Anti-leukocyte adhesion for the mitigation of potential adverse events caused by CD3-specific binding domains
The present invention relates in essence to 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 therapy which comprises re-directing of T-cells against target cells in a patient. 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.
1. A method of ameliorating, treating, or preventing a neurological adverse event in a patient caused by administering to the patient a CD19xCD3 bispecific antibody comprising
(a) a CD3 binding domain comprising
(i) anti-CD3 heavy chain CDRs comprising CDR-H1 as set out in SEQ ID NO: 11, CDR-H2 as set out in SEQ ID NO: 12, and CDR-H3 as set out in SEQ ID NO: 13; and
(ii) anti-CD3 light chain CDRs comprising CDR-L1 as set out in SEQ ID NO: 14, CDR-L2 as set out in SEQ ID NO: 15, and CDR-L3 as set out in SEQ ID NO: 16; and
(b) a CD19 binding domain comprising
(i) anti-CD19 heavy chain CDRs comprising CDR-H1 as set out in SEQ ID NO: 17, CDR-H2 as set out in SEQ ID NO: 18, and CDR-H3 as set out in SEQ ID NO: 19; and
(ii) anti-CD19 light chain CDRs comprising CDR-L1 as set out in SEQ ID NO: 20, CDR-L2 as set out in SEQ ID NO: 21, and CDR-L3 as set out in SEQ ID NO: 22,
the method comprising administering to the patient an effective amount of a non-glucocorticoidal compound, wherein the non-glucocorticoidal compound is pentosanpolysulfate (PPS) or a pharmaceutically acceptable salt thereof, minocycline, or natalizumab.
2. The method of claim 1 , wherein the non-glucocorticoidal compound is administered prior to or concomitantly with an initial dosing, a re-exposure, or an increase in the therapy comprising the CD3 binding domain.
3. The method of claim 1 , wherein the neurological adverse event is one or more of:
(a) a cognitive disorder comprising disorientation, confusion or word-finding problems (aphasia);
(b) a seizure, or
(c) a cerebellar symptom partly observed as an optional prodromal phase of (a) or (b) comprising kinetic tremor, ataxia, dysarthria or handwriting problems.
4. The method of claim 1 , wherein the CD19xCD3 bispecific antibody is a bispecific single chain antibody.
5. The method of claim 1 , wherein the patient comprises a B:T cell ratio of less than 1:5 or a B cell number of less than about 50 B cells per microliter peripheral blood.
6. The method of claim 1 , wherein the mammalian T cells are re-directed mammalian T cells.
7. The method of claim 1 , wherein the patient is a mammal.
8. The method of claim 7 , wherein the mammal is a primate.
9. The method of claim 8 , wherein the primate is a human.
10. The method of claim 1 , wherein the CD19xCD3 bispecific antibody comprises:
(a) a CD3 binding domain comprising
(i) an anti-CD3 variable heavy chain as set out in SEQ ID NO: 7; and
(ii) an anti-CD3 variable light chain as set out in SEQ ID NO: 9; and
(b) a CD19 binding domain comprising
(i) an anti-CD19 variable heavy chain as set out in SEQ ID NO: 3; and
(ii) an anti-CD19 variable light chain as set out in SEQ ID NO: 5.
11. The method claim 1 , wherein the CD19xCD3 bispecific antibody comprises an amino acid sequence encoded by a nucleic acid sequence having at least 70% identity to the nucleotide sequence set out in SEQ ID NO: 2.
12. The method of claim 1 , wherein the CD19xCD3 bispecific antibody comprises:
(a) the amino acid sequence set out in SEQ ID NO: 1; or
(b) an amino acid sequence encoded by the nucleotide sequence set out in SEQ ID NO: 2.
13. The method of claim 1 , wherein the CD19xCD3 bispecific antibody further comprises a short polypeptide spacer between the anti-CD3 variable region and the anti-CD19 variable region.
14. The method of claim 13 , wherein the short polypeptide spacer comprises the amino acid sequence set out in SEQ ID NO: 23 (G-G-G-G-S) or repeats thereof.