XTEN protein polymers enable high drug loads in Antibody-Drug Conjugates
Antibody-drug conjugates (ADCs) utilize the specificity of monoclonal antibodies to target tumor-associated antigens and deliver highly potent cytotoxic agents to malignant cells. High drug loads are often required to maximize the therapeutic potential of ADCs. Utilizing biodegradable hydrophilic XTEN protein polymers as drug linkers enables both high drug-antibody ratios and facilitates use of very hydrophobic compounds whose direct conjugation to the antibody is not amenable due to adverse effects on ADC stability and PK.
Attributes that make XTEN protein polymer a favorable drug linker:
- Highly hydrophilic
- Precisely-controlled chemical structure
- Drug conjugation with defined stoichiometry
- High drug-XTEN ratio achievable even for poorly-soluble drugs
- Compatible with RP-HPLC purification
- Stable in circulation
- Rapid degradation by intracellular proteases
XTEN polymers loaded with up to 9 hydrophobic cytotoxic drug moieties and purified to homogeneity show high solubility in aqueous solutions and low propensity to aggregation. Targeted XTEN-drug conjugates with defined drug load can be prepared in various formats by conjugation to antibodies, antibody fragments, metabolites, and peptides. The latter conjugates also benefit from long half lives characteristic of the unmodified XTEN polymers. Targeted XTEN-drug conjugates of all formats show high in vivo efficacy and low toxicity in mouse xenograft models.