Anti-leukocyte adhesion for the mitigation of potential adverse events caused by CD3-specific binding domains
The present invention relates in essence to use of a compound, which decreases or inhibits the binding of mammalian T-cells to mammalian endothelial cells for use in a method of prophylaxis and/or amelioration and/or treatment of clinical adverse events caused by a therapy which comprises re-directing of T-cells against target cells in a patient. Such a therapy includes, but is not limited to, treatment with an antibody comprising a CD3 binding domain, such as a CD20×CD3 or a CD19×CD3 bispecific single chain antibody, e.g., blinatumomab (MT-103). Methods of treatment of patients having or being at risk of clinical adverse events caused by therapy which comprises re-directing of T-cells against target cells are also contemplated, as are methods of identifying a compound for administration in the methods of prophylaxis, amelioration and/or treatment. Such anti-adhesive type compounds include, but are not limited to, antibodies, like natalizumab, efalizumab, and etrolizumab; minocycline, (acetyl-)salicyclic acid, astilbin, and flavonoids; and thrombin and pentosanpolysulfate (PPS), or a pharmaceutically acceptable salt thereof.
1. A method of ameliorating, treating, or preventing a clinical adverse event in a patient caused by administering blinatumomab to the patient, the method comprising administering to the patient an effective amount of pentosanpolysulfate (PPS) or a pharmaceutically acceptable salt thereof, minocycline, or natalizumab.
2. The method according to claim 1 , wherein the method further comprises administering to the patient genetically engineered T-cells having a chimeric antigen receptor (CAR).
3. The method according to claim 2 , wherein said chimeric antigen receptor (CAR) comprises a CD19 binding domain.
4. The method according to claim 1 , wherein the pentosanpolysulfate (PPS) or the pharmaceutically acceptable salt thereof, minocycline, or natalizumab is administered prior to or concomitantly with an initial dosing, a re-exposure, or an increase in dose of blinatumomab.
5. The method according to claim 1 , wherein said clinical adverse event comprises a neurological adverse event.
6. The method according to claim 5 , wherein said neurological adverse event is one or more of (i) a cognitive disorder comprising disorientation, confusion or word-finding problems (aphasia), (ii) a seizure, (iii) a cerebellar symptom partly observed as an optional prodromal phase of (i) or (ii) comprising a kinetic tremor, ataxia, dysarthria and/or handwriting problems.
7. The method according to claim 1 , wherein said patient is characterized by a B:T-cell ratio of less than 1:5 or a B-cell number of less than about 50 B-cells per μl peripheral blood.
8. The method according to claim 1 , wherein said patient is a mammal.
9. The method according to claim 8 , wherein said mammal is a primate.
10. The method according to claim 9 , wherein said primate is a human.