CN115611981A

CN115611981A - Use of anti-PD-1 antibodies in the treatment of peripheral T cell lymphoma

Info

Publication number: CN115611981A
Application number: CN202110783389.1A
Authority: CN
Inventors: 谢帆
Original assignee: GENOR BIOPHARMA CO Ltd
Current assignee: GENOR BIOPHARMA CO Ltd
Priority date: 2021-07-12
Filing date: 2021-07-12
Publication date: 2023-01-17

Abstract

The present disclosure relates to the use of anti-PD-1 antibodies in the treatment of peripheral T-cell lymphoma. In particular, the disclosure relates to the use of an anti-PD-1 antibody or antigen-binding fragment thereof in the manufacture of a medicament for the treatment or prevention of peripheral T-cell lymphoma, and also to methods of treating or preventing peripheral T-cell lymphoma using an anti-PD-1 antibody or antigen-binding fragment thereof, or a pharmaceutical composition comprising the anti-PD-1 antibody or antigen-binding fragment thereof.

Description

Use of anti-PD-1 antibodies in the treatment of peripheral T cell lymphoma

Technical Field

The present disclosure relates to the field of tumor therapy, more specifically to the use of an anti-PD-1 antibody or antigen-binding fragment thereof in the manufacture of a medicament for the treatment or prevention of peripheral T-cell lymphoma, and also to methods of treating or preventing peripheral T-cell lymphoma using an anti-PD-1 antibody or antigen-binding fragment thereof or a pharmaceutical composition comprising said anti-PD-1 antibody or antigen-binding fragment thereof.

Background

Peripheral T-cell lymphoma (PTCL) is a group of highly heterogeneous lymphoid malignancies derived from mature T cells and NK cells. According to The 2016 Classification criteria for hematopoietic and lymphoid tissue tumors of The World Health Organization (WHO) (Swerdlow SH, campo E, pileri SA, et al, the 2016 vision of The World Health Organization classification of lymphoid neoplasms [ J ],. Blood, 2016, 127 (20): 2375-2390), PTCL includes Extranodal rhinoid NK/T Cell Lymphoma (Exronodal NK-/T-Cell Lymphoma, nasal type, ENKTL), nonspecific Peripheral T Cell Lymphoma (Peripheral T-Cell Lymphoma, NOS, PTCL-NOS), angioimmunoblastic T Cell Lymphoma (AITL), ALK-positive Anaplastic large Cell Lymphoma (Anaplastic large-Cell Lymphoma, ALK + ALCL), ALK-negative Anaplastic large-Cell Lymphoma (ALK-ALCL), and The like, with other less common pathological subtypes, such as intestinal-disease-Associated T-Cell Lymphoma (EATL), mycosis Fungoides (MF), szary Syndrome (SS), primary cutaneous γ/δ T-Cell Lymphoma (Primary cutaneous γ/δ T-Cell Lymphoma), and The like.

In 2015, the number of the disease and death of lymphoma in China is 8.8 million and 5.2 million respectively (see Chen W, zheng R, baade PD, et al Cancer standards in China, 2015[ 2 ] J Clin, 2016, 66 (2): 115-132). The incidence of PTCL is clearly regionally different, accounting for about 25% -30% of Non-Hodgkin lymphomas (NHL) in China (see Sun J, yang Q, lu Z, et al Distribution of lymphoma neoplasms in China: analysis of 4,638 cases recording to the World Health Organization classification [ J ]. Am J Clin Pathol, 2012, 138 (3): 429-434), significantly higher than 10-15% in the Western countries (see Hennessy BT, hanrahan EO, daly PA, non-Hodgkin lymphoma: an update [ J ]. Lancet Oncol, 2004, 5 (6): 341-353 and Vose J, armitage J, weisenburger D. International perpersonal T-cell and natural kit/T-cell lymphoma description: path scanning and clinical 2008. J ]. J, 26 (25): 4124-4130). The distribution of different pathological subtypes also differs in China, most commonly ENKTL (28%), followed by PTCL-NOS (20%), AITL (12%), ALK + ALCL (7%) and ALK-ALCL (4%).

For PTCL, there is no standard treatment at present, and first-line therapy is still based on CHOP (cyclophosphamide + doxorubicin + vincristine + prednisone) or CHOP modified (such as CHOEP, hyper-CVAD and ACVBP). But anthracycline-based chemotherapy regimens have been less effective on ENKTL. Furthermore, PTCL has poor prognosis, low first-line treatment response rate and high recurrence rate, and there is a need to explore new drugs to improve the overall prognosis of PTCL patients (see Vose J, armitage J, weisenburger D. International patent T-cell and natural kit/T-cell lymphoma study: pathology finding and clinical experiments [ J ]. J Clin Oncol, 2008, 26 (25): 4124-4130; absoyabis AN, shonoPJ, lechowicz, et al, identification and experiments of the clinical of the laboratory T-cell lymphoma in the United States [ J ]. Leuch, 2008, NK 49, 11 (2099-2107; and Wesencell X, efficial T-cell lymphoma. Dominant in the United States [ J ]. 2008, NK, N, NK 49 (11: J), and J. Experiment J, li, sample and clinical trial [ 12. J ]: 11. J.: 11. 6215. Simulation J.: 11.

Recurrent or refractory PTCL (r/r PTCL) with progression or recurrence after first line therapy, if not suitable for hematopoietic stem cell transplantation, has a median progression-free survival (PFS) of only 3.1-4.0 months and a median OS of about 5.5-9.2 months (Ito Y, makita S, tobinai K. Development of new agents for periphytol T-cell lymphoma [ J ]. Expert Opin Biol Ther, 2019, 19 (3): 197-209). Conventional chemotherapy regimens are not ideal for the treatment of relapsed or refractory PTCL. Other combination chemotherapy regimens include DHAP (cisplatin + cytarabine + dexamethasone), ESHAP (etoposide + methylprednisolone + cisplatin + cytarabine), GDP (gemcitabine + dexamethasone + cisplatin), GEMOX (gemcitabine + oxaliplatin) and ICE (ifosfamide + carboplatin + etoposide), but combined chemotherapy is toxic and poorly tolerated. Additionally recommended new drug therapies include Pralatrexate (Pralatrexate), romidepsin (Romidepsin), beliestat (Belinostat) and BrentuximabVedotin (systemic ALCL and CD30+ PTCL only) approved for marketing by the U.S. Food and Drug Administration (FDA), patients who are not eligible for hematopoietic stem cell transplantation. Currently neither romidepsin nor belinostat is domestically approved, pralatrexate is domestically approved but not marketed, and cidandamide was approved by CFDA in 2015 and marketed for treatment of relapsing or refractory PTCL, overall, clinical treatment options for relapsing or refractory PTCL are very limited, and there is an urgent and unmet clinical need. The literature reports that Objective Remission Rate (ORR) of the above single-drug treatment of recurrent or refractory PTCL is between 25% and 28%, wherein the pralatrexate is an antifolate treatment drug, and the most common adverse events are mucositis, nausea, thrombocytopenia, fever and the like; romidepsin, belinostat and sidaxanide are Histone Deacetylase (HDAC) inhibitors, and the adverse events are similar to those of sidaxanide, mainly hematological adverse reactions, and other potential adverse reactions include weakness, fever, decreased appetite, gastrointestinal reactions, dyspnea, etc. (see O 'Connor OA, pro B, pinter-Brown L, et al., pralatrexate in Patients with delayed or recurrent clinical T-cell lymphoma: results from the spleen PROPEL study [ J ]. J Clin Oncol, 2011, 29 (9): 1182-1189; coiffier B, pro B, prince HM, et al, results from a pivot, open-label, phase II study of romidepsin in replay or replay personal T-cell simple ghost after printer system thermal [ J ]. J Clin Oncol, 2012, 30 (6): 631-636, O' Connor OA, horwitz S, masszi T, et al, belinostat in paper with replay in question T-cell simple manipulation: results of the pivot II BELIEF (CLN-19) study [ J ]. Clin Oncol, 33 (23): 92-2499; and Shi Y, hong M, hong HM 176K, et al, study [ J ]. J in Oncol, 33 (23): 248-2499; and Shi Y, hong M, replay X, replay in question [ J ]. J in Oncol, 33 (23): 11-2426, J-copy of copy in.

In conclusion, there is no standard treatment for PTCL at present, the prognosis is poor, the first-line treatment response rate is low, the recurrence rate is high, the treatment means for relapsed or refractory PTCL is very limited and the Objective Remission Rate (ORR) of clinical endpoint index is low. Thus, there is an urgent need for improved therapeutic regimens for PTCL, particularly for relapsed or refractory PTCL.

Disclosure of Invention

The present inventors have surprisingly found that the anti-PD-1 antibodies of the present disclosure show superior clinical efficacy and improved prognosis as anti-cancer therapeutics, clinically significant, compared to certain known chemotherapeutic agents alone. The present disclosure demonstrates that by administering the anti-PD-1 antibodies of the present disclosure to PTCL subjects, the subjects' therapeutic efficacy is significantly superior to existing commonly used drugs, and the Objective Remission Rate (ORR) is significantly higher than existing commonly used drugs, such as cidandamide, indicating superior clinical efficacy and improved prognosis.

It has also been surprisingly found that objective remission and improvement in prognosis can still be obtained upon treatment with an anti-PD-1 antibody of the present disclosure in PTCL (i.e., relapsed or refractory PTCL) subjects who have relapsed after previous treatment with first, second or third line and beyond or who have not responded to previous treatment. The present disclosure demonstrates that treatment with the anti-PD-1 antibodies of the present disclosure still results in significantly improved Objective Remission Rates (ORR), indicating superior clinical efficacy and improved prognosis, in PTCL subjects who have failed previous therapy with xidabenamine and in PTCL subjects who have received autologous stem cell transplantation.

The present inventors have surprisingly found that, using the presently disclosed dosing regimen, the presently disclosed anti-PD-1 antibodies show significant clinical efficacy as anti-cancer therapeutics, while being well tolerated, particularly in the treatment of relapsed or refractory PTCL.

It has also been unexpectedly found that PTCL subjects, particularly relapsed or refractory PTCL subjects, can benefit from treatment with the anti-PD-1 antibodies of the present disclosure regardless of age, sex, clinical stage, previous exposure to several lines of anti-tumor therapy, different pathological subtypes, and PD-L1 positive rate, etc., indicating superior clinical efficacy and improved prognosis.

Accordingly, in one aspect, the present disclosure provides the use of an anti-PD-1 antibody or antigen-binding fragment thereof in the manufacture of a medicament for treating or preventing peripheral T-cell lymphoma in a subject in need thereof, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises one or more CDRs comprising or consisting of SEQ ID NO:1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain CDR1 (LCDR 1), wherein the light chain LCDR1 sequence has at least 80% homology, at least 81% homology, at least 82% homology, at least 83% homology, at least 84% homology, at least 85% homology, at least 86% homology, at least 87% homology, at least 88% homology, at least 89% homology, at least 90% homology, at least 91% homology, at least 92% homology, at least 93% homology, at least 94% homology, at least 95% homology, at least 96% homology, at least 97% homology, at least 98% homology, or at least 99% homology to the amino acid sequence of SEQ ID No. 1.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain CDR2 (LCDR 2), wherein the light chain LCDR2 sequence has at least 80% homology, at least 81% homology, at least 82% homology, at least 83% homology, at least 84% homology, at least 85% homology, at least 86% homology, at least 87% homology, at least 88% homology, at least 89% homology, at least 90% homology, at least 91% homology, at least 92% homology, at least 93% homology, at least 94% homology, at least 95% homology, at least 96% homology, at least 97% homology, at least 98% homology, or at least 99% homology with the amino acid sequence of SEQ ID No. 2.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain CDR3 (LCDR 3), wherein the light chain LCDR3 sequence has at least 80% homology, at least 81% homology, at least 82% homology, at least 83% homology, at least 84% homology, at least 85% homology, at least 86% homology, at least 87% homology, at least 88% homology, at least 89% homology, at least 90% homology, at least 91% homology, at least 92% homology, at least 93% homology, at least 94% homology, at least 95% homology, at least 96% homology, at least 97% homology, at least 98% homology, or at least 99% homology to the amino acid sequence of SEQ ID No. 3.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain CDR1 (HCDR 1), wherein the heavy chain HCDR1 sequence has at least 80% homology, at least 81% homology, at least 82% homology, at least 83% homology, at least 84% homology, at least 85% homology, at least 86% homology, at least 87% homology, at least 88% homology, at least 89% homology, at least 90% homology, at least 91% homology, at least 92% homology, at least 93% homology, at least 94% homology, at least 95% homology, at least 96% homology, at least 97% homology, at least 98% homology, or at least 99% homology to the amino acid sequence of SEQ ID No. 4.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain CDR2 (HCDR 2), wherein the heavy chain HCDR2 sequence has at least 80% homology, at least 81% homology, at least 82% homology, at least 83% homology, at least 84% homology, at least 85% homology, at least 86% homology, at least 87% homology, at least 88% homology, at least 89% homology, at least 90% homology, at least 91% homology, at least 92% homology, at least 93% homology, at least 94% homology, at least 95% homology, at least 96% homology, at least 97% homology, at least 98% homology, or at least 99% homology to the amino acid sequence of SEQ ID No. 5.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain CDR3 (HCDR 3), wherein the heavy chain HCDR3 sequence has at least 80% homology, at least 81% homology, at least 82% homology, at least 83% homology, at least 84% homology, at least 85% homology, at least 86% homology, at least 87% homology, at least 88% homology, at least 89% homology, at least 90% homology, at least 91% homology, at least 92% homology, at least 93% homology, at least 94% homology, at least 95% homology, at least 96% homology, at least 97% homology, at least 98% homology, or at least 99% homology to the amino acid sequence of SEQ ID No. 6.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain LCDR1, LCDR2, and LCDR3, said light chain LCDR1, LCDR2, and LCDR3 comprising an amino acid sequence having at least 80% homology, at least 85% homology, at least 90% homology, at least 91% homology, at least 92% homology, at least 93% homology, at least 94% homology, at least 95% homology, at least 96% homology, at least 97% homology, at least 98% homology, or at least 99% homology with the amino acid sequences of

SEQ ID NOs

1, 2, and 3, respectively; and heavy chain HCDR1, HCDR2 and HCDR3, said heavy chain HCDR1, HCDR2 and HCDR3 comprising an amino acid sequence having at least 80% homology, at least 85% homology, at least 90% homology, at least 91% homology, at least 92% homology, at least 93% homology, at least 94% homology, at least 95% homology, at least 96% homology, at least 97% homology, at least 98% homology or at least 99% homology to the amino acid sequences of SEQ ID NOs 4, 5 and 6, respectively.

In one embodiment, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain comprising LCDR1, LCDR2, and LCDR3 as shown in SEQ ID No. 1, SEQ ID No. 2, and SEQ ID No. 3, respectively; the heavy chain comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO. 4, SEQ ID NO. 5 and SEQ ID NO. 6, respectively.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain variable region and a heavy chain variable region, wherein the light chain variable region comprises an amino acid sequence having at least 80% homology, at least 85% homology, at least 90% homology, at least 91% homology, at least 92% homology, at least 93% homology, at least 94% homology, at least 95% homology, at least 96% homology, at least 97% homology, at least 98% homology, or at least 99% homology to the amino acid sequence of SEQ ID No. 7; the heavy chain variable region comprises an amino acid sequence having at least 80% homology, at least 85% homology, at least 90% homology, at least 91% homology, at least 92% homology, at least 93% homology, at least 94% homology, at least 95% homology, at least 96% homology, at least 97% homology, at least 98% homology, or at least 99% homology to the amino acid sequence of SEQ ID NO. 8.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID No. 7; the heavy chain variable region comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO 8.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a full-length light chain having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% homologous to the amino acid sequence of SEQ ID No. 9.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a full-length heavy chain having an amino acid sequence at least 80% homologous, at least 85% homologous, at least 90% homologous, at least 91% homologous, at least 92% homologous, at least 93% homologous, at least 94% homologous, at least 95% homologous, at least 96% homologous, at least 97% homologous, at least 98% homologous, or at least 99% homologous to the amino acid sequence of SEQ ID No. 10.

In one embodiment, the light and heavy chain sequences of the anti-PD-1 antibody or antigen-binding fragment thereof comprise or consist of SEQ ID NO 9 and SEQ ID NO 10, respectively. In one embodiment, the antibody of the present disclosure is designated "G-Ab1" and its light and heavy chain sequences are shown in SEQ ID NO 9 and SEQ ID NO 10, respectively.

In some embodiments, the peripheral T cell lymphoma is relapsed or refractory peripheral T cell lymphoma.

In some embodiments, the peripheral T-cell lymphoma includes, but is not limited to, extranodal nasal NK/T-cell lymphoma (ENKTL), non-specific peripheral T-cell lymphoma (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), ALK-positive anaplastic large-cell lymphoma (ALK + ALCL), ALK-negative anaplastic large-cell lymphoma (ALK-ALCL), enteropathy-associated T-cell lymphoma (EATL), mycosis Fungoides (MF), S-zary syndrome (SS), and primary cutaneous gamma/delta T-cell lymphoma, among others.

Preferably, the peripheral T-cell lymphoma is selected from extranodal rhino-type NK/T-cell lymphoma (ENKTL) and ALK-negative anaplastic large cell lymphoma (ALK-ALCL).

In some embodiments, there is provided a use of an anti-PD-1 antibody or antigen-binding fragment thereof in the manufacture of a medicament for treating or preventing peripheral T-cell lymphoma in a subject in need thereof, wherein the medicament is a pharmaceutical composition, and wherein the pharmaceutical composition comprises a therapeutically effective amount of the anti-PD-1 antibody or antigen-binding fragment thereof and a pharmaceutically acceptable excipient or adjuvant.

In some embodiments, the pharmaceutically acceptable excipient or adjuvant comprises glutamic acid, proline, mannitol, sucrose, polysorbate-80, and sodium hydroxide.

In some embodiments, the medicament is administered at a dose of the anti-PD-1 antibody or antigen-binding fragment thereof in the range of about 1 mg/kg to about 10 mg/kg body weight about 1 time every 1, 2, 3, or 4 weeks. In still other embodiments, the medicament is administered at a fixed dose of at least about 200 mg, at least about 220 mg, at least about 240 mg, at least about 260 mg, at least about 280 mg, at least about 300 mg, at least about 320 mg, at least about 340 mg, at least about 360 mg, at least about 380 mg, or at least about 400 mg of the anti-PD-1 antibody or antigen-binding fragment thereof about 1 time every 1, 2, 3, or 4 weeks. In a specific embodiment, the medicament is administered at a fixed dose of about 280 mg of the anti-PD-1 antibody or antigen-binding fragment thereof about 1 time every 3 weeks.

In one embodiment, the medicament is administered at a dose of about 3mg/kg body weight of the anti-PD-1 antibody or antigen-binding fragment thereof about 1 time every 2 weeks.

In some embodiments, the tumor of the subject has at least about 1%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50% PD-L1 positive cells.

In some embodiments, the subject has previously received a therapy with sildendrine or other anti-tumor chemotherapy or radiation therapy, and/or the subject has previously received an autologous stem cell transplant.

In some embodiments, the subject has one or more of the following baseline characteristics: (ii) (i) an age of less than 65 years; (ii) no bone marrow infringement at baseline; and (iii) baseline LDH values were normal.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is for administration in combination with one or more additional chemotherapeutic agents, radiotherapeutic agents, cytokines, or other antibodies.

In one aspect, there is provided a method of treating or preventing peripheral T cell lymphoma in a subject in need thereof, comprising administering to the subject an effective amount of an anti-PD-1 antibody or antigen-binding fragment thereof, wherein said anti-PD-1 antibody or antigen-binding fragment thereof is as defined above.

In some embodiments, the peripheral T-cell lymphoma includes, but is not limited to, extranodal nasal NK/T-cell lymphoma (ENKTL), non-finger peripheral T-cell lymphoma (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), ALK-positive anaplastic large cell lymphoma (ALK + ALCL), ALK-negative anaplastic large cell lymphoma (ALK-ALCL), enteropathy-associated T-cell lymphoma (EATL), mycosis Fungoides (MF), szary (SS), and primary cutaneous gamma/delta T-cell lymphoma, among others.

In some embodiments, there is provided a method of treating or preventing peripheral T cell lymphoma in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising one or more anti-PD-1 antibodies or antigen-binding fragments thereof of the present disclosure and a pharmaceutically acceptable excipient or adjuvant.

In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the anti-PD-1 antibody or antigen-binding fragment thereof and a pharmaceutically acceptable excipient or adjuvant.

In some embodiments, there is provided a method of treating or preventing peripheral T cell lymphoma in a subject in need thereof, comprising administering said pharmaceutical composition to said subject about 1 time every 1, 2, 3, or 4 weeks at a dose of said anti-PD-1 antibody or antigen-binding fragment thereof in the range of about 1 mg/kg to about 10 mg/kg body weight. In some further embodiments, there is provided a method of treating or preventing peripheral T cell lymphoma in a subject in need thereof, comprising administering to the subject the pharmaceutical composition at a fixed dose of at least about 200 mg, at least about 220 mg, at least about 240 mg, at least about 260 mg, at least about 280 mg, at least about 300 mg, at least about 320 mg, at least about 340 mg, at least about 360 mg, at least about 380 mg, or at least about 400 mg of the anti-PD-1 antibody or antigen-binding fragment thereof about 1 time every 1, 2, 3, or 4 weeks. In a specific embodiment, there is provided a method of treating or preventing peripheral T cell lymphoma in a subject in need thereof, comprising administering to the subject the pharmaceutical composition at a fixed dose of about 280 mg of the anti-PD-1 antibody or antigen-binding fragment thereof about 1 time every 3 weeks.

In one embodiment, there is provided a method of treating or preventing peripheral T cell lymphoma in a subject in need thereof, comprising administering said pharmaceutical composition at a dose of about 3mg/kg body weight of said anti-PD-1 antibody or antigen-binding fragment thereof about 1 time every 2 weeks.

In some embodiments, there is provided a method of treating or preventing peripheral T cell lymphoma in a subject in need thereof, comprising administering to the subject an anti-PD-1 antibody or antigen-binding fragment thereof of the present disclosure in combination with one or more additional chemotherapeutic agents, radiotherapeutic agents, cytokines, or other antibodies.

In another aspect, the present disclosure provides an anti-PD-1 antibody or antigen-binding fragment thereof for use in treating or preventing peripheral T-cell lymphoma in a subject in need thereof, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is as defined above.

The following detailed description and examples illustrate embodiments of the invention in detail. It is to be understood that this invention is not limited to the particular embodiments described herein and, thus, may include many variations and modifications. Those skilled in the art will recognize that variations and modifications are within the scope and spirit of the invention.

Drawings

FIG. 1 shows that the G-Ab1 antibody inhibits the binding of PD-1 to PD-L1.

Detailed Description

Unless defined otherwise, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In case of conflict, the present specification, including definitions, will control.

The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. Although only certain exemplary materials and methods are described herein, many methods and materials similar or equivalent to those described herein can be used in the practice of the present disclosure.

As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. Furthermore, the open-ended expressions "comprising" and "comprise" should be interpreted as meaning that they can also contain structural elements or method steps not mentioned, but it is to be understood that they also cover the case where they consist only of the stated components or method steps (i.e. the closed-ended expression "consisting of 8230; \8230; consists of).

In general, the term "about" is used herein to refer to a change in numerical values above and below the stated value by 5% modification.

As used throughout, ranges are used as shorthand for describing each and every value that is within the range. Any number within the range, such as an integer value, a value that increments by one tenth (when the end of the range is one digit after the decimal point), or a value that increments by one hundredth (when the end of the range is two digits after the decimal point) may be selected as the end of the range. For example, a range of 1 through 10 is intended to describe all values within that range, e.g., 1, 2, 3, 4, 5, 6, 7, 8, \ 8230 \ 82309, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, and 10 (in tenths of increasing values), and to include all subranges such as1 through 1.5, 2.0 through 3.0, 4.0 through 5.0, 6.0 through 7.0, 8.0 through 9.0, and the like.

The present disclosure has demonstrated that the anti-PD-1 antibodies of the present disclosure exhibit superior clinical efficacy and improved prognosis as anti-cancer therapeutics, clinically significant, compared to certain known chemotherapeutic agents alone. More specifically, by administering the anti-PD-1 antibodies of the present disclosure to PTCL subjects, the subjects' Objective Remission Rate (ORR) is significantly higher than existing commonly used drugs, such as cidentamine, indicating superior clinical efficacy and improved prognosis.

The present disclosure has demonstrated that treatment with an anti-PD-1 antibody of the present disclosure still results in significantly improved clinical efficacy and prognosis in subjects who have relapsed in PTCL (i.e., relapsed or refractory PTCL) even after receiving first, second or more lines of therapy. More specifically, in PTCL subjects who have failed therapy with sidaxomine and in PTCL subjects who have undergone autologous stem cell transplantation, treatment with the anti-PD-1 antibody of the present disclosure still results in significantly improved Objective Remission Rate (ORR), indicating superior clinical efficacy and improved prognosis.

The present disclosure has demonstrated that, using the dosing regimen of the present disclosure, the anti-PD-1 antibodies of the present disclosure exhibit significant clinical efficacy, improved tolerability, and safety as anti-cancer therapeutics, particularly in use for treating relapsed or refractory PTCL.

The disclosure also demonstrates that PTCL subjects, particularly relapsed or refractory PTCL subjects, can benefit from treatment with the anti-PD-1 antibodies of the disclosure regardless of age, sex, clinical stage, previous exposure to several lines of anti-tumor therapy, different pathological subtypes, and PD-L1 positive rate, etc., indicating superior clinical efficacy and improved prognosis.

Accordingly, in one aspect, the present disclosure provides the use of an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the anti-PD-1 antibody or an antigen-binding fragment thereof comprises one or more CDRs selected from the group consisting of SEQ ID NO 1, SEQ ID NO 2, SEQ ID NO 3, SEQ ID NO 4, SEQ ID NO 5 and SEQ ID NO 6, in the manufacture of a medicament for treating or preventing peripheral T cell lymphoma in a subject in need thereof.

As used herein, the term "subject" means a mammal, such as a rodent, feline, canine, and primate, and the like. Preferably, the subject of the present disclosure is a human.

The term "treatment" as used herein refers to both therapeutic and prophylactic treatment. Subjects in need of treatment include those already with the disease or condition as well as those who are likely to develop the disease or condition as well as those targeted to prevent, delay or alleviate the disease or condition.

anti-PD-1 antibodies or antigen-binding fragments thereof

As used herein, the term "antibody" refers to a binding protein having at least one antigen binding domain. The antibody or antigen binding fragment thereof of the present disclosure may be a whole antibody or any fragment thereof. Accordingly, the antibodies or antigen-binding fragments thereof of the present disclosure include monoclonal antibodies or fragments thereof and antibody variants or fragments thereof, as well as immunoconjugates. Examples of antigen-binding fragments include Fab fragments, fab 'fragments, F (ab)' fragments, fv fragments, isolated CDR regions, single chain Fv molecules (scFv), and other antigen-binding fragments known in the art. Antibodies or antigen-binding fragments thereof may also include recombinant polypeptides, fusion proteins, and bispecific antibodies. The anti-PD-1 antibodies or antigen-binding fragments thereof of the present disclosure can have an IgG1, igG2, igG3, or IgG4 isotype. The term "isotype" refers to the class of antibodies encoded by the heavy chain constant region gene. In one embodiment, an anti-PD-1 antibody or antigen-binding fragment thereof of the present disclosure has an IgG1 or IgG4 isotype. The anti-PD-1 antibodies or antigen-binding fragments thereof of the present disclosure can be derived from any species, including, but not limited to, mouse, rat, rabbit, primate, llama, and human. The anti-PD-1 antibody or antigen-binding fragment thereof can be a chimeric antibody, a humanized antibody, or a fully human antibody. In one embodiment, the anti-PD-1 antibody is a murine antibody. In another embodiment, the anti-PD-1 antibody is a chimeric antibody. In another embodiment, the chimeric antibody is a mouse-human chimeric antibody. In another embodiment, the antibody is derived from a mouse and is humanized. In a further embodiment, the antibody is a fully human antibody.

As used herein, the term "antigen-binding fragment" refers to one or more antibody fragments that retain the ability to specifically bind to the antigen to which the intact antibody binds.

A "chimeric antibody" is an antibody having at least a portion of a heavy chain variable region and at least a portion of a light chain variable region derived from one species and at least a portion of a constant region derived from another species. For example, in one embodiment, a chimeric antibody can comprise a murine variable region and a human constant region.

A "humanized antibody" is an antibody comprising Complementarity Determining Regions (CDRs) derived from a non-human antibody, and framework and constant regions derived from a human antibody. For example, an anti-PD-1 antibody provided herein can comprise CDRs derived from one or more murine antibodies as well as human framework and constant regions. Thus, in one embodiment, a humanized antibody provided herein binds to the same epitope on PD-1 as a murine antibody from which the CDRs of the antibody are derived. Exemplary humanized antibodies are provided herein. Additional anti-PD-1 antibodies or variants thereof comprising the light and heavy chain CDRs provided herein can be produced using any human framework sequence and are also encompassed by the invention. In one embodiment, suitable for the invention of the framework sequences include the structure similar to the framework sequences provided herein those framework sequences. Other modifications in the framework regions can be made to improve the properties of the antibodies provided herein. Such other framework modifications may include chemical modifications; point mutations to reduce immunogenicity or to remove T cell epitopes; or back-mutated to a residue in the original germline sequence.

The antibodies and antigen binding fragments thereof disclosed herein are specific for PD-1. In one embodiment, the antibodies and fragments thereof are specific for human PD-1. In one embodiment, the antibodies and fragments provided herein bind to human or primate PD-1, but do not bind to PD-1 from any other mammal. In another embodiment, the antibodies and fragments thereof do not bind to mouse PD-1. Specific "for" means that the antibody and fragments thereof bind to the PD-1 receptor with greater affinity than to any other target. In one embodiment, the PD-1 antibodies and fragments provided herein are specific for PD-1 and do not cross-react with CTLA4, ICOS, or CD 28.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain LCDR1 sequence having at least 80% homology, at least 81% homology, at least 82% homology, at least 83% homology, at least 84% homology, at least 85% homology, at least 86% homology, at least 87% homology, at least 88% homology, at least 89% homology, at least 90% homology, at least 91% homology, at least 92% homology, at least 93% homology, at least 94% homology, at least 95% homology, at least 96% homology, at least 97% homology, at least 98% homology, or at least 99% homology to the amino acid sequence of SEQ ID No. 1.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain LCDR2 sequence having at least 80% homology, at least 81% homology, at least 82% homology, at least 83% homology, at least 84% homology, at least 85% homology, at least 86% homology, at least 87% homology, at least 88% homology, at least 89% homology, at least 90% homology, at least 91% homology, at least 92% homology, at least 93% homology, at least 94% homology, at least 95% homology, at least 96% homology, at least 97% homology, at least 98% homology, or at least 99% homology to the amino acid sequence of SEQ ID No. 2.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain LCDR3 sequence having at least 80% homology, at least 81% homology, at least 82% homology, at least 83% homology, at least 84% homology, at least 85% homology, at least 86% homology, at least 87% homology, at least 88% homology, at least 89% homology, at least 90% homology, at least 91% homology, at least 92% homology, at least 93% homology, at least 94% homology, at least 95% homology, at least 96% homology, at least 97% homology, at least 98% homology, or at least 99% homology to the amino acid sequence of SEQ ID No. 3.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain HCDR1 sequence having at least 80% homology, at least 81% homology, at least 82% homology, at least 83% homology, at least 84% homology, at least 85% homology, at least 86% homology, at least 87% homology, at least 88% homology, at least 89% homology, at least 90% homology, at least 91% homology, at least 92% homology, at least 93% homology, at least 94% homology, at least 95% homology, at least 96% homology, at least 97% homology, at least 98% homology, or at least 99% homology to the amino acid sequence of SEQ ID No. 4.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain HCDR2 sequence having at least 80% homology, at least 81% homology, at least 82% homology, at least 83% homology, at least 84% homology, at least 85% homology, at least 86% homology, at least 87% homology, at least 88% homology, at least 89% homology, at least 90% homology, at least 91% homology, at least 92% homology, at least 93% homology, at least 94% homology, at least 95% homology, at least 96% homology, at least 97% homology, at least 98% homology, or at least 99% homology to the amino acid sequence of SEQ ID No. 5.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain HCDR3 sequence having at least 80% homology, at least 81% homology, at least 82% homology, at least 83% homology, at least 84% homology, at least 85% homology, at least 86% homology, at least 87% homology, at least 88% homology, at least 89% homology, at least 90% homology, at least 91% homology, at least 92% homology, at least 93% homology, at least 94% homology, at least 95% homology, at least 96% homology, at least 97% homology, at least 98% homology, or at least 99% homology to the amino acid sequence of SEQ ID No. 6.

SEQ ID NOs

In one embodiment, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain comprising LCDR1, LCDR2, and LCDR3 as shown in SEQ ID No. 1, SEQ ID No. 2, and SEQ ID No. 3, respectively; the heavy chain comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO 4, SEQ ID NO 5 and SEQ ID NO 6, respectively.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain variable region and a heavy chain variable region, wherein the light chain variable region comprises an amino acid sequence having at least 80% homology, at least 85% homology, at least 90% homology, at least 91% homology, at least 92% homology, at least 93% homology, at least 94% homology, at least 95% homology, at least 96% homology, at least 97% homology, at least 98% homology, or at least 99% homology to the amino acid sequence of SEQ ID No. 7; the heavy chain variable region comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% homology to the amino acid sequence of SEQ ID No. 8.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a full-length light chain having an amino acid sequence at least 80% homologous, at least 85% homologous, at least 90% homologous, at least 91% homologous, at least 92% homologous, at least 93% homologous, at least 94% homologous, at least 95% homologous, at least 96% homologous, at least 97% homologous, at least 98% homologous, or at least 99% homologous to the amino acid sequence of SEQ ID No. 9.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a full-length heavy chain having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% homologous to the amino acid sequence of SEQ ID No. 10.

In one embodiment, the full length light and heavy chain sequences of the anti-PD-1 antibody or antigen-binding fragment thereof comprise or consist of SEQ ID NO 9 and SEQ ID NO 10, respectively.

In one embodiment, the antibodies and fragments provided herein comprise a light chain and a heavy chain, each comprising three CDR regions. Exemplary LCDR1, LCDR2, LCDR3, HCDR1, HCDR2, and HCDR3 of PD-1 antibodies described herein are provided in table 1 below. Exemplary light chain variable region and heavy chain variable region sequences of the PD-1 antibodies described herein are provided in table 2 below. Exemplary full-length light and full-length heavy chain sequences of the PD-1 antibodies described herein are provided in table 3 below.

TABLE 1 light and heavy chain CDR sequences

Name(s)	Numbering	Sequence of
			LCDR1	SEQ ID NO: 1	RASESVDNYGYSFMN
LCDR2	SEQ ID NO: 2	RASNLES
			LCDR3	SEQ ID NO: 3	QQSNADPT
HCDR1	SEQ ID NO: 4	NFGMN
			HCDR2	SEQ ID NO: 5	WISGYTREPTYAADFKG
HCDR3	SEQ ID NO: 6	DVFDY

TABLE 2 light and heavy chain variable region sequences

TABLE 3 full Length light chain and full Length heavy chain sequences

The anti-PD-1 antibodies or antigen-binding fragments thereof, including chimeric, humanized or human monoclonal antibodies, described herein can be prepared and isolated by methods well known in the art.

Peripheral T cell lymphoma

As described above and as demonstrated in the examples herein, common pathological subtypes of PTCL can benefit from the anti-PD-1 antibody treatment described herein. In particular, the present inventors have also unexpectedly found that for ALK-negative anaplastic large cell lymphoma (ALK-ALCL) with a poor prognosis and highly-developed ENKTL in china, the ORR of subjects receiving treatment with the anti-PD-1 antibodies described herein is greater than 50%, significantly greater than the ORR of existing drugs.

In some embodiments, the peripheral T-cell lymphoma includes, but is not limited to, extranodal nasal NK/T-cell lymphoma (ENKTL), non-specific peripheral T-cell lymphoma (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), ALK-positive anaplastic large-cell lymphoma (ALK + ALCL), ALK-negative anaplastic large-cell lymphoma (ALK-ALCL), enteropathy-associated T-cell lymphoma (EATL), mycosis Fungoides (MF), S-zary (SS), and primary cutaneous gamma/delta T-cell lymphoma, among others.

The term "T-cell lymphoma" is a malignant tumor in which T-cells abnormally proliferate, and belongs to a special type of non-hodgkin lymphoma, accounting for about 10-15% of lymphoid malignancies. T cell lymphomas include: t lymphoblastic lymphoma/leukemia, mature T/NK cell lymphoma.

The term "PTCL (Peripheral T-cell lymphoma)" or "Peripheral T-cell lymphoma", also known as "Mature T/NK-cell lymphoma" (mate T and NK neoplasms), refers to a group of highly heterogeneous lymphoid malignancies derived from Mature T-cells and NK-cells.

PTCL was classified into 4 categories according to the 2016 World Health Organization (WHO) classification criteria for hematopoietic and lymphoid tissue tumors: lymph node type, node exterior type, leukemia type and skin type, and more than 25 subtypes in total. The term "PTCL" or "Peripheral T-Cell Lymphoma" as used herein includes, but is not limited to, extranodal rhino-type NK/T-Cell Lymphoma (endothelial NK-/T-Cell Lymphoma, nasal type, ENKTL), non-specific Peripheral T-Cell Lymphoma (periapical T-Cell Lymphoma, NOS, PTCL-NOS), vascular immunoblastic T-Cell Lymphoma (Angioimmunoblastic T-Cell Lymphoma, AITL), ALK-positive Anaplastic large Cell Lymphoma (Anaplastic large-Cell Lymphoma, ALK + l, also referred to herein as "ALK-positive Anaplastic large Cell Lymphoma" or "ALCL ALK +"), ALK-negative Anaplastic large Cell Lymphoma (Anaplastic large-Cell Lymphoma, ALK-ALCL, also referred to herein as "ALK-negative Anaplastic large Cell Lymphoma" or "ALK +"), and other Primary pathological Cell Lymphoma (e.g., lymphoblastic T-Cell Lymphoma), more commonly referred to as "ALK-negative Anaplastic large Cell Lymphoma" or "ALK-", more commonly found in "Primary pathological Lymphoma", more commonly known as "Cell Lymphoma", more commonly known as "ALK-Cell Lymphoma", more commonly found in "lymphomato-Cell Lymphoma. The term "PTCL" or "peripheral T cell lymphoma" as used herein also includes mature T cell lymphomas that cannot be classified.

"extranodal nasal NK/T cell lymphoma" is also referred to herein as "extranodal NK/T cell lymphoma, nasal" (ENKTL) is one of the most common PTCL in our country, which is highly malignant and highly associated with EB virus infection. ENKTL is usually found in organs such as nasal cavity or upper respiratory tract, but sometimes it is found in other than nasal cavity or nasopharynx (gastrointestinal tract, skin, testis, liver, spleen and bone marrow). The common symptoms are nasal obstruction, epistaxis and face swelling, sometimes accompanied by malodor, and the B symptom is common. Age 60 or more, regional lymph node and local tissue invasion, B symptom, LDH increase, EBV DNA titer 6.1 × 10 ⁷ Copy/ml et al often indicate poor prognosis (see Au WY, weisenburger DD, intraguratonchai T, et al. Clinical differences between beta. And extracellular library/T-cell lymphoma: a study of 136 cases from the intracellular transdermal T-cell lymphoma project [ J]. Blood, 2009, 113(17):3931-3937; Kim SJ, Yoon DH, Jaccard A, et al. A prognostic index for natural killer cell lymphoma after non-anthracycline-based treatment: a multicenter, retrospective analysis[J]. Lancet Oncol, 2016, 17(3):389-400.)。

"peripheral T-cell lymphoma of the nonspecific type", also referred to herein as "peripheral T-cell lymphoma, nonspecific type", (PTCL-NOS) is a common subtype of PTCL, and is highly heterogeneous and classified as intranodal PTCL in the WHO classification, but most patients have extranodal involvement, including gastrointestinal tract, liver, bone marrow and skin, and are diagnosed in stages III-IV.

Anaplastic Large Cell Lymphoma (ALCL) accounts for about 3% of adult non-Hodgkin's lymphomas and 10% -15% of childhood lymphomas (see Armitage JO. A clinical evaluation of the international lymphoma group classification of non-Hodgkin's lymphoma [ J ]. Blood, 1997, 89 (11): 3909-3918). According to the expression state of ALK protein, the ALCL can be divided into ALK + ALCL and ALK-ALCL, and the ALK + ALCL and the ALK-ALCL have distinct clinical and pathological characteristics. Previous studies have considered The prognosis of ALK + ALCL to be far superior to ALK-ALCL, with 5-year OS of 70-89% and 15-58%, respectively (see Hapgood G, savage KJ. The biology and management of system and adaptive large cell lymphoma [ J ]. Blood, 2015, 126 (1): 17-25).

Angioimmunoblastic T-cell lymphoma (AITL), also referred to herein as "angioimmunoblastic T-cell lymphoma", is a unique invasive PTCL among PTCLs, and AITL is widely believed to be derived from follicular helper T cells. The disease is mostly caused by old patients, is often manifested by lymphadenectasis, hepatosplenomegaly, hemolytic anemia and hyperglycemic globulin blood disease, is often accompanied by rash, pruritus, chest, ascites and the like, and is clinically moderate-high malignant. Chemotherapy, although providing transient remission in some cases of AITL, has high recurrence rates, poor prognosis and high complications of infection, making chemotherapy difficult again.

Enteropathy-associated T-cell lymphoma (EATL) is a rare T-cell lymphoma, often associated with chronic diarrhea, most commonly occurring in the jejunum and invading other parts of the intestine. EATL can be divided into 2 types according to clinical and immunological characteristics. Pleomorphic-anaplastic cell types are often associated with diarrhea and intestinal lesions, and CD56-; the simple form is not associated with diarrhea, is associated with intestinal lesions to varying degrees, and is CD56+. The most common type of pathology in China is EATL, type II, also known as intestinal monomorphic epitheliophilic T cell lymphoma.

Mycosis fungoides and Szary syndrome (MF/SS) are the most common cutaneous T-cell lymphoma (CTCL), accounting for 2-3% of all NHLs. MF is a mature T cell lymphoma of primary skin characterized by an inert appearance. SS is an aggressive, erythrodermic leukemia MF variant characterized by marked blood invasion and lymphadenectasis. The prognosis of MF is better, with a 5-year survival rate of nearly 90%, with generally poor prognosis in SS patients, with a median survival time of about 2-4 years (see Horwitz SM, ansell SM, ai WZ, et al. NCCN Clinical Practice Guidelines in Oncology: T-Cell Lymphomas, version 1.2019 [ J ]. J Natl Comp cancer Net, 2019).

As used herein, the term "relapse" is defined as the subject having both received first line intensive therapy for post-remission disease progression, including: (1) Completing treatment according to clinically recommended standard or conventional scheme (early stage patient combined with first-line radiotherapy and receiving recommended chemotherapy for at least 2 cycles; advanced stage patient with first-line whole body treatment mainly, receiving hemopoietic stem cell transplantation for at least 4 cycles, and not receiving transplantation for at least 6 cycles); (2) Relieving for 1-3 years, and is not suitable or accepted for autologous hematopoietic stem cell transplantation rescue treatment.

As used herein, the term "refractory" is defined as the progression of the disease within 1 year of the subject's past receiving either first-line intensive therapy without remission, or the period of treatment/intensive therapy completed, and includes: (1) Treating according to clinically recommended standard or conventional scheme, with a treatment course of more than 2 cycles not reaching Stable Disease (SD), or with a treatment course of more than 4 cycles not reaching Partial Remission (PR); (2) If the optimal curative effect or the reason for ending is disease Progression (PD), the treatment course number is not required; (3) Disease progression again after receiving clinically recommended standard or conventional regimen treatment for more than or equal to 2 lines; (4) patients who relapse after autologous hematopoietic stem cell transplantation.

As used herein, the term "remission" includes Complete Remission (CR) and Partial Remission (PR).

Dosing regimens

In some embodiments, there is provided a use of an anti-PD-1 antibody or antigen-binding fragment thereof in the manufacture of a medicament for treating or preventing peripheral T-cell lymphoma in a subject in need thereof, wherein the medicament is a pharmaceutical composition and comprises one or more anti-PD-1 antibodies or antigen-binding fragments thereof described herein and one or more pharmaceutically acceptable excipients or adjuvants.

As used herein, "pharmaceutically acceptable excipient or adjuvant" refers to physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, such as salts, buffers, antioxidants, sugars, aqueous or non-aqueous carriers, preservatives, wetting agents, surfactants or emulsifiers, or combinations thereof.

In some embodiments, the pharmaceutically acceptable excipient or adjuvant includes, for example, a buffer, a protectant, an osmotic pressure modifier, a surfactant, and/or a pH modifier.

In some embodiments, the buffer is, for example, glutamic acid, phosphate buffered saline, sodium acetate, sodium citrate, and Tris buffer; such as mannitol, sucrose and proline; the surfactant is, for example, polysorbate such as polysorbate-80, polysorbate-60, polysorbate-40 and polysorbate-20; the pH adjuster is, for example, sodium hydroxide.

In one embodiment, the pharmaceutically acceptable excipient or adjuvant comprises glutamic acid, proline, mannitol, sucrose, polysorbate-80, and sodium hydroxide.

In some embodiments, the pharmaceutical composition comprises about 1-11 mg/mL, e.g., 1-10 mg/mL, of the anti-PD-1 antibody or antigen-binding fragment thereof and one or more pharmaceutically acceptable excipients or adjuvants selected from the group consisting of glutamic acid, proline, mannitol, sucrose, polysorbate-80, and sodium hydroxide.

By "administering" is meant introducing a composition comprising a therapeutic agent to a subject using any of a variety of methods and delivery systems known to those of skill in the art. Routes of administration of the pharmaceutical compositions of the present disclosure include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, for example by injection or infusion. The phrase "parenteral administration" as used herein refers to modes of administration, other than enteral and topical administration, which are typically by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion, and in vivo electroporation. In some embodiments, the composition is administered by a non-parenteral route, and in some embodiments, by oral administration. Other non-parenteral routes include topical, epidermal or mucosal routes of administration, such as intranasal, vaginal, rectal, sublingual or topical. Administration may also be performed, for example, once, multiple times, and/or over one or more extended periods of time.

Dosage regimens can be adjusted as needed to provide the optimal response, e.g., the maximum therapeutic response and/or the minimum adverse effect. In some embodiments, an anti-PD-1 antibody or antigen-binding fragment thereof of the present disclosure is administered in a weight-based dose. For administration of the anti-PD-1 antibody as a monotherapy or in combination with another anti-cancer agent, at a weight-based dose, the dose can range from about 0.01 mg/kg to about 20 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 5 mg/kg, from about 1 mg/kg to about 5 mg/kg, from about 2 mg/kg to about 5 mg/kg, from about 7.5 mg/kg to about 12.5 mg/kg, or from about 0.1 mg/kg to about 30 mg/kg of the subject's body weight. For example, the dose may be about 0.1 mg/kg, about 0.3 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3mg/kg, about 5 mg/kg or about 10 mg/kg body weight, or about 0.3 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3mg/kg or about 5 mg/kg body weight. Based on the typical pharmacokinetic properties of antibodies, dosing schedules are typically designed to achieve exposures that result in sustained Receptor Occupancy (RO). Exemplary treatment regimens require administration about weekly, about every 2 weeks, about every 3 weeks, about every 4 weeks, about monthly, about every 3-6 months, or more. In certain embodiments, an anti-PD-1 antibody of the present disclosure is administered to a subject about once every 2 weeks. In other embodiments, the anti-PD-1 antibody of the present disclosure is administered about once every 3 weeks. The dosage and timing may vary during the course of treatment. For example, a dosing schedule for an anti-PD-1 antibody monotherapy of the present disclosure can include administering an antibody: (i) about every 2 weeks for about 6-weeks; (ii) About every 4 weeks for about 6 doses, then about every 3 months; (iii) about every 3 weeks; (iv) About 3mg/kg to about 10 mg/kg once, followed by about 1 mg/kg every about 2 to 3 weeks.

In some embodiments, the pharmaceutical composition is administered to the subject at a dose of the anti-PD-1 antibody or antigen-binding fragment thereof in the range of about 1 mg/kg to about 10 mg/kg body weight about 1 time every 1, 2, 3, or 4 weeks.

In one embodiment, the pharmaceutical composition is administered at a dose of about 3mg/kg body weight of the anti-PD-1 antibody or antigen-binding fragment thereof about 1 time every 2 weeks.

In some embodiments, a dosage regimen of an anti-PD-1 antibody of the present disclosure comprises administering at least about 0.3 mg/kg to at least about 10 mg/kg body weight, at least about 1 mg/kg to at least about 5 mg/kg body weight, or at least about 1 mg/kg to at least about 3mg/kg body weight intravenously, wherein the antibody is administered every about 14-21 days over a period of up to about 6-weeks or about 12-weeks, until complete response or confirmation of a progressive disease. In certain embodiments, an anti-PD-1 antibody monotherapy of the present disclosure is administered at 3mg/kg every 2 weeks until progressive disease or unacceptable toxicity. In some embodiments, the anti-PD-1 antibody treatment of the present disclosure, or any combination treatment disclosed herein, lasts for at least about 1 month, at least about 3 months, at least about 6 months, at least about 9 months, at least about 1 year, at least about 18 months, at least about 24 months, at least about 3 years, at least about 5 years, or at least about 10 years.

When used in combination with other cancer agents, the dose of the anti-PD-1 antibodies of the present disclosure can be reduced, e.g., above 0.001 mg/kg and below 3mg/kg, compared to a monotherapy dose. In some embodiments, the dose is from about 0.001 mg/kg to about 1 mg/kg, from about 0.01 mg/kg to about 1 mg/kg, from about 0.1 mg/kg to about 1 mg/kg, or from about 0.001 mg/kg to about 0.1 mg/kg of body weight. In some embodiments, the dose is at least about 0.001 mg/kg, at least about 0.005 mg/kg, at least about 0.01 mg/kg, at least about 0.05 mg/kg, at least about 0.1 mg/kg, at least about 0.5 mg/kg, or at least about 1.0 mg/kg body weight.

In certain embodiments, the dose of the anti-PD-1 antibody of the present disclosure is a fixed dose in a pharmaceutical composition. In embodiments, the fixed dose of the anti-PD-1 antibody or antigen-binding fragment thereof is at least about 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480mg, 500 mg, 520 mg, 540 mg, 560 mg, or 600 mg. For example, a fixed dose of an anti-PD-1 antibody of the present disclosure may be about 280 mg. In embodiments, an anti-PD-1 antibody or antigen-binding fragment thereof of the present disclosure is administered at a dose of about 240 mg. In embodiments, an anti-PD-1 antibody or antigen-binding fragment thereof of the present disclosure is administered at a dose of about 360 mg. In embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof of the present disclosure is administered at a dose of about 480 mg. In embodiments, the fixed dose of the anti-PD-1 antibody or antigen-binding fragment thereof of the present disclosure is administered about once every week, every two weeks, every three weeks, every four weeks, every five weeks, or every six weeks. In one embodiment, 360 mg of the anti-PD-1 antibody or antigen-binding fragment is administered once every 3 weeks. In another embodiment, 480mg of the anti-PD-1 antibody or antigen-binding fragment is administered once every 4 weeks.

In some embodiments, the pharmaceutical composition is administered to the subject at a fixed dose of at least about 200 mg, at least about 220 mg, at least about 240 mg, at least about 260 mg, at least about 280 mg, at least about 300 mg, at least about 320 mg, at least about 340 mg, at least about 360 mg, at least about 380 mg, or at least about 400 mg of the anti-PD-1 antibody or antigen-binding fragment thereof about 1 time every 1, 2, 3, or 4 weeks.

In a specific embodiment, the pharmaceutical composition is administered to the subject at a fixed dose of about 280 mg of the anti-PD-1 antibody or antigen-binding fragment thereof about 1 time every 3 weeks.

Baseline characteristics

As described above and demonstrated in the examples of the present application, PTCL subjects, particularly relapsed or refractory PTCL subjects, can benefit from treatment with the anti-PD-1 antibodies described herein regardless of age, sex, clinical stage, previous exposure to several lines of anti-tumor therapy, different pathological subtypes, and PD-L1 positivity, among others, and result in significantly improved Objective Remission Rate (ORR) and significantly improved efficacy and prognosis.

The present inventors have surprisingly found that an antibody as described herein having an ORR of 38.4% is clinically significant in its effectiveness in treating relapsed or refractory PTCL, as compared to 25% to 28% for Objective Remission Rate (ORR) of several other agents (e.g., cidandamide) in treating relapsed or refractory PTCL. In particular, as demonstrated in the examples herein, the anti-PD-1 antibodies described herein can achieve significantly improved efficacy and prognosis in patients with relapsed or refractory PTCL who are less than 65 years of age, without baseline bone marrow invasion, with baseline LDH values at normal levels, or with a PD-L1 positive rate (TPS) ≧ 50%. Wherein the anti-PD-1 antibody of the present disclosure is administered in a relapsed or refractory PTCL subject with a PD-L1 positive rate (TPS) of > 50% with an ORR up to 51.4%.

In some embodiments, the tumor of the subject has at least about 1%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50% PD-L1 positive cells. Alternatively, in some embodiments, the subject has a tumor cell PD-L1 positive rate of at least about 1%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%.

In one embodiment, the PD-L1 expression level can be measured by methods known in the art. The detection of PD-L1 is based on the detection of cell protein level, so that the clinical test mainly comprises an immunohistochemical method. Immunohistochemistry is a classic method for detecting protein expression, and evaluates expression conditions by staining antibodies, preparing digital sections and observing staining depth. In another embodiment, PD-L1 expression levels are measured by automated IHC. A PD-L1 positive tumor can have at least about 1%, at least about 2%, at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100% PD-L1-expressing tumor cells as measured by an automated IHC.

As used herein, the term "PD-L1 positive" means that the number of tumor cells expressing PD-L1 in membrane staining is greater than or equal to 1% of the total number of tumor cells, TPS. TPS (Tumor pathology Score, TPS) was calculated as (number of PD-L1 membrane staining positive Tumor cells/total number of Tumor cells at any intensity) 100%. In some embodiments, the subject has previously received a therapy with sildendrine or other anti-tumor chemotherapy or radiation therapy, and/or the subject has previously received an autologous stem cell transplant.

In some embodiments, the subject has one or more of the following baseline characteristics: (i) an age of less than 65 years; (ii) no bone marrow invasion at baseline; and (iii) normal baseline LDH values.

Combination drug

In some embodiments, there is provided a method of treating or preventing peripheral T cell lymphoma in a subject in need thereof, comprising administering to the subject an anti-PD-1 antibody or antigen-binding fragment thereof described herein in combination with one or more additional therapeutic agents selected from chemotherapeutic agents, radiotherapeutic agents, cytokines, or other antibodies.

In one embodiment, the anti-PD-1 antibodies and antigen-binding fragments thereof can be administered to a subject before, during, and/or after the additional therapeutic agent is administered to the subject. In one embodiment, the anti-PD-1 antibody and the additional therapeutic agent exhibit therapeutic synergy when administered together (whether simultaneously or sequentially). In one embodiment, the anti-PD-1 antibody and the additional therapeutic agent are administered in separate formulations. In another embodiment, the anti-PD-1 antibody and the additional therapeutic agent are administered in the same formulation. In one embodiment, the anti-PD-1 antibody or antigen-binding fragment thereof provided herein enhances the immunomodulatory effect of the one or more additional therapeutic agents. In another embodiment, the one or more additional therapeutic agents enhance the effect of the anti-PD-1 antibody or antigen-binding fragment thereof.

Method of treatment

In one aspect, the invention provides a method of treating or preventing peripheral T cell lymphoma in a subject in need thereof, comprising administering to the subject an effective amount of an anti-PD-1 antibody or antigen-binding fragment thereof, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is as defined herein.

As used herein, the term "effective amount" refers to the amount of active agent required to provide a therapeutic and/or prophylactic benefit to a subject.

Preferably, the peripheral T-cell lymphoma is selected from extranodal nasal NK/T-cell lymphoma (ENKTL) and ALK-negative anaplastic large cell lymphoma (ALK-ALCL).

While various embodiments of the present invention have been described above, it should be understood that they have been presented by way of example only, and not limitation. Many modifications to the disclosed embodiments may be made in accordance with the disclosure herein without departing from the spirit or scope of the invention. Thus, the breadth and scope of the present invention should not be limited by any of the above-described embodiments.

All documents referred to in this disclosure are incorporated herein by reference. All publications and patent documents cited in this application are incorporated by reference for all purposes to the same extent as if each individual publication or patent document were individually indicated to be so incorporated.

Examples

The light and heavy chain sequences of the anti-PD-1 antibody used in the examples are shown in SEQ ID NO 9 and SEQ ID NO 10 and designated G-Ab1.

Example 1 inhibition of PD-1 Signaling by G-Ab1

Experimental methods

PD-1 acts as an important regulatory immune checkpoint molecule, negatively regulating the activation of T-cells. This experiment simulates the regulatory mechanism of the above APC on T-cells by constructing a luciferase reporter gene driven by a stably activated NFAT promoter and a Jurkat T-cell line (Jurkat/PD-1 cell) stably expressing PD-1, functioning as a T effector cell, and a CHOK cell line (CHO/PD-L1 cell) stably expressing PD-L1 as an artificial APC cell. When Jurkat/PD-1 and CHO/PD-L1 cells were cultured in admixture, PD-L1 and PD-1 bound to inhibit luciferase reporter gene expression induced by the activating NFAT promoter in Jurkat T-cells. After the G-Ab1 is added, the G-Ab1 is combined with PD-1 on the cell surface of Jurkat/PD-1, the combination path of PD-1 and PD-L1 is blocked, the inhibition effect of PD-1 on the expression of NFAT-Luciferase reporter gene is relieved, the expression of the Luciferase reporter gene is increased, chemiluminescence is enhanced under the action of a reaction substrate, and the increase of the chemiluminescence intensity is in direct proportion to the inhibition activity of the G-Ab1 on the combination of PD-1 and PD-L1.

Collecting CHO/PD-L1 cells (Promega Corporation, cat. No. CS187108, lot. No. 0000141847) in logarithmic growth phase, digesting with pancreatin, counting, centrifuging appropriate amount of cell suspension, re-suspending with cell culture medium, and adjusting cell density to 4 × 10 ⁵ Per ml, 100. Mu.L per well was added to a white impermeable cell culture plate (white 96 well plate, costa, cat. No. 3917) for overnight culture. RPMI 1640 (Gibco, cat. No. 22400-089, lot No. 1687968) +2% FBS (Gibco, cat. No. 11765-054, lot No. 1674921) medium was prepared as a dilute mediumG-Ab1 (concentration: 10.4 mg/ml) and isotype control IgG4 antibody (control IgG4-AB150092 shown in FIG. 1, zhongguanke, cat # E0849-T1501, lot # AB150092, concentration 4.8 mg/ml) were diluted to 50. Mu.g/ml (2X), and 2.5-fold dilutions were made therefrom with 11 concentration gradients as 2X working solutions. Counting the cell suspension of Jurkat/PD1 (Promega Corporation, cat. No. CS187102, batch No. 0000129197) in logarithmic growth phase, centrifuging, re-suspending with diluent, and adjusting the cell density to 1.25 × 10 ⁶ One per ml. The CHO/PD-L1-seeded cell plate was removed, and after sucking out 95. Mu.L of the culture supernatant per well, 40. Mu.L of the working solution and 40. Mu.L of Jurkat/PD1 cell suspension were added, respectively, to set a negative control well (containing no antibody). Subjecting the loaded cell culture plate to 37 ℃ and 5% ₂ After 6 h incubation in the incubator, the cells were removed and left at room temperature for 10 min, and 80. Mu.L of Bio-Glo was added to each well ^TM Substrate solution (Bio-Glo Luciferase assay system, promega Corporation, cat # G7940, lot # 0000165135) was incubated at room temperature for 10 min. The full wavelength chemiluminescence (Luminescence) of each well was read with a multifunctional microplate reader (Molecular Devices, model M5, code A-04-035), with the average value of the negative control wells being RLU _{no antibody control} The ratio Induction Fold of Induction = RLU per well was calculated _{Ab dilution} /RLU _{no antibody control} 。

As a result, the

The G-Ab1 concentration was logarithmized as the abscissa, and the chemiluminescence value (RLU) per well was determined _{Ab dilution} ) Divided by the mean value of the luminescence (RLU) of the negative control wells (without antibody) _{no antibody control} ) As a vertical coordinate, a nonlinear regression analysis method in GraphPad Prism (GraphPad Software Inc., san Diego, california) is adopted, and a Sigmoidal dose-Response (Variable Slope) mode is selected to fit a curve for drawing, so that an inhibition curve of G-Ab1 for blocking the combination of PD-1 and PD-L1 is obtained (figure 1). The results show that G-Ab1 inhibits the combination of PD-1 and PD-L1 in a dose-dependent manner, and can reach saturation, and the inhibition curve is in an S shape. Isotype control IgG4 did not show any inhibitory effect, indicating that G-Ab1 is capable of specifically binding to PD-1, blocking its binding to PD-L1.

EXAMPLE 2 therapeutic Effect of G-Ab1 on relapsed or refractory Peripheral T Cell Lymphoma (PTCL)

Design of research

This example is intended to evaluate the effectiveness, safety, and immunogenicity of G-Ab1 treatment of relapsed or refractory PTCL. The primary endpoint is ORR; secondary endpoints are security, DOR, TTR, PFS, OS, etc. Relapsed or refractory PTCL subjects, enrolled into a cohort, received treatment with the antibody at 3mg/kg administered once every 2 weeks until the subject had established disease Progression (PD), intolerable toxicity, withdrawal of informed consent, initiation of other anti-tumor therapy, loss of visit or death, the investigator or subject decided to terminate therapy, or the study ended. Tumor efficacy assessments were performed every 6 weeks, every second year and every 12 weeks thereafter from the first study dose during the study period. Subjects who finished treatment entered the follow-up period and received a safety follow-up or survival follow-up. If the subject has terminated treatment, its imaging assessment has not yet reached PD, and disease progression follow-up is also required.

Criteria for effectiveness evaluation

Imaging examination

The imaging tumor evaluation is carried out on the subjects every 6 weeks (+ -7 days) in the first year, every 12 weeks (+ -7 days) in the second year and later (the interval between the first curative effect evaluation and the first study medication is required to be more than or equal to 6 weeks except for the disease progress), and the lymphoma focuses are identified by adopting positron emission computed tomography (PET-CT) and/or electronic Computed Tomography (CT) enhancement technology, such as CT contrast agent allergy, feasible chest CT flat scan, feasible enhanced MRI examination or CT flat scan examination on parts such as cervical, abdominal and pelvic cavities, mediastinum and the like. Imaging examination results were replicated for efficacy by an independent review committee for delivery (IRC).

The study stipulates that, in the screening period, the baseline imaging evaluation needs to simultaneously comprise PET-CT and CT or MRI examination of neck, chest, abdomen and pelvic cavity with diagnostic value; extranodal NK/T cell lymphoma (nasal type) also needs nasopharyngeal reinforced MRI examination; if special clinical indications exist, a skull MRI examination is required, PET-CT indicates possible bone metastasis sites, if the conventional examination sites are not covered, the positions of diseases need to be confirmed by CT or X rays, and follow-up is required in the same scanning mode. The imaging examination which is conventionally performed as a clinical diagnosis and treatment can be used as a screening examination, but is required to achieve diagnostic quality and is performed within 28 days before the first administration. CT or MRI examinations were taken as the imaging assessment every 6 weeks during the study, and subjects should be taken with the same imaging technique throughout the study. The positive patient of baseline PET-CT scan recommends that the treatment visit at 13 weeks and 19 weeks later should be added with PET-CT examination as the imaging evaluation; evaluation of efficacy at other time points if the investigator judges that the addition of PET-CT examination is beneficial to accurate evaluation of efficacy, the applicant agrees to use PET-CT examination. The time for performing the imaging examination should follow the calendar day and should not be adjusted according to the cycle start time delay or the treatment cycle extension. After first obtaining evidence of progression (if the subject is clinically stable) that meets the definition of the Lugano 2014 standard, a repeat examination is performed at the next evaluation time point (at least 4 weeks) to confirm efficacy.

Imaging examination method for tumor assessment during study:

enhanced CT: enhanced MRI or CT panning may be used for contrast-sensitized subjects;

PET-CT: the important auxiliary detection means of the conventional screening, the baseline stage of tumor evaluation and the end of treatment visit at week 13 and week 19 in the research process;

nasopharyngeal, head MRI: extranodal NK/T cell lymphoma (nasal type) subjects need nasopharynx enhancement MRI examination during the screening period; if a subject with special clinical indications exists in a screening period or a research process, performing skull MRI examination according to the conventional diagnosis and treatment if necessary;

an X-piece: only used as an auxiliary detection means for non-target focuses at parts such as bones, chests and the like.

Evaluation of therapeutic effects

Efficacy evaluation was performed in parallel by the Independent Review Committee (IRC) and researchers, using the recommendations of the International Working Group (IWG) 2014 "initial evaluation, staging, efficacy evaluation of hodgkin lymphoma and non-hodgkin lymphoma: lugano classification).

There is increasing evidence that objective remission of immunotherapy may be delayed by weeks or months, before which significant imaging progression or new lesion or lesion enlargement may occur while some target lesions shrink. Investigators evaluated efficacy in considering that some subjects may develop transient Tumor growth (Tumor Flare) and pseudoprogression within the first few months after initiation of immunotherapy, followed by remission, so clinically stable subjects were allowed to continue treatment after the first imaging Progression (PD), and the investigators continued to receive treatment and again imaging evaluation for efficacy confirmation at the next efficacy evaluation time point if they considered that the subjects would be likely to have clinical benefit.

If PD was confirmed again by the 2014Lugano standard and the investigator believes that continued treatment of the subject may no longer have clinical benefit, data and survival follow-up were collected by the last visit; if disease progression is still Uncertain (UPD), treatment and follow-up is continued on the visit plan.

Main index for evaluating therapeutic effect

Objective Remission Rate (ORR) refers to the proportion of subjects achieving Complete Remission (CR) or Partial Remission (PR) as assessed by IRC based on 2014Lugano standard imaging.

Duration of remission (DOR) refers to the time from the start of a tumor assessed as CR or PR to the first assessment as disease Progression (PD) or death from any cause. Immune-related DOR refers to the time from the first appearance of CR or PR to the appearance of established disease Progression (PD) in tumor assessments (excluding pseudoprogression and again confirming PD) or death from any cause. For subjects who have not yet been clearly progressed or died, DOR will be missed at the time of last effective assessment.

Time To Remission (TTR) refers to the time from the first study drug treatment to the first appearance of CR or PR in the tumor assessment. If the subject did not develop CR or PR before the data collection was cut off, TTR will be missed at the time of the last valid assessment.

Disease Control Rate (DCR) refers to the proportion of subjects that achieve CR, PR and Stable Disease (SD) by imaging evaluation.

Progression Free Survival (PFS) is defined as the time from the first study drug treatment to disease Progression (PD) or to death of the subject for any reason. Immune-related PFS refers to the time from the first study drug treatment to the appearance of confirmed disease Progression (PD) (excluding spurious progression and again confirming PD) or to death of the subject for any reason. For subjects who have not yet become clear whether to progress or die, PFS will be missed at the time of the last effective assessment.

Overall Survival (OS) refers to the time from the first study medication to death due to any cause (missed patients were last visit); if the subject did not die at the last follow-up for survival or before data collection was cut off, OS will be missed at the last visit for survival.

Pharmaceutical composition

The PD-1 antibody pharmaceutical composition is prepared by Jia and biological medicine Limited, and comprises G-Ab1 with the concentration of 10.0 mg/ml; and 2.94mg/mL glutamic acid, 9.8mg/mL proline, 30mg/mL mannitol, 15mg/mL sucrose, 1.0mg/mL polysorbate-80, 0.63mg/mL sodium hydroxide and water for injection. The specification was 7mL: 70mg.

The anti-PD-1 antibody pharmaceutical composition was prepared in 100ml of a 0.9% sodium chloride solution. The administration concentration is controlled to be 1 mg/ml-10 mg/ml, the infusion is finished after the first administration for 60 minutes (+ -10 minutes), and if no adverse reaction related to the infusion exists, the subsequent administration time can be shortened to 30 minutes (+ -10 minutes).

Subject distribution

102 subjects (FAS) were successfully enrolled in the study and received at least one study medication. Of these, 73 subjects were finally diagnosed as PTCL (excluding primary cutaneous T cell lymphoma) by the central pathology, and conformed to the definition of recurrent or refractory PTCL, entered the total analysis set (FAS 1) determined by the central pathology, and served as the main analysis set, providing the main basis for the efficacy analysis. See tables 4-5 for details.

TABLE 4 study baseline characteristics of disease (FAS 1)

TABLE 5 summary of previous antitumor therapy receiving information

Overall therapeutic effect

IRC-assessed ORR in FAS1 population was 38.4% (95% ci, 27.21%, 50.48%) and DCR was 58.9% (95% ci. Of these 8 (11.0%) subjects reached CR,20 (27.4%) subjects reached PR, and 15 (20.5%) subjects maintained SD. The ORR assessed by the investigator in the FAS1 population was 38.4% (95% ci. The effectiveness of the anti-PD-1 antibodies described herein in a relapsed or refractory PTCL population is of clinical significance, as detailed in table 6.

TABLE 6 Overall efficacy assessment best Total response (BOR) summary-IRC, 2014Lugano (FAS 1)

Taken together, the overall ORR of G-Ab1 in the population of relapsed or refractory PTCL patients was 38.4% (95% ci. Meanwhile, the Objective Remission Rate (ORR) achieved by the scheme is significantly higher than the ORR (25% -28%) of other clinically applied single-drug treatment relapsed or refractory PTCL drugs (see O 'Connor OA, pro B, pinter-Brown L, et al. Pralatrexate in Patients with delayed or recurrent clinical procedure T-cell lymphoma: results from the same PROPEL study [ J ]. J Clin Oncol, 2011, 29 (9): 1182-1189; covifier B, pro B, prince HM, et al. Results from a pivot, open-label, phase II study of romidepsin replay or reaction per T-cell simple ghost after scanner system therapy [ J ]. J Clin Oncol, 2012, 30 (6): 631-636; O' Connor OA, horwitz S, masszi T, et al, belinostat in Patients with diseases with reused or recycled patient T-cell lymphoma: results of the pivotal phase II BELIEF (CLN-19) study [ J ]. J Clin Oncol, 2015, 33 (23): 2492-2499, and Shi Y, dong M, hong X, et al, results from a multicenter, open-label, pivotal phase II study of cardiac in recycled or recycled patient T-cell lymphoma [ J ]. Ann col, 2015, 26 (8 1766-71), which demonstrates that the treatment provided by the present invention is more effective in Patients with relapse or refractory PTCL.

EXAMPLE 3 subgroup efficacy of G-Ab1 in the treatment of relapsed or refractory Peripheral T Cell Lymphoma (PTCL)

Only a subset analysis of efficacy was performed based on the IRC assessment of FAS1 in example 2.

Subgroup analysis showed that subjects younger than 65 years of age had a significant prolongation of median PFS (2.7 vs. 1.4 months, P = 0.0387) compared to subjects older than 65 years and older by administration of G-Ab1. Subjects without bone marrow invasion at baseline had significantly longer median PFS than subjects with bone marrow invasion at baseline (2.8 vs. 1.8 months, P = 0.0219). Baseline LDH values were significantly elevated at normal levels compared to abnormal levels of ORR in subjects (50.0% vs.18.5%, P = 0.0120), with a significant prolongation of median PFS (4.2vs. 1.5 months, P = 0.0044). Subjects with a PD-L1 positive rate (TPS) of > 50% showed a significant improvement in ORR (51.4% vs. 24.1%, P = 0.0415), a significant improvement in DCR (70.3% vs. 41.4%, P = 0.0248), and a significant prolongation of median PFS (6.2 vs.1.5 months, P = 0.0054) in PD-L1 positive rate (TPS) > 50%. In general, multiple efficacy or prognostic assessment indicators were statistically significantly different in age (< 65 years/. Gtoreq.65 years), baseline bone marrow invasion (yes/no), baseline LDH values (normal/abnormal), PD-L1 positive rates (< 50%/. Gtoreq.50%) subgroups. This indicates that G-Ab1 achieves better therapeutic efficacy in relapsed or refractory PTCL patients under the age of 65 years, without baseline bone marrow invasion, with baseline LDH values at normal levels, or with a PD-L1 positivity of 50% or more.

Furthermore, in PTCL subjects who failed to receive the sildenamine treatment before, the benefit of receiving G-Ab1 treatment was still obtained, with an ORR of 37.5% (6/16, 95% ci. Significant benefit was also seen even in subjects who had received autologous stem cell transplantation who received G-Ab1 treatment (table 8), with an ORR of 80.0% (4/5, 95% ci.

TABLE 7 previous use of therapeutic efficacy analysis under the xidapamide subgroup-IRC, 2014Lugano (FAS 1)

Note: NR = not reached; ORR and DCR will calculate 95% CI using the Clopper-pearson method; PFS is analyzed by adopting a Kaplan-Meier method and calculated according to a main deletion rule. * For ORR and DCR, P values were based on Fisher's test; PFS and P values were based on the Log-Rank test.

TABLE 8 therapeutic efficacy analysis of previous accepted or not accepted by ASCT (autologous stem cell transplantation) subgroup-IRC, 2014Lugano (FAS 1)

Note: NR = not reached; ORR and DCR will calculate 95% CI using the Clopper-pearson method; PFS is analyzed by adopting a Kaplan-Meier method and calculated according to a main deletion rule.

* For ORR and DCR, P values were based on Fisher's test; PFS and P values were based on the Log-Rank test.

From the above results, it is clear that by administration of G-Ab1, subjects with the common pathological subtype of PTCL all benefited, and 73 subjects in the FAS1 population were pathologically diagnosed as PTCL, with ORR of ENKTL as high as 58.8% in the chinese population (10/17, 95% ci; poor prognosis of ALK-ALCL has ORR up to 53.8% (7/13, 95% CI; ORR of ALK + ALCL can reach 40.0% (2/5, 95% CI; the ORR of mature T cell lymphoma (not classifiable) can also reach 50% (4/8, 95% ci. Furthermore, subjects pathologically diagnosed as AITL achieved remission by administration of G-Ab1, with an ORR of 50% (1/2, 95% ci.

As can be seen from the above examples, the anti-PD-1 antibodies of the present disclosure exhibit superior clinical efficacy as anti-cancer therapeutic agents. Administration of the anti-PD-1 antibodies of the disclosure to PTCL subjects significantly improved the objective remission rate. In particular, in relapsed or refractory PTCL subjects, treatment with the anti-PD-1 antibodies of the present disclosure still enables objective remission and improvement in prognosis. In PTCL subjects who have failed the previous therapy with xidabenamine and PTCL subjects who have received autologous stem cell transplantation, the treatment with the anti-PD-1 antibody of the present disclosure can still achieve significantly improved objective remission rates, show superior clinical efficacy and improved prognosis. In addition, the anti-PD-1 antibodies of the present disclosure significantly improve the rate of objective remission in treating the PTCL subgroup, achieving significant efficacy.

While various embodiments of the present invention have been described above, it should be understood that they have been presented by way of example only, and not limitation. The present invention is susceptible to various changes and modifications without departing from the spirit and scope of the present invention, and such changes and modifications are intended to be within the scope of the present invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.

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Claims

1. Use of an anti-PD-1 antibody or antigen-binding fragment thereof in the manufacture of a medicament for treating or preventing peripheral T-cell lymphoma in a subject in need thereof, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain comprising LCDR1, LCDR2 and LCDR3 as set forth in SEQ ID No. 1, SEQ ID No. 2 and SEQ ID No. 3, respectively, and a heavy chain comprising HCDR1, HCDR2 and HCDR3 as set forth in SEQ ID No. 4, SEQ ID No. 5 and SEQ ID No. 6, respectively.

2. The use of claim 1, wherein the light chain variable region of the anti-PD-1 antibody or an antigen-binding fragment thereof comprises an amino acid sequence having at least 80% homology with the amino acid sequence of SEQ ID NO. 7 and the heavy chain variable region comprises an amino acid sequence having at least 80% homology with the amino acid sequence of SEQ ID NO. 8.

3. The use according to claim 1 or 2, wherein the light chain and the heavy chain of the anti-PD-1 antibody or an antigen-binding fragment thereof comprise or consist of the sequences shown as SEQ ID NO 9 and 10, respectively.

4. The use of any one of claims 1-3, wherein the peripheral T cell lymphoma is relapsed or refractory peripheral T cell lymphoma.

5. The use of any one of claims 1-4, wherein the peripheral T-cell lymphoma is selected from the group comprising extranodal rhino-type NK/T-cell lymphoma (ENKTL), non-specific peripheral T-cell lymphoma (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), ALK-positive anaplastic large-cell lymphoma (ALK + ALCL), ALK-negative anaplastic large-cell lymphoma (ALK-ALCL), enteropathy-associated T-cell lymphoma (EATL), mycosis Fungoides (MF), szary Syndrome (SS), and primary cutaneous gamma/delta T-cell lymphoma.

6. The use of claim 5, wherein the peripheral T cell lymphoma is selected from extranodal nasal NK/T cell lymphoma (ENKTL) and ALK-negative anaplastic large cell lymphoma (ALK-ALCL).

7. The use of any one of claims 1-6, wherein the medicament comprises a therapeutically effective amount of the anti-PD-1 antibody or antigen-binding fragment thereof and a pharmaceutically acceptable excipient or adjuvant.

8. The use of claim 7, wherein the medicament comprises glutamic acid, proline, mannitol, sucrose, polysorbate-80, and sodium hydroxide.

9. The use of any one of claims 1-8, wherein the medicament is administered (i) about 1 time every 1, 2, 3, or 4 weeks at a dose of the anti-PD-1 antibody or antigen-binding fragment thereof in the range of about 1 mg/kg to about 10 mg/kg body weight; or (ii) the medicament is administered about 1 time every 1, 2, 3, or 4 weeks at a fixed dose of at least about 200 mg, at least about 220 mg, at least about 240 mg, at least about 260 mg, at least about 280 mg, at least about 300 mg, at least about 320 mg, at least about 340 mg, at least about 360 mg, at least about 380 mg, or at least about 400 mg of the anti-PD-1 antibody or antigen-binding fragment thereof.

10. The use of any one of claims 1-9, wherein the tumor of the subject has at least about 1%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50% PD-L1 positive cells.

11. The use of any one of claims 1-10, wherein the subject has previously received therapy with cidalimine or other anti-tumor chemotherapy or radiation therapy, and/or the subject has previously received an autologous stem cell transplant.

12. The use of any one of claims 1-11, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is for administration in combination with one or more additional chemotherapeutic agents, radiotherapeutic agents, cytokines, or other antibodies.