Combination therapy with targeted 4-1bb (CD137) agonists

a technology of cd137 and agonist, which is applied in the field of conjugation therapies, can solve the problems of only effective therapies, significant improvement, poor prognosis of patients with advanced cancer, etc., and achieve the effect of reducing fc receptor binding and/or effector function, higher and more efficacious doses

Inactive Publication Date: 2020-10-15
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0014]In particular, the 4-1BB agonist is an antigen binding molecule comprising a tumor-associated antigen. In one aspect, the 4-1BB agonist is an antigen binding molecule comprising a Fc domain. In a particular aspect, the 4-1BB agonist is an antigen binding molecule comprising a Fc domain with modifications reducing Fcγ receptor binding and / or effector function. The crosslinking by a tumor associated antigen makes it possible to avoid unspecific FcγR-mediated crosslinking and thus higher and more efficacious doses of the 4-1BB agonists may be administered in comparison to common 4-1BB antibodies.

Problems solved by technology

Despite advances in treatment options, prognosis of patients with advanced cancer remains poor.
Despite these promising results, current immune-based therapies are only effective in a proportion of patients and combination strategies are needed to improve therapeutic benefit.
However, systemic administration of 4-1BB-specific agonistic antibodies with the functionally active Fc domain resulted in influx of CD8+ T-cells associated with liver toxicity (Dubrot et al., 2010, Cancer Immunol Immunother 59, 1223-1233) that is diminished or significantly ameliorated in the absence of functional Fc-receptors in mice.

Method used

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  • Combination therapy with targeted 4-1bb (CD137) agonists
  • Combination therapy with targeted 4-1bb (CD137) agonists
  • Combination therapy with targeted 4-1bb (CD137) agonists

Examples

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example 1

[0736]Preparation, Purification and Characterization of FAP-4-1BBL Antigen Binding Molecules

[0737]FAP-targeted 4-1BB ligand trimer-containing Fc fusion antigen binding molecules were prepared as described in International Patent Appl. Publ. No. WO 2016 / 075278 A1.

[0738]In particular, the following molecules were made:

[0739]a) Monovalent FAP-targeted and untargeted 4-1BB ligand trimer-containing Fc fusion antigen binding molecules

[0740]A polypeptide encoding a dimeric 4-1BB ligand fused to human CL domain was subcloned in frame with the human IgG1 heavy chain CH2 and CH3 domains on the knob (Merchant, Zhu et al. 1998, Nature Biotechnol. 16, 677-681). A polypeptide containing one ectodomain of the 4-1BB ligand was fused to the human IgG1-CH1 domain. In Construct 2.4, in order to improve correct pairing the following mutations were additionally introduced in the crossed CH-CL (charged variant). In the dimeric 4-1BB ligand fused to human CL, E123R and Q124K, in the monomeric 4-1BB ligand...

example 2

[0745]Preparation, purification and characterization of T-cell bispecific (TCB) antibodies TCB molecules have been prepared according to the methods described in WO 2014 / 131712 A1 or WO 2016 / 079076 A1.

[0746]The preparation of the anti-CEA / anti-CD3 bispecific antibody (CEA CD3 TCB or CEA TCB) used in the experiments is described in Example 3 of WO 2014 / 131712 A1. CEA CD3 TCB is a “2+1 IgG CrossFab” antibody and is comprised of two different heavy chains and two different light chains. Point mutations in the CH3 domain (“knobs into holes”) were introduced to promote the assembly of the two different heavy chains. Exchange of the VH and VL domains in the CD3 binding Fab were made in order to promote the correct assembly of the two different light chains. 2+1 means that the molecule has two antigen binding domains specific for CEA and one antigen binding domain specific for CD3. CEACAM5 CD3 TCB has the same format, but comprises another CEA binder and comprises point mutations in the CH...

example 3

[0751]Potent Anti-Tumor Effect by Combination Therapy of FAP-4-1BBL and CEA TCB In Vivo

[0752]a) Experiments with Mono- and Bivalent FAP(4B9)-4-1BBL

[0753]The human monovalent FAP-targeted 4-1BBL (mono FAP-4-1BBL, FAP binder 4B9) was tested as single agent and in combination with the human CEA CD3 TCB against the bivalent FAP-targeted 4-1BBL (bi FAP-4-1BBL, FAP binder 4B9) and the monovalent and bivalent untargeted-4-1BBL as single agent and in combination. Human gastric MKN45 cancer cells were cografted subcutaneously with a mouse fibroblast cell line (3T3) in NOG humaniced mice from the Jackson Laboratory.

[0754]Human MKN45 cells (human gastric carcinoma) were originally obtained from ATCC and after expansion deposited in the Glycart internal cell bank. Cells were cultured in DMEM containing 10% FCS at 37° C. in a water-saturated atmosphere at 5% CO2. In vitro passage 9 was used for subcutaneous injection at a viability of 97%. Human fibroblasts NIH-3T3 were originally obtained from ...

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Abstract

The present invention relates to combination therapies employing tumor targeted anti-CD3 bispecific antibodies and/or agents blocking PD-L1/PD-1 interaction in combination with 4-1BB (CD137) agonists, in particular 4-1BBL trimer containing antigen binding molecules, the use of these combination therapies for the treatment of cancer and methods of using the combination therapies.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is a Continuation of U.S. application Ser. No. 16 / 446,484, filed Jun. 19, 2019 (abandoned), which is a Continuation of International Application No. PCT / EP2017 / 083235, filed Dec. 18, 2017, which claims the benefit of priority to EP Application No. 16205190.8, filed Dec. 19, 2016, and EP Application No. 17158771.0, filed Mar. 1, 2017, and EP Application No. 17160857.3, filed Mar. 14, 2017, and EP Application No. 17192936.7, filed Sep. 25, 2017, each of which is incorporated herein by reference in its entirety.SEQUENCE LISTING[0002]This application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Mar. 20, 2020, is named P33996-US-1_Sequence_Listing.txt and is 5,270,916 bytes in size.FIELD OF THE INVENTION[0003]The present invention relates to combination therapies employing tumor targeted anti-CD3 bispecif...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K16/28C07K14/705C07K16/30A61P35/00
CPCC07K2317/565A61P35/00C07K16/2809A61K2039/505C07K14/70575C07K2317/31C07K16/3007A61K39/395C07K14/5255C07K16/2803C07K16/2863C07K16/2878C07K2317/526C07K2317/55C07K2317/60C07K2317/71A61P43/00A61K2039/507A61K2039/54A61K2039/545A61K2300/00C07K16/40
Inventor BACAC, MARINACLAUS, CHRISTINAFERRARA KOLLER, CLAUDIAKLEIN, CHRISTIANLANG, SABINELEVITSKI, VIKTORUMAÑA, PABLO
Owner F HOFFMANN LA ROCHE & CO AG
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