Pro-Drug Conjugates

The pro-drug polymer conjugation approach can optimize the pharmacokinetics and pharmacodynamics of a drug to substantially increase both its efficacy and side effect profile. Nektar is currently using this platform with oncolytics, which typically have sub-optimal half-lives which can limit their therapeutic efficacy. With Nektar's platform, these drugs can be modulated to optimize bioactivity and increase the sustained exposure of active drug to tumor cells in the body.

Nektar is using this approach with the lead oncology candidate in our pipeline, NKTR-102.

Read more about NKTR-102 »

With a pro-drug design, several drug molecules are attached to a large molecular weight polymer in a multi- arm architecture. The drug molecules are conjugated with programmable releasable linkers. The linkers themselves can be customized to achieve the target product pharmacokinetic profile by controlling the rate of release. The active parent molecule is then cleaved from the prodrug through pH or enzymatic hydrolysis. The linkers release the drug, either sequentially or simultaneously, to achieve the desired target pharmacokinetics profile needed to maximize therapeutic efficacy.

Targeting Tumor Tissue Through the Enhanced Permeability and Retention (EPR) Effect

Nektar's pro-drug conjugate approach creates a unique macromolecular structure that targets tumor tissue through the enhanced permeation and retention (EPR) effect. Tumors are hypervascularized, with abnormal blood vessels that have poorly-aligned and leaky endothelial cell layers. Since Nektar's polymer-bound prodrugs are macromolecules, they do not easily penetrate the tight endothelial junctions of normal blood vessels, as would be observed with a typical small molecule chemotherapeutic. Instead, the macromolecular structure extravasates easily into the abnormal tumor tissue and becomes trapped there due to a lack of effective lymphatic drainage. Over time, drug accumulates in the tumor tissue resulting in enhanced intratumoral drug concentrations. Tumor exposure was increased four-fold with Nektar compounds in nonclinical tumor models as compared to the parent chemotherapy molecule and was also associated with increased anti-tumor activity.*

*Eldon et. al. "NKTR-102, a novel PEGylated irinotecan conjugate, results in sustained tumor growth inhibition in mouse models of human colorectal and lung tumors that is associated with increased and sustained SN38 exposure." AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, October 2007.

Large Molecule Polymer Conjugates »

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