Dosage regimen for administrating a CD19×CD3 bispecific antibody to patients at risk for potential adverse effects

1. A method for treating a human patient suffering from malignant CD19-positive lymphoma or leukemia, wherein the patient is at risk for potential adverse effects resulting from treatment with a CD19×CD3 bispecific antibody comprising an amino acid sequence encoded by the nucleic acid sequence set forth in SEQ ID NO: 2 or the amino acid sequence set forth in SEQ ID NO: 1, the method comprising:

(a) determining in the peripheral blood of the patient a ratio of B cells to T cells and total B cell count; and

(b) identifying the patient at risk as comprising a ratio of B cells to T cells of about 1:8 or lower;

(i) wherein a total B cell count of less than 40 B cells per microliter of peripheral blood is indicative of a higher risk for potential adverse effects for said patient; and

(ii) wherein a total B cell count of 40 B cells or greater per microliter of peripheral blood is indicative of a lower risk of potential adverse effects for said patient,

(c) administering the CD19×CD3 bispecific antibody

(i) to the patient who is at higher risk in an incremental dosage schedule to reduce the possibility of potential adverse effects in the patient,

wherein a first dose is administered for a first period of time and a second dose is consecutively administered for a second period of time,

wherein said second dose is greater than said first dose, and

wherein said second period of time exceeds said first period of time; or

(ii) to the patient who is at lower risk in a constant dose for at least four weeks.

2. The method of claim 1 , wherein the specific dosage schedule for said higher risk patient comprises:

(a) administering a first dose of the CD19×CD3 bispecific antibody for a first period of time of 7 days; and consecutively

(b) administering a second dose of said antibody for a second period of time that exceeds the first period of time; and optionally consecutively,

(c) administering a third dose of said antibody for the first or second period of time or for a third period of time,

wherein said second dose exceeds said first dose and said third dose exceeds said second dose.

3. The method of claim 1 , wherein said adverse effect is characterized by a neurological reaction.

4. The method of claim 2 , wherein:

said second period of time exceeds said first period of time;

said third period of time exceeds said first period of time and/or said second period of time;

said first period of time exceeds 3 days;

said first period of time is between 3 and 10 days, or is 7 days;

said second period of time exceeds 18 days; said second period of time is between 18 and 81 days, is 21 days, or is 49 days;

said first period of time is between 3 days and 10 days, and said second period of time is between 18 and 81 days; or

said first period of time is 7 days and said second period of time is 21 days or is 49 days.

5. The method of claim 2 , wherein

said first dose is between 1 and 15 μg/m 2 /d, or 5 or 15 μg/m 2 /d; or

said second dose is between 15 and 60 μg/m 2 /d, or is 60 μg/m 2 /d.

6. The method of claim 2 , further comprising administering a third dose of said antibody for a third period of time after a first and second dose for a first and second period of time.

7. The method of claim 6 , wherein

said third period of time exceeds said first and second period of time, and wherein said second dose exceeds said first dose;

said first period of time exceeds 3 days;

said first period of time is between 3 and 10 days, or is 7 days;

said second period of time exceeds 3 days;

said second period of time is between 3 and 10 days, or is 7 days;

said third period of time exceeds 8 days;

said third period of time is between 8 and 78 days, or is 14 days, or is 42 days;

said first period of time is between 3 and 10 days, and said second period of time is between 3 and 10 days, and said third period of time is between 8 and 78 days; or

said first period of time is 7 days, said second period of time is 7 days, and said third period of time is 14 days, or is 42 days.

8. The method of claim 6 , wherein

said third dose exceeds said first and second dose;

said first dose is 5 μg/m 2 /d or is between 1 and 15 μg/m 2 /d, or wherein said first dose is between 2 and 29 μg/d, or is 9 or 10 μg/d;

said second dose is 15 μg/m 2 /d or is between 1 and 15 μg/m 2 /d, or wherein said second dose is between 2 and 29 μg/d, or is 28 or 29 μg/d; or

said third dose is 60 μg/m 2 /d or is between 15 and 60 μg/m 2 /d, or wherein said third dose is between 28 and 116 μg/d, or is 112 μg/d.

9. The method of claim 1 , wherein the lymphoma comprises indolent or aggressive B cell non-Hodgkin lymphoma (B NHL), mantle cell lymphoma (MCL) or chronic lymphatic leukemia (CLL).

10. The method of claim 1 , wherein the leukemia comprises B-lineage acute lymphoblastic leukemia (ALL).

11. The method of claim 1 , further comprising periodically determining the ratio of B cells to T cells and/or total B cell counts during administration of said antibody.

12. The method of claim 11 , wherein the administering of the bispecific antibody may be adjusted based upon results of periodically determining the ratio of B cells to T cells and/or total B cell count to reduce the risk for potential adverse effects during the treatment.

13. The method of claim 1 , wherein said second period of time exceeds 18 days.

14. The method of claim 13 , wherein said second period of time is between 18 days and 81 days, or between 21 and 49 days.

15. The method of claim 13 , wherein said first period of time is 7 days and said second period of time is 21 or 49 days.

16. The method of claim 1 , wherein said first dose is between 1 and 15 μg/m 2 /d, or wherein said first dose is between 2 and 29 μg/d.

17. The method of claim 1 , wherein said second dose is between 15 and 60 μg/m 2 /d, or wherein said second dose is between 28 and 116 μg/d.

18. The method of claim 1 , wherein the method further comprises administering a third dose of said antibody for a third period of time after a first and second dose for a first and second period of time.

19. The method of claim 18 , wherein said third period of time exceeds said first and second period of time, and wherein said second dose exceeds said first dose.

20. The method of claim 18 , wherein said third dose exceeds said first and second dose.