IP Library › Granted Patent US 12,729,243
Granted Patent B2
US 12,729,243 · App. 17/733,909 · Granted Sep 8, 2026

Dosing for treatment with anti-CD20/anti-CD3 bispecific antibody

Inventors: Linda Lundberg (Binningen, CH); Peter N. Morcos (Marlboro, NJ); Martin Weisser (Penzberg, DE); Axel Boehnke (Muenchenstein, CH); David Carlile (Princes Risborough, GB); Nassim Djebli (Rixheim, FR)
Assignee: Hoffmann-La Roche Inc.
C07K16/2887A61K31/475A61K31/573A61K31/664A61K31/704A61K39/3955A61P35/00C07K16/2809A61K2039/505A61K2039/507A61K2039/54A61K2039/545C07K2317/24C07K2317/31C07K2317/52C07K2317/522C07K2317/55C07K2317/56C07K2319/30C12N2320/35
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Quick Facts
Patent No.
US 12,729,243
App. No.
17/733,909
Granted
Sep 8, 2026
Kind
B2
Abstract

The present invention relates to methods of treating a B-cell proliferative disorder by administering an anti-CD20/anti-CD3 bispecific antibody, and methods for reduction of adverse effects in response to the administration of the anti-CD20/anti-CD3 bispecific antibody. The present invention further relates to combination treatment methods of treating a B-cell proliferative disorder.

Claims (155)

1 . A method of treating a subject having a CD20-positive B cell proliferative disorder comprising administering to the subject an anti-CD20/anti-CD3 bispecific antibody in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein: (a) the first dosing cycle comprises a first dose (C1D1) and a second dose (C1D2) of the anti-CD20/anti-CD3 bispecific antibody, wherein the C1D1 is 2.5 mg, and the C1D2 is 10 mg; and (b) the second dosing cycle comprises a single dose (C2D1) of either 16 or 30 mg of the anti-CD20/anti-CD3 bispecific antibody,

wherein the anti-CD20/anti-CD3 bispecific antibody comprises:

(a) at least one antigen binding domain that specifically binds to CD20, comprising

a heavy chain variable region comprising:

(i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

(ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and

(iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO:3;

and a light chain variable region comprising:

(i) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4;

(ii) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and

(iii) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6; and

(b) at least one antigen binding domain that specifically binds to CD3, comprising

a heavy chain variable region comprising:

(i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 9;

(ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 10; and

(iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO:11;

and a light chain variable region comprising:

(i) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12;

(ii) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 13; and

(iii) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14:

wherein

(i) the first dose (C1D1) is administered on day 1 of the first dosing cycle and the second dose (C1D2) is administered on day 8 of the first dosing cycle;

(ii) the single dose of the second dosing cycle (C2D1) is administered on day 1 of the second dosing cycle; and

(iii) one dosing cycle comprises 14 days or 21 days; and

wherein the method further comprising administering to the subject obinutuzumab,

wherein:

(iv) obinutuzumab is administered 7 days before the first dose of the anti-CD20/anti-CD3 bispecific antibody (C1D1); and

(v) obinutuzumab is administered at one single dose of 1000 ma or a first and a second dose of each 1000 ma obinutuzumab.

2 . The method of claim 1 , wherein:

(a) the method comprises 1 to 10 additional dosing cycles (C3 to C12);

(b) the anti-CD20/anti-CD3 bispecific antibody is administered intravenously;

(c) the subject is human; and/or

(d) the subject is a high-risk subject.

3 . The method of claim 2 , wherein the 1 to 10 additional dosing cycles (C3 to C12) each comprises a single dose (C3D1 to C12D1) of either 16 or 30 mg of the anti-CD20/anti-CD3 bispecific antibody.

4 . The method of claim 3 , wherein the single dose of the additional dosing cycles (C3D1 to C12D1) is administered on day 1 of the respective additional dosing cycle.

5 . The method of claim 1 , comprising 12 dosing cycles in total.

6 . The method of claim 1 , wherein the CD20-positive B cell proliferative disorder is a non-Hodgkin's lymphoma (NHL).

7 . The method of claim 6 , wherein the NHL is:

(a) relapsed or refractory NHL;

(b) indolent NHL (iNHL) or aggressive NHL (aNHL); and/or

(c) a diffuse large B cell lymphoma (DLBCL), high grade B cell lymphoma (HGBCL), primary mediastinal large B-cell lymphoma (PMBCL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), or follicular lymphoma (FL).

8 . The method of claim 7 , wherein:

(a) the DLBCL is a Richter's transformation;

(b) the DLBCL is a previously untreated DLBCL;

(c) the MCL is a relapsed or refractory (R/R) MCL;

(d) the FL is Grade 1, 2, or 3a FL;

(e) the FL is a transformed FL; or

(f) the FL is an R/R FL.

9 . The method of claim 7 , wherein:

(a) the subject has an MCL, and the subject has received at least one prior systemic treatment regimen comprising a Bruton tyrosine kinase inhibitor (BTKi); or

(b) the subject has an FL, and the subject is a high-risk subject who:

(i) has relapsed after or is refractory to at least two prior therapies;

(ii) has relapsed after or is refractory to treatment with a phosphoinositide 3-kinase (PI3K) inhibitor;

(iii) experiences progression of disease within 24 months of frontline treatment; and/or

(iv) has lesions, wherein the sum of the product of the lesion diameters is ≥3,000 mm 2 .

10 . The method of claim 9 , wherein the BTKi comprises ibrutinib, acalabrutinib, or zanubrutinib.

11 . The method of claim 1 , wherein a population of subjects having the CD20-positive B cell proliferative disorder exhibits cytokine release syndrome after being administered the anti-CD20/anti-CD3 bispecific antibody, and wherein the rate of the cytokine release syndrome of a grade of 3 or greater (as defined by the American Society for Transplantation and Cellular Therapy, 2019; ASTCT) is less than or about 5%.

12 . The method of claim 1 , wherein:

(a) administration of the anti-CD20/anti-CD3 bispecific antibody to a plurality of subjects having CD20-positive B cell proliferative disorder results in a complete response rate of at least about 70%;

(b) administration of the anti-CD20/anti-CD3 bispecific antibody to a plurality of subjects having MCL results in an overall response rate of at least about 80%;

(c) administration of the anti-CD20/anti-CD3 bispecific antibody to a plurality of subjects having MCL results in a complete response rate of at least about 65%;

(d) administration of the anti-CD20/anti-CD3 bispecific antibody to a plurality of subjects having FL results in an overall response rate of at least about 80%; and/or

(e) administration of the anti-CD20/anti-CD3 bispecific antibody to a plurality of subjects having FL results in a complete metabolic response rate of at least about 40%.

13 . The method of claim 1 , wherein the first and second dose of obinutuzumab are administered on the same day.

14 . The method of claim 1 , wherein the subject has an MCL and has received at least two prior systemic therapies.

15 . The method of claim 1 , wherein obinutuzumab is administered on the first day of the second dosing cycle (C2) and on the first day of any subsequent dosing cycle.

16 . The method of claim 15 , wherein obinutuzumab is administered at a dose of 1000 mg.

17 . The method of claim 1 , wherein the subject receives corticosteroid premedication prior to the anti-CD20/anti-CD3 bispecific antibody.

18 . The method of claim 17 , wherein the corticosteroid premedication comprises prednisolone and methylprednisolone, and/or dexamethasone; and/or the corticosteroid premedication is given prior to the first dose (C1D1) of the anti-CD20/anti-CD3 bispecific antibody.

19 . The method of claim 1 , wherein the anti-CD20/anti-CD3 bispecific antibody comprises:

(a) at least one antigen binding domain that specifically binds to CD20 comprising a VH domain comprising an amino acid sequence of SEQ ID NO: 7 and a VL domain comprising an amino acid sequence of SEQ ID NO: 8; and

(b) at least one antigen binding domain that specifically binds to CD3 comprising a VH domain comprising an amino acid sequence of SEQ ID NO: 15 and a VL domain comprising an amino acid sequence of SEQ ID NO: 16.

20 . The method of claim 1 , wherein the anti-CD20/anti-CD3 bispecific antibody comprises:

(a) an antigen binding domain that specifically binds to CD3 and is a cross-Fab molecule wherein the variable domains or the constant domains of the Fab heavy and light chain are exchanged;

(b) an IgG1 Fc domain comprising one or more amino acid substitutions that reduce binding to an Fc receptor and/or effector function;

(c) an IgG1 Fc domain comprising the amino acid substitutions L234A, L235A, and P329G (numbering according to Kabat EU index);

(d) at least one Fab molecule comprising an antigen binding domain that specifically binds to CD20, wherein in the constant domain CL of the Fab molecule the amino acid at position 124 is substituted by lysine (K) (numbering according to Kabat) and the amino acid at position 123 is substituted by arginine (R) or lysine (K) (numbering according to Kabat), and wherein in the constant domain CH1 of the Fab molecule the amino acid at position 147 is substituted by glutamic acid (E) (numbering according to Kabat EU index) and the amino acid at position 213 is substituted by glutamic acid (E) (numbering according to Kabat EU index); and/or

(e) two antigen binding domains that specifically bind to CD20 and one antigen binding domain that specifically binds to CD3.

21 . The method of claim 1 , wherein:

(a) the anti-CD20/anti-CD3 bispecific antibody is bivalent for CD20 and monovalent for CD3;

(b) the anti-CD20/anti-CD3 bispecific antibody comprises

(i) an antigen binding domain that specifically binds to CD3 which is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first subunit of the Fc domain;

(ii) a first antigen binding domain that specifically binds to CD20 which is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the antigen binding domain that specifically binds to CD3; and

(iii) a second antigen binding domain that specifically binds to CD20 which is fused at the C-terminus of the Fab heavy chain to the N-terminus of the second subunit of the Fc domain; and/or

(c) the anti-CD20/anti-CD3 bispecific antibody is glofitamab.

22 . A method of treating a subject having a non-Hodgkin lymphoma comprising administering to the subject an anti-CD20/anti-CD3 bispecific antibody in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein: (a) the first dosing cycle comprises a first dose (C1D1) and a second dose (C1D2) of the anti-CD20/anti-CD3 bispecific antibody, wherein the C1D1 is 2.5 mg, and the C1D2 is 10 mg; and (b) the second dosing cycle comprises a single dose (C2D1) of 30 mg of the anti-CD20/anti-CD3 bispecific antibody,

wherein the anti-CD20/anti-CD3 bispecific antibody comprises:

(a) at least one antigen binding domain that specifically binds to CD20, comprising

a heavy chain variable region comprising:

(i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

(ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and

(iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO:3;

and a light chain variable region comprising:

(i) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4;

(ii) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and

(iii) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6; and

(b) at least one antigen binding domain that specifically binds to CD3, comprising

a heavy chain variable region comprising:

(i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 9;

(ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 10; and

(iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO:11;

and a light chain variable region comprising:

(i) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12;

(ii) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 13; and

(iii) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14; and

wherein

(i) the first dose (C1D1) is administered on day 1 of the first dosing cycle and the second dose (C1D2) is administered on day 8 of the first dosing cycle;

(ii) the single dose of the second dosing cycle (C2D1) is administered on day 1 of the second dosing cycle; and

(iii) one dosing cycle comprises 14 days or 21 days; and

wherein the method further comprising administering to the subject obinutuzumab,

wherein:

(iv) obinutuzumab is administered 7 days before the first dose of the anti-CD20/anti-CD3 bispecific antibody (C1D1); and

(v) obinutuzumab is administered at one single dose of 1000 mg or a first and a second dose of each 1000 mg obinutuzumab.

23 . A method of treating a subject having a diffuse large B cell lymphoma comprising administering to the subject an anti-CD20/anti-CD3 bispecific antibody in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein: (a) the first dosing cycle comprises a first dose (C1D1) and a second dose (C1D2) of the anti-CD20/anti-CD3 bispecific antibody, wherein the C1D1 is 2.5 mg, and the C1D2 is 10 mg; and (b) the second dosing cycle comprises a single dose (C2D1) of 30 mg of the anti-CD20/anti-CD3 bispecific antibody,

wherein the anti-CD20/anti-CD3 bispecific antibody comprises:

(a) a first antigen binding domain that specifically binds to CD20, comprising

a heavy chain variable region comprising:

(i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

(ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and

(iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO:3;

and a light chain variable region comprising:

(i) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4;

(ii) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and

(iii) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6;

(b) second antigen binding domain that specifically binds to CD3, comprising

a heavy chain variable region comprising:

(i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 9;

(ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 10; and

(iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO:11;

and a light chain variable region comprising:

(i) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12;

(ii) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 13; and

(iii) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14; and

(c) a third antigen binding domain that specifically binds to CD20, comprising

a heavy chain variable region comprising:

(i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

(ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and

(iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO:3;

and a light chain variable region comprising:

(i) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4;

(ii) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and

(iii) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6; and

wherein

(i) the first dose (C1D1) is administered on day 1 of the first dosing cycle and the second dose (C1D2) is administered on day 8 of the first dosing cycle;

(ii) the single dose of the second dosing cycle (C2D1) is administered on day 1 of the second dosing cycle; and

(iii) one dosing cycle comprises 14 days or 21 days; and

wherein the method further comprising administering to the subject obinutuzumab,

wherein obinutuzumab is administered 7 days before the first dose of the anti-CD20/anti-CD3 bispecific antibody (C1D1); and obinutuzumab is administered at one single dose of 1000 mg.

24 . A method of treating a subject having a diffuse large B cell lymphoma comprising administering to the subject glofitamab in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein: (a) the first dosing cycle comprises a first dose (C1D1) and a second dose (C1D2) of glofitamab, wherein the C1D1 is 2.5 mg, and the C1D2 is 10 mg; and (b) the second dosing cycle comprises a single dose (C2D1) of 30 mg of glofitamab; wherein

(a) the first dose (C1D1) is administered on day 1 of the first dosing cycle and the second dose (C1D2) is administered on day 8 of the first dosing cycle;

(b) the single dose of the second dosing cycle (C2D1) is administered on day 1 of the second dosing cycle;

(c) the method comprises 10 additional dosing cycles (C3 to C12), wherein the 10 additional dosing cycles (C3 to C12) each comprises a single dose (C3D1 to C12D1) of 30 mg of glofitamab, and wherein the single dose of the additional dosing cycles (C3D1 to C12D1) is administered on day 1 of the respective additional dosing cycle;

(d) one dosing cycle comprises 14 days or 21 days; and

(e) glofitamab is administered intravenously; and

wherein the method further comprising administering to the subject obinutuzumab, wherein obinutuzumab is administered 7 days before the first dose of glofitamab (C1D1); and obinutuzumab is administered at one single dose of 1000 mg.

Assignments (16)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 5, 2022
From: ROCHE DIAGNOSTICS GMBH
To: F. HOFFMANN-LA ROCHE AG
Reel/Frame 061320/0351 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 5, 2022
From: F. HOFFMANN-LA ROCHE AG
To: HOFFMANN-LA ROCHE INC.
Reel/Frame 061612/0205 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 5, 2022
From: BARRETT, MARTIN
To: ROCHE PRODUCTS LIMITED
Reel/Frame 061320/0315 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 5, 2022
From: ROCHE PRODUCTS LIMITED
To: F. HOFFMANN-LA ROCHE AG
Reel/Frame 061612/0202 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 5, 2022
From: LECHNER, KATHARINA; MOORE, THOMAS FRANCIS
To: ROCHE DIAGNOSTICS GMBH
Reel/Frame 061320/0310 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 5, 2022
From: BACAC, MARINA
To: ROCHE GLYCART AG
Reel/Frame 061320/0321 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 5, 2022
From: ROCHE GLYCART AG
To: F. HOFFMANN-LA ROCHE AG
Reel/Frame 061320/0318 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 20, 2022
From: CARLILE, DAVID
To: ROCHE PRODUCTS LIMITED
Reel/Frame 061148/0205 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 20, 2022
From: LUNDBERG, LINDA; DJEBLI, NASSIM
To: F. HOFFMANN-LA ROCHE AG
Reel/Frame 061149/0678 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 20, 2022
From: ROCHE DIAGNOSTICS GMBH
To: F. HOFFMANN-LA ROCHE AG
Reel/Frame 061149/0969 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 20, 2022
From: MORCOS, PETER N.
To: ROCHE TCRC, INC.
Reel/Frame 061149/0470 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 20, 2022
From: F. HOFFMANN-LA ROCHE AG
To: HOFFMANN-LA ROCHE INC.
Reel/Frame 061150/0329 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 20, 2022
From: WEISSER, MARTIN
To: ROCHE DIAGNOSTICS GMBH
Reel/Frame 061148/0402 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 20, 2022
From: BOEHNKE, AXEL
To: F. HOFFMANN-LA ROCHE AG
Reel/Frame 061149/0562 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 20, 2022
From: ROCHE PRODUCTS LIMITED
To: F. HOFFMANN-LA ROCHE AG
Reel/Frame 061149/0901 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 20, 2022
From: ROCHE TCRC, INC.
To: HOFFMANN-LA ROCHE INC.
Reel/Frame 061150/0300 →
Continuity (3)
Provisional Application 63226962 · Jul 29, 2021
Provisional Application 63182398 · Apr 30, 2021
Related Publication 20220372156A1 · Nov 24, 2022
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