Dosage regimen for administering a CD19xCD3 bispecific antibody to patients at risk for potential adverse effects

Abstract

A method for assessing the risk of potential adverse effects for a human patient receiving is provided. The method comprises determining the total B count in the patient, and identifying a B cell number indicative of a patient at risk of potential adverse effects from the antibody. The method further provides a dosing schedule for administering the antibody to the patient identified as at risk of potential adverse effects. Also provided is a pharmaceutical package or kit comprising a first dose and a second dose, and optionally a third dose, the CD19×CD3 bispecific antibody as defined in the methods/dosage regimen of the disclosure.

Claims

1. A method for identifying and treating a human patient suffering from malignant CD19-positive lymphoma or leukemia who is at risk for a potential adverse effect resulting from treating the patient with a CD19×CD3 bispecific antibody comprising an amino acid sequence encoded by a nucleotide sequence comprising at least 80% identity to the nucleotide sequence set forth in SEQ ID NO: 2, and wherein the amino acid sequence also comprises (i) an anti-CD19 variable heavy chain comprising a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 17 or 25, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 18, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 19; (ii) an anti-CD19 variable light chain comprising a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 20, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 21, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an anti-CD3 variable heavy chain comprising a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 11 or 24, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 12, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 13; and (iv) an anti-CD3 variable light chain comprising a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 14, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 15, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 16, the method comprising: (a) determining the ratio of B cells to T cells and total B cell count in a blood sample from the patient; (b) identifying the patient as having (i) a greater risk for the potential adverse effect when the patient has a total B cell count of less than 40 B cells per microliter of peripheral blood and a ratio of B cells to T cells of about 1:8 or lower; or (ii) a lesser risk for the potential adverse effect when the patient has a total B cell count of greater than or equal to 40 B cells per microliter of peripheral blood and a ratio of B cells to T cells of greater than 1:8; and (c) administering to the patient identified as having (i) the greater risk an incremental dosing regimen of the CD19×CD3 bispecific antibody to reduce the risk for adverse effect of the CD19×CD3 bispecific antibody; or (ii) the lesser risk a flat dosing regimen of the CD19×CD3 bispecific antibody.

2. The method of claim 1, wherein the adverse effect is a neurological reaction.

3. The method of claim 1, wherein the method is conducted prior to treating the patient with the CD19×CD3 bispecific antibody.

4. The method of claim 1, wherein the antibody is Blinatumomab.

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

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

7. The method of claim 1, wherein the CD19×CD3 bispecific antibody comprises a CD19 variable heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 3, a CD19 variable light chain comprising the amino acid sequence set forth in SEQ ID NO: 5, a CD3 variable heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 7, and a CD3 variable light chain comprising the amino acid sequence set forth in SEQ ID NO: 9.

8. The method of claim 1, wherein the CD19×CD3 bispecific antibody comprises a CD19 variable heavy chain comprising an amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 4, a CD19 variable light chain comprising an amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 6, a CD3 variable heavy chain comprising an amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 8, and a CD3 variable light chain comprising an amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO: 10.

9. The method of claim 1, wherein the CD19×CD3 bispecific antibody comprises a polypeptide encoded by a nucleotide sequence comprising at least 90% identity to the nucleotide sequence set forth in SEQ ID NO: 2.

10. The method of claim 1, wherein the CD19×CD3 bispecific antibody comprises a polypeptide (i) encoded by the nucleotide sequence set forth in SEQ ID NO: 2, or (ii) comprising the amino acid sequence set forth in SEQ ID NO: 1.

11. The method of claim 1, wherein the CD19×CD3 bispecific antibody comprises an amino acid sequence encoded by a nucleotide sequence comprising at least 95% identity to the nucleotide sequence set forth in SEQ ID NO: 2.

Description

(1) The Figures show:

(2) FIG. 1: B cell counts from patient samples are stratified as predictor of risk of adverse effects in patients treated with a CD19×CD3 bispecific antibody.

(3) FIG. 2: B cell counts of patient samples as a predictor in comparison to B:T cell ratios. A) and B) are results from two clinical studies treating patients with a CD19×CD3 bispecific antibody (A: trial 103-104, NHL; B: trial 103-202, ALL).

EXAMPLES

(4) The following examples illustrate the invention. These examples should not be construed as to limit the scope of this invention. The examples are included for purposes of illustration and the present invention is limited only by the claims.

Example 1

(5) Identification of a Predictive Factor for Reversible Neurological Adverse Events in a Subset of Non-Hodgkin Lymphoma Patients Treated with CD19-Specific BiTE Antibody Blinatumomab

(6) Blinatumomab is a CD19/CD3-bispecific antibody construct of the bispecific T cell engager (BiTE®) class showing as single agent a high rate and duration of responses in patients with relapsed non-Hodgkin lymphoma (NHL) and B-precursor acute lymphocytic leukemia (ALL). Blinatumomab has a favorable safety profile with exception of a subset of patients developing neurological adverse events (AEs) during the first days of treatment, such as confusion, speech impairment or cerebellar symptoms. Thus far, all relevant neurological AEs (11 out of 48 patients) were transient, fully reversible and resolved without sequelae within 3 to 72 hours after stop of infusion. In no case, pathological findings were seen upon cranial magnetic resonance imaging. Despite treatment discontinuation, 4 patients with neurological AEs have achieved an objective lymphoma remission. Analysis of cerebrospinal fluid (CSF) taken within hours after stop of infusion showed detectable levels of blinatumomab in the majority of affected patients, while in one patient without neurological symptoms no blinatumomab was detectable in CSF during infusion. Moreover, increased levels of albumin and T lymphocytes in CSF support a disturbance of the blood brain barrier (BBB) as a possible underlying event. Analyses of patient serum samples for angiopoetin-2 and S100β are ongoing to investigate whether levels of the endothelial stress and BBB integrity marker, respectively, correlate with neurological AEs. In a retrospective analysis of 39 NHL patients, a baseline B cell to T cell (B:T) ratio in peripheral blood at or below 1:10 was identified as the only predictive factor for the subsequent occurrence of neurological AEs. The predictive value was then prospectively confirmed in 8 additional patients. In conclusion, a simple measure to prospectively identify patients at risk of developing neurological AEs after onset of blinatumomab treatment has been identified. Mitigating measures are currently being tested in these high-risk patients in order to avoid discontinuation of treatment.

Example 2

(7) Synopsis of Observations (1) in Patients Treated with a CD19×CD3 Bispecific Antibody

(8) Common Features of Early CNS Events

(9) First symptoms appear 12-48 h after start of MT103 infusion: Agitation, speech impairment, sometimes tremor, ataxia More severe symptoms leading to infusion stop appear after 24-72 h: Confusion, disorientation, ataxia, aphasia, seizure After stop of MT103 infusion, complete resolution of CNS symptoms seen within 1-3 days; generally no sequelae Most CNS events fall into early activation and redistribution phase of polyclonal T cells
Features of CNS Events with Slow Onset Biased to cerebellar symptoms Occur at various time points during treatment, frequently at begging of treatment or at step increase Tremor, mild speech impairment, mild writing impairment; can last for several days
Other CNS Events Additional symptoms observed without proven relationship to other CNS events: Headache, fever, nausea
MT103 Dose Response Relationship of CNS Events Dose response relationship of CNS events is evident; cut off between dose level of 5 and 15 μg/m.sup.2/

Example 3

(10) Synopsis of Observations (2) in Patients Treated with a CD19×CD3 Bispecific Antibody

(11) CNS Events to Appear to be Predictable

(12) Correlation of CNS events with low B: T cell ratio (or low B cell count) B:T ratio of <1:10 identified as apparent cut off for development of CNS events No other biochemical or clinical parameters appear to correlate with CNS events
Cranial MRI Patients with CNS Events Mostly Without Pathological Findings CSF Analyses Suggest Opening of BBB and Neuroinflammatory Event Detectable levels of MT103 and increased levels of protein and serum albumin found in majority of affected patients suggest temporary breakdown of blood brain barrier (BBB) No MT103 found in CSF of one patient free of CNS events CSF analysis also shows in some affected patients increased counts of monocytes and T lymphocytes indicative of neuroinflammatory process Are CNS events reflecting gradual opening of BBB (agitation>confusion>aphasia, ataxia>seizure)?
Incidence of CNS Events May Correlate with Disease and/or Tumor Load At 15 μg/m.sup.2/d, ⅜ NHL patients (37%) and only one of 1/11 ALL ‘high risk’ patients (9%) developed CNS events B-ALL patients routinely receive intrathecal chemotherapy (and i.v. high-dose methotrexate) likely reducing tumor cell load in CNS (“occult meningeosis neoplastica”)

Example 4

(13) Summary of CNS Events in Patients Treated with a CD19×CD3 Bispecific Antibody

(14) TABLE-US-00001 Summary of Clinically Relevant CNS Events in NHL Patients First or Dose in Treatment Complete Neurological B:T cell Additional μg/m.sup.2/ Stop after Resolution, Best Patient # Assessment Disease ratio Gender, Age Treatment Day Start Time Response 105-005 Confusion, FL 1:23.9 Female, 65 First 15 15 h Yes, 24 h SD communication disorder 102-004 Organic Brain MCL 1:757 Male, 75 First 15 50 h Yes, 34 h n.d. Syndrome 102-006 Generalized MZL 1:1740 Male, 59 First 30 48 h Yes, 48 h n.d. seizure (acidosis) 109-011 Cerebellar MCL 1:9:2 Male, 73 Restart 60 48 h Yes, 24 h PR Symptoms (first) 109-012 Encephalopathy MCL 1:19520 Male, 55 Additional 60 24 h Yes, 24 h CR (first) 102-007 Seizure, aphasia FL 1:197 Male, 61 First 90 48 h Yes, 48 h ?PR? 109-023 Encephalopathy MCL 1:368 Male, 60 First 60 17 h Yes, 56 h n.d. 109-025 Encephalopathy MCL 1:873 Male, 58 First 15 41 h Yes, 48 h n.d. 108-004 Speech FL 0:431 Male, 66 First 60 624 h  Yes, 3 h PR Impairment Palsy Face and Arm 109-261 Desorientation, MCL 1:20 Male, 42 Additional 60 30 h Yes, 72 h PR Speech (first Impairment cycle)

Example 5

(15) Dose Dependency of CNS Events of Patients Treated with a CD19×CD3 Bispecific Antibody in Clinical Trials

(16) TABLE-US-00002 Dose Dependency of CNS Events in Ongoing NHL Trial ‘High risk’ patients defined by having low B:T cell ratio (<1:10) Initial dose considered for classification in dose groups Dose All ‘High Risk’ ‘Low Risk' ≤5  0/14 (0%)  0/4+ (0%)  .sup.   0/10 (0%)  15 3/16 (19%) 3/8+ (38%) .sup.  0/8 (0%) 30  1/6 (17%) 1/1 (100%) 0/5 (0%) 60 5/13 (38%) 4/5 (80%)  1*/8 (13%) 90  2/3 (66%) 1/1 (100%)  1/2 (50%) All 11/52.sup.§ (21%)  9/19 (47%)  2/33 (6%)  .sup.§>48 patients is due to additional treatments and re-starts of individual patients (resulting in conversion to ‘high risk’) *Reached borderline B:T ratio after first treatment cycle +Incl. patients with step-wise dose increase

Example 6

(17) A Patient Having an Increased Risk of Potential Adverse Effects Who Received 15 μg/m.sup.2/d for 7 Days and 60 μg/m.sup.2/d for 21 Days Showed No Adverse Effects (Neurological Reactions)

(18) Patient 108-003 Female, 66 y FL grade 2, IVB (FD: September 2006) Relevant medical history: anemia, thrombocytopenia, (pre-treatment 2× Zevalin and bone marrow infiltration by FL) elevation of gGT and AP, abuse of benzodiazepines, status after 2, aureaus sepsis with spondylodiscitis and abscesses Prior lymphoma treatment: 6×R-CHOP 14, 8×R September 2006-February 2007 R mono May 2007 1. Zevalin November 2007 2. Zevalin January 2008 According to initial B:T cell ratio (1:10,5) high-risk cohort 15/60) Jan. 5, 2009 Treatment start (15 μg/m.sup.2/24 h) Fever, headache for 2 days—easily handled by oral paracetamol and novalgin January 12th dose increase to 60 μg/m.sup.2/24 h Again fever, headache—easily handled by oral paracetamol and novalgin No neurological events Well tolerated dose “step” Suspected improvement of bone marrow function

Example 7

(19) A Patient Having an Increased Risk of Potential Adverse Effects Who Received 5 μg/m.sup.2/d for 7 Days and 60 μg/m.sup.2/d for 21 Days Showed Mild Adverse Effects (Neurological Reactions)

(20) MCL, male 42 y B:T 1:12 Treatment start Jan. 19, 2009 with 5 micg/m.sup.2/d Day 1: fever and chills, headache, no further problems Step: January 26th: after 6 h fever, strong headache 27.01.09: tiredness, nausea, vomiting, endoscopy without pathological findings), absolute arrhythmia with frequency up to 170/min.fwdarw.resolution within one day after substitution of potassium and digitoxin. Cranial CT scan and CSF performed, CT: no pathological findings CSF: slightly elevated protein 55 mg/dL, cells: 23 Zellen/micL, mainly monocytic cells and some activated lymphocytes 27.01.09 afternoon: mild tremor, apraxia, “slow mental state”, evening: mild speech impairment (cerebellar ?), slow improvement over the next two days 29.01.09 due to ongoing mild symptoms decision to give dexamethasone Slow improvement of symptoms, complete resolution 31.03.09 During the further course of treatment: recurrent difficulties to play the guitar. After 4 weeks treatment: −37% After 8 weeks of treatment: PR/CRu

Example 8

(21) A Patient Having an Increased Risk of Potential Adverse Effects Who Received a Treatment Regimen According to the Present Invention.

(22) Patient 108-005 Mate, 71 y, FL IIIB B:T cell ratio: 57:1363 (low, 1:23.9) First diagnosis: 1997 Multiple prior treatments: 12× Rituximab (mono), 6× Rituximab-Bendamustin, 6× R-CHOP, autologous SCT Date of Blinatumomab start: 17.8.2009 Treatment duration: 8 weeks Well tolerated (no SAE) No neurological adverse event 8 Week CT Scan: −65%=partial remission of the lymphoma

Example 9

(23) A Further Patient Having an Increased Risk of Potential Adverse Effects Who Received a Treatment Regimen According to the Present Invention.

(24) Patient 109-031 Male, 60 y, Follicular Lymphoma IVA B:T cell ratio: 0:429 (low) First diagnosis: May 2009 Prior treatments: Pre-phase w<Vincristin/Decortin, 6× R-CHOP Blinatumomab treatment Start: Nov. 11, 2009 Treatment duration: 8 weeks Well tolerated (flush symptoms at steps—responsive to steroids) No neurological adverse event Lymphoma −56% after 8 weeks (partial remission of the lymphoma)