TECHNICAL FIELD

The present invention relates to an anti-CEACAM1 antibody that specifically binds to CEACAM1, and a use thereof.

BACKGROUND ART

Carcinoembryonic antigen-related cell adhesion molecule 1 (hereinafter, referred to as CEACAM1), a transmembrane glycoprotein, belongs to the carcinoembryonic antigen (CEA) family. Among CEA family members, CEACAM1, CEACAM3, CEACAM4, CEACAM5, CEACAM6, CEACAM7 and CEACAM8 are expressed in humans. More importantly, CEACAM1 is the only member of CEA family expressed in lymphocyte populations including activated T cells and natural killer cells. CEACAM1 has been reported highly expressed in cancer cells. In addition, low levels of CEACAM1 expression has also been observed in epithelial cells, endothelial cells, and myeloid cells.

On the surface of lymphocytes, CEACAM1 plays a role in the regulation of immune responses. Specifically, CEACAM1 has turned out to be an inhibitory receptor for activated T cells including those contained within the human intestinal epithelium (Gray-Owen & Bloomberg,Nat. Rev. Immunol.2006; 6:433-446; Morales et al.,J. Immunol,1999; 163: 1363-1370).

In particular, CEACAM1 is recognized as an immune checkpoint molecule similar to PD-1 and CTLA-4, playing a crucial role in modulating T cell activation. The immune checkpoint pathways protect tissues from immune-mediated damages under non-inflammatory physiological conditions. When CEACAM1 is activated on T lymphocytes, mainly upon CEACAM1-CEACAM1 trans-homophilic engagement, CEACAM1 signals to inhibit TCR-mediated inflammatory pathways by recruiting phosphatases to its own cytoplasmic ITIM motif (Chen et al.,J. Immunol.2008; 180: 6085-6093). Thus, suppression of immune checkpoint pathways in the context of cancer has emerged as a promising anti-cancer treatment strategy.

Studies on several human tumor types have reported that tumors can avoid immunity by inducing CEACAM1. In addition, in preclinical animal tumor models, it has been shown that blocking CEACAM1 interactions using monoclonal antibodies (mAbs) can enhance immune responses against tumors, promoting tumor suppression (Ortenberg et al.,Mol. Cancer Ther.2012; 11(6):1300-1310).

One of the biggest issues with conventional anti-cancer drugs is that treatment renders detrimental side effects as compared to their limited anti-cancer efficacies with high recurrence rates. On the other hand, a recently spotlighted approach, so-called immune checkpoint blockade, eliminates cancer by reactivating tumor-reactive exhausted T cells instead of directly killing cancer cells. This type of approach seems relatively safe and effective because it utilizes host immune functions to eliminate cancer with being able to keep irrelevant normal cells untouched. In the case of PD-1-targeting nivolumab from Bristol-Myers Squibb, the toxicity profile is in the manageable range as compared to those of conventional anti-cancer drugs, while its anti-cancer effects are dramatically higher than those of conventional drugs. In a phase III study of head-to-head comparison between nivolumab and dacarbazine, a standard chemotherapeutic agent, in treating metastatic melanoma patients, published in 2015, for example, nivolumab showed 40% objective response rate (95% CI, 33.3 to 47.0) compared to 13.9% ORR (95% CI, 9.5 to 19.4) by dacarbazine. The median progression-free survival was 5.1 months in the nivolumab group versus 2.2 months in the dacarbazine group. Toxicity profiling also convinced superiority of nivolumab to dacarbazine (Robert et al.,New Engl. J. Med.2015; 372:320-330).

Meanwhile, CEACAM1-blocking antibody acts on CEACAM1 expressed on the surface of cytotoxic T cells and of natural killer cells, interacting with CEACAM1 molecules overexpressed on tumor cells. Therefore, in case of CEACAM1-overexpressing tumors, CEACAM1-targeting antibody is expected to block CEACAM1-CEACAM1 homophilic suppressive interaction between T/NK cell and tumor cell, thereby reactivating anti-tumor T/NK cell responses. The CEACAM1-targeting antibody currently under development (a phase 1 clinical trial was prematurely terminated in February 2017) recognizes CEACAM3 and CEACAM5 in addition to CEACAM1. Such an off-target recognition property of this BMS clone may be due to its epitope sequences in N-domain that are highly homologous among human CEACAM1, CEACAM3 and CEACAM5.

DISCLOSURE OF INVENTION

Technical Problem

Therefore, in order to develop an anti-CEACAM1 antibody that specifically binds to CEACAM1, the present inventors have endeavored to find that an anti-CEACAM1 antibody binds to the N-domain of CEACAM1 and does not cross-react with CEACAM3, CEACAM5, CEACAM6 or CEACAM8, and have completed the present invention.

Solution to Problem

In accordance with one object of the present invention, there is provided an anti-CEACAM1 antibody or a fragment thereof comprising: light chain CDR1 comprising one of the amino acid sequences selected from the group consisting of SEQ ID NOS: 1 to 8; light chain CDR2 comprising one of the amino acid sequences selected from the group consisting of SEQ ID NOS: 9 to 16; light chain CDR3 comprising one of the amino acid sequences selected from the group consisting of SEQ ID NOS: 17 to 29; heavy chain CDR1 comprising one of the amino acid sequences selected from the group consisting of SEQ ID NOS: 30 to 38; heavy chain CDR2 comprising one of the amino acid sequences selected from the group consisting of SEQ ID NOS: 39 to 46; and heavy chain CDR3 comprising one of the amino acid sequences selected from the group consisting of SEQ ID NOS: 47 to 55.

In accordance with another object of the present invention, there is provided an anti-CEACAM1 antibody or a fragment thereof comprising: light chain CDR1 comprising the amino acid sequence represented by SEQ ID NO: 1, light chain CDR2 comprising the amino acid sequence represented by SEQ ID NO: 9, light chain CDR3 comprising the amino acid sequence represented by SEQ ID NO: 23, heavy chain CDR1 comprising the amino acid sequence represented by SEQ ID NO: 30, heavy chain CDR2 comprising the amino acid sequence represented by SEQ ID NO: 39, and heavy chain CDR3 comprising the amino acid sequence represented by SEQ ID NO: 47.

Further, in accordance with another object of the present invention, there is provided an anti-cancer agent comprising the anti-CEACAM1 antibody or a fragment thereof described above as an active ingredient.

Furthermore, in accordance with another object of a present invention, there is provided an anti-cancer adjuvant comprising the anti-CEACAM1 antibody or the fragment thereof described above as an active ingredient.

Also, in accordance with another object of the present invention, there is provided a composition for treating cancer comprising the anti-cancer adjuvant described above and a cell therapeutic agent.

Moreover, in accordance with another object of the present invention, there is provided a method for treating cancer comprising administering to a subject lymphocytes contacted with the anti-CEACAM1 antibody or a fragment thereof described above.

In addition, in accordance with another object of the present invention, there is provided a method for inhibiting proliferation of CEACAM1-expressing tumor cells, which comprises contacting the CEACAM1-expressing tumor cells with the anti-CEACAM1 antibody or a fragment thereof.

Advantageous Effects of Invention

An anti-CEACAM1 antibody according to the present invention specifically binds to CEACAM1, and thereby activates the anti-cancer immune functions of cytotoxic T cells and natural killer cells, and thus, it can be effectively used as an anti-cancer agent and a composition for treating cancer.

