Antibody-coated stent

Model Combination Product Antibody-Coated Stent 789... 

MODEL COMBINATION PRODUCT ANTIBODY-COATED STENT... 

In order to present clearly and specifically the unique preclinical testing challenges associated with the early-stage development of biologic/device combination products, an antibody-coated stent will be used as a model. For this particular case study the antibody chosen for manufacturing has either not yet been approved for use in humans or, if it has, not for the newly targeted indications. In addition, the combination product utilizes a previously approved stent and delivery system. 

Once immune cells become bound to the surface of the antibody-coated stent via multivalent interactions with exposed Fc domains, there is the potential for a variety of immunomodulatory effects (cytokine release, inhibition of normal Fc receptor mediated events, etc.) that could lead to the generation of adverse events, in vivo. 

In terms of antibody-coated stents, the following is a list of potential antibody-containing species that could, in theory, be eluted directly from the surface of the implanted biologic/device combination product, in vivo (Figure 34.2) ... 

These parameters include, but are not limited to, establishment of a minimal effective dose (MED), a no observable dose (NOEL), a no observable adverse effect dose (NOAEL), and a maximum tolerated dose (MTD). From the standpoint of our antibody-coated stent model, and antibody dose, it is possible that the product (device) labeling could limit the dose of mAb a patient is allowed to receive to how much protein is able to be coated onto just one stent. Alternatively, since stents are made in various lengths in order to match the length of the lesion, the longer the stent, the more antibodies that can be delivered. 

Since all of the potential immunotoxicological effects mentioned above related to the use of antibody-coated stents are typically highly concentration dependent, it is possible that the use of only very small amounts of protein on the surface of the device to exert a desired localized therapeutic effect, will mitigate, but certainly not eliminate these potential toxicities. Nevertheless, the purpose of the preclinical toxicological evaluation will be to address the potential impact of these theoretical concerns. 

Assessment of biologic/device combination product functionality needs to include all of the testing typically performed on bare metal stents (BMS). In the case of our antibody-coated stent model the BMS have been previously approved by CDRH, allowing some of the BMS data to be cross-referenced and not repeated when the effect of the antibody coating on the functionality of the device is considered negligible. These judgments must be made on a case-by-case basis and should be confirmed with the Office for Device Evaluation. 

Aggarwal R, Ireland D, Azrin M, Ezekowitz M, De Bono D, Gershlick A, Antithrombotic potential of polymer-coated stents eluting platelet glycoprotein llb/llla receptor antibody. Circulation 1996 94 331 1-3317. 

The potential for immune responses against biologies (hypersensitivity, anti-drug antibodies, immune complexes, etc.) is something that most stent (alone or as drug-coated stents) manufacturers have not had to consider in prior development programs. 

Lin, Q. K., Ding, X., Qiu, F. Y, Song, X. X., Fu, G. S. and Ji, J. (2010). In situ endotheU-ahzation of intravascular stents coated with an anti-CD34 antibody functionalized heparin-coUagen multilayer. Biomaterials, 31,4017-4025. 

FIG U RE 2 The novel generation cardiovascular stents coating with special nanocomposite polymers like POSS-PCU (polyhedral oligomeric silsesquioxane and copolymer caibonate-urea urethane trade named UCL-NanoTM) has been developed specifically to capture oxide nitrogen and EPC specific antibodies (factor of endothelialization) simultaneously. 

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