easily stored frozen without any stabilizer |
Unstable even with low loading |