| |
 |
| |
|
|
Avidimer Therapeutics’ proprietary pharmaceuticals are formed from dendrimers which are nanometer size polymers that serve as an inert scaffolding. Therapeutic and / or diagnostic agents are covalently attached to this scaffolding through chemical linkers. Additionally, targeting vectors are attached to the dendrimers and serve as the precision guidance system which directs the system to sites of disease, while ignoring / bypassing healthy tissue. Targeting vectors are molecules that associate strongly with cell surface markers expressed selectively on disease cells (e.g., cancer) and not on healthy cells or tissues. The constructs formed by simultaneously docking targeting vectors, drugs and imaging agents to dendrimers are referred to as avidimers (i.e. “smart drugs”).
 |
| Figure: Illustration of the dendrimer compared in size to hemoglobin. |
|
As applied to cancer, avidimers offer dramatically improved tumor specific delivery, resulting in improvements in both efficacy and safety relative to the corresponding untargeted drugs. Additionally, by incorporating an anti-cancer drug into an avidimer, the drug’s biodistribution can be altered in a manner controlled by the targeting vector; thus, potentially broadening its spectrum of activity to include tumor types to which the untargeted drug fails to show activity.
There are several unique features of avidimers that result in their superior performance relative to other carrier systems. The first is the particle’s size and shape. At approximately 5nm in diameter, dendrimers are approximately the size and shape of a hemoglobin molecule (Figure), while a fully configured avidimer is less than 15nm in diameter. Dendrimers are globular in shape. An avidimer’s shape, flexibility and small size permit it to maneuver freely through the body without encountering the resistance to extravasation, target recognition, and cellular uptake observed with carrier systems of larger dimensions. Avidimers are administered by injection (IV or subcutaneously) and despite their size and apparent structural complexity, they are excreted primarily in the urine in less than 72 hours without causing apparent harm to the test subjects.
Secondly, avidimers are created by attaching multiple copies of a targeting vector and drug to the dendrimer. The ability to attach multiple targeting vector molecules results in a significantly tighter binding of the avidimer to complementary cell surface markers (i.e. greater avidity) and higher efficiency of internalization of the avidimer into target cells. By having multiple copies of the drug bound to the avidimer, the delivery payload is greatly increased. This capability to attach multiple molecules of both the chosen targeting vector and drug is particularly valuable for therapeutics intended to treat cancer, where high intra-tumoral pressures create substantial opposition to delivery of traditional particulate systems.
Thirdly, the linker chemistries used to attach various drugs to dendrimers can be selected to either retain the drug on the dendrimer throughout its lifetime or allow the drug to disassociate (i.e. cleave) from the dendrimer following delivery to the intended target. Maintaining the drug attached to the dendrimer in transit to the disease target is important in sparing healthy tissue, i.e., minimizing toxicity, but in some cases, the drug must be released from the dendrimer at its intended destination to express biological activity, while in other cases, the drug retains its activity when attached to the dendrimer. It is generally preferable for the targeting vector to remain permanently attached to the dendrimers to avoid eliciting a pharmacologic or physiologic response that may be associated with free targeting vector.
And finally, the versatility of the dendrimer and its various linker chemistries provide a platform from which a broad portfolio of products can be derived that incorporate a diverse set of drugs and targeting vectors, all leveraging the same underlying technology platform and discovery and development methodologies.
The Company’s lead product candidates feature low development risks, cost efficient development plans, and leverage well-defined clinical development pathways while providing significant partnering potential with the first product candidate expected to enter human clinical trials in late 2007.
|
|
|
|
