Bispecific antibodies against ceacam5 and cd47

Abstract

The invention provides bispecific antibodies binding to human carcinoembryonic antigen CEACAM5 and human CD47, polynucleotides encoding such bispecific antibodies and vectors and host cells comprising such polynucleotides. The invention further provides methods for selecting and producing such antibodies and methods of using such antibodies in the treatment of diseases inmonotherapy as well in combination.

Description

REFERENCE TO SEQUENCE LISTING[0001]The content of the electronically submitted sequence listing (“2020-12-03-Sequence-Listing-4130-0020008.txt”, 122,769 bytes, created on Dec. 3, 2020) filed with the application is incorporated herein by reference in its entirety.FIELD OF THE INVENTION[0002]The present invention relates to bispecific antibodies which bind to human carcinoembryonic antigen CEACAM5 (CEA) and human CD47 (CEAxCD47 bispecific antibodies). In addition, the present invention relates to polynucleotides encoding such bispecific antibodies and vectors and host cells comprising such polynucleotides. The invention further relates to methods for selecting and producing such antibodies and to methods of using such antibodies in the treatment of diseases. The invention also relates to the therapeutic use of the CEAxCD47 bispecific antibodies in monotherapy and in combination therapy, especially with CEAxCD3 T-cell bispecific antibodies (TCB) and / or inhibitors of PD-1 or PD-L1.BACK...

AI Technical Summary

Benefits of technology

[0063]In one embodiment the bispecific antibody according to the invention is characterized that a bispecific antibody specifically binding to human CEACAM5 and CD3c (further named also as CEA-TCB), comprising as heavy and light chains the chains of amino acid sequences SEQ ID NO: 96 to 99 in a concentration of 300 nM does not shift the EC50 of the phagocytosis index curve of the bispecific antibody of the invention to MKN-45 cells by more than a factor of 3, in one embodiment towards higher concentrations.. In such case the bispecific antibody according to the invention and CEA-TCB are defined as “not competitive” and considered able to bind simultaneously to CEA without significantly interfering in their binding to said CEA and can therefore develop its effect on phagocytosis (CEAxCD47) undisturbed and also its effect on T-cell activation (CEA-TCB) undisturbed, even if therapeutic levels of both drugs are simultaneously present in the tumor tissue (see FIG. 18). This facilitates combination treatment of CEA-TCB / TCB1 with CEAxCD47 of this invention (see FIG. 18).

[0093]In one embodiment, the bispecific antibody according to the invention is characterized in that said glycoengineered bispecific antibody comprises one or more increased effector functions such as those from the group consisting of increased binding affinity to FcγRs, increased binding of macrophages (increased antibody dependent cellular phagocytosis; ADCP), increased binding of NK cells (increased antibody-mediated cellular cytotoxicity; ADCC), and increased binding to monocytes.

[0114]A further embodiment of the invention is a method of increasing survival time in a subject having a cancer that expresses CEA, said method comprising administering to said subject a therapeutically effective amount of a bispecific antibody according to the invention.

[0162]Another aspect of the invention provides a method of increasing progression free survival and / or overall survival time in a subject having a cancer that abnormally expresses CEA, said method comprising administering to said subject a therapeutically effective amount of the bispecific antibody of any of above described embodiments. In one embodiment, the cancer is colorectal cancer, non-small cell lung cancer (NSCLC), gastric cancer, pancreatic cancer or breast cancer or another cancer expressing CEA.

[0165]Another aspect of the invention provides a method of increasing progression free survival time and / or overall survival time in a subject having a cancer that abnormally expresses CEA, said method comprising administering to said subject a therapeutically effective amount of the bispecific antibody of any of above described embodiments. In one embodiment, the cancer is colorectal cancer, non-small cell lung cancer (NSCLC), gastric cancer, pancreatic cancer or breast cancer.

Problems solved by technology

Soluble CEA can compete with therapeutic anti-CEA antibodies for binding to the CEA on the tumor cells potentially causing decreased efficacy of the anti-CEA antibody.

But in the past years for many of the advanced / metastatic solid tumors the progress of drug therapy was limited.

Much hope has been put into cancer immunotherapy and there are certain, but limited, successes.

Until recently results of clinical trials with T-cell bispecific antibodies TAA x CD3 (TAA =Tumor Associated Antigen) in patients with advanced solid tumors were disappointing.

But in monotherapy and also in the combination with a PD-L1 inhibitor, most of the patients were still progressing and those reacting showed at best partial responses and stable disease, but no complete responses have been achieved.

But so far, to the best of our knowledge, there are no promising clinical data for such a combination approach available.

Limited availability of T-cells within advanced solid tumors is certainly an important mechanism limiting the efficacy achievable with T-cell bispecific antibodies plus PD-1 axis inhibitors and / or other checkpoint inhibitors or agonists for T-cells.

The disappointing results with CAR T-cells in solid tumors may have a simple explanation—the number of CAR T-cells penetrating the solid tumor and distributed in it are just not sufficient.

Monoclonal antibodies and also bispecific antibodies used in therapy can cause a variety of adverse effects.

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