Claims for Patent: 8,445,219

Summary for Patent: 8,445,219

Title:	Method of determination of receptor binding saturation effected by monoclonal antibodies
Abstract:	The invention relates to the determination of the degree of membrane receptor binding by specific monoclonal antibodies. This method is notably beneficial for monoclonal antibodies that are used in targeted therapies in order to define a target effective dose (TED). Especially the invention relates to the determination of the saturation degree of receptor binding effected by an anti-EGFR antibody of interest.
Inventor(s):	Reiffen; Karl-August (Muehltal, DE), Rosen; Oliver (Boston, MA)
Assignee:	Merck Patent GmbH (Darmstadt, DE)
Application Number:	13/055,567
Patent Claims:	1. A method for determining the degree of receptor binding saturation effected by a monoclonal antibody of interest (Ab1) by means of a first (Ab1A) and a second (Ab2) monoclonal antibody each provided with an individual detection system, wherein Ab1 specifically binds to an epitope (E1) of a receptor domain in a tissue sample, Ab1A recognizes and binds to the same epitope E1 of the receptor domain, and Ab2 binds to an epitope (E2) of the same receptor domain that is different from E1, and said binding of Ab2 does not interact with binding of Ab1 or Ab1A to E1, the method comprising the steps: (i) applying antibody Ab2 to a tissue sample of an individual in an amount which is sufficient to achieve receptor binding saturation towards E2 and determining the signal strength provided by the individual detection system associated with antibody Ab2, (ii) applying antibody Ab1A to a tissue sample of the same individual that was treated before with said antibody Ab1, in an amount which is sufficient to bind to receptor epitope E1 not already bound by antibody Ab1, and determining the signal strength provided by the individual detection system associated with antibody Ab1A, and (iii) calculating from the difference of the signal strength obtained by steps (i) and (ii), the amount of receptor domains which can still bind antibody Ab1, thus determining the degree of receptor binding saturation effected by antibody Ab1. 2. The method of claim 1, comprising as initial step adjusting the signal strength provided by the individual detection system associated with antibody Ab2 to the signal strength provided by the individual detection system associated with antibody Ab1A, wherein Ab2 and Ab1A have been applied to any tissue sample from the same source but not treated with antibody Ab1. 3. The method of claim 1, wherein the binding affinity of antibody Ab1 to epitope E1 is identical or similar to that of antibody Ab1A to E1. 4. The method of claim 1, wherein the binding affinity of antibody Ab2 to epitope E2 is identical or similar to that of antibody Ab1 to epitope E1. 5. The method of claim 1, wherein the individual detection system unique detection marker associated with antibody Ab2 and antibody Ab1A is a detection marker, and exploiting of the signal strength generated is done in a semi-quantitative manner. 6. The method of claim 5, wherein the detection marker is a dye. 7. The method of claim 1, wherein antibody Ab1 and antibody Ab1A have the same heavy and light chain sequences. 8. The method of claim 1, wherein the receptor domain is a tyrosine kinase membrane receptor selected from the group consisting of EGFR (Her1, ErbB1), Her2 (ErbB2) and Her3 (ErbB3), and antibodies Ab1, Ab2 and Ab1A are antibodies directed to at least one of these receptors. 9. The method of claim 8, wherein antibody Ab1 is matuzumab (Mab h425) or cetuximab (Mab c225, Erbitux.RTM.) or a binding-active fragment/derivative or a respective murine, chimeric or humanized version thereof. 10. The method of claim 8, wherein the tissue sample from said individual is from skin tissue. 11. The method of claim 10, wherein the receptor pattern and profile of the skin tissue is related to the receptor pattern and profile of tumor tissue in said individual. 12. The method of claim 10, wherein said tissue sample derives from an individual suffering from cancer or a respective disease or disorder. 13. The method of claim 1, wherein antibody Ab1 is a therapeutic antibody. 14. The method of claim 1, wherein antibody Ab1 is a human or humanized or chimeric antibody and antibody Ab2 is a mouse or rat antibody. 15. The method of claim 1, wherein the method is used for finding and optimizing ex vivo an effective dose of an antibody suitable for application in a therapy, especially an anti-tumor therapy. 16. An ex vivo-method of finding and optimizing an effective dose of a therapeutic antibody of interest, which is administered to a patient, comprising the method of claim 1, optionally followed by repeating at least one time steps (i) to (iii) after an altered dose of antibody Ab1 has been administered to the patient, until saturation of the receptor with antibody Ab1 can be measured and the optimum individual effective dose for said patient is found. 17. The method of claim 16, wherein the finding of optimum receptor saturation is used to avoid underdosing or overdosing of the therapeutic antibody.

Details for Patent 8,445,219

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	02/12/2004		2028-07-25
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	03/28/2007		2028-07-25