TW202144007A - Use of an anti-pd-1 antibody in the preparation of a medicament for the treatment of acral melanoma - Google Patents

Use of an anti-pd-1 antibody in the preparation of a medicament for the treatment of acral melanoma Download PDF

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TW202144007A
TW202144007A TW110112949A TW110112949A TW202144007A TW 202144007 A TW202144007 A TW 202144007A TW 110112949 A TW110112949 A TW 110112949A TW 110112949 A TW110112949 A TW 110112949A TW 202144007 A TW202144007 A TW 202144007A
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antibody
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鄒建軍
郭軍
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大陸商江蘇恆瑞醫藥股份有限公司
大陸商蘇州盛迪亞生物醫藥有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants

Abstract

The disclosure relates to the use of an anti-PD-1 antibody in the preparation of a medicament for the treatment of acral melanoma. Specifically, it provides an anti-PD-1 antibody and apatinib in the preparation of a medicament for the treatment of acral melanoma This program has a disease control rate of 72.2% for acral melanoma, and an objective disease remission rate of 22.2%. Compared with single-drug PD-1, it significantly improves the objective disease remission rate and improves the safety and effectiveness of patient medication. On the other hand, the disclosure also provides the use of an anti-PD-1 antibody, apatinib and temozolomide in the preparation of a medicine for treating melanoma.

Description

一種抗PD-1抗體在製備治療肢端黑色素瘤的藥物中的用途 Use of an anti-PD-1 antibody in the preparation of a drug for the treatment of acral melanoma

本揭露涉及一種抗PD-1抗體或其抗原結合片段和VEGFR抑制劑聯合在製備治療肢端黑色素瘤的藥物中的用途。 The present disclosure relates to the use of an anti-PD-1 antibody or an antigen-binding fragment thereof in combination with a VEGFR inhibitor in the preparation of a medicament for treating acral melanoma.

早期臨床試驗顯示特異性結合抗程序性死亡受體(抗PD-1)，如nivolumab和pembrolizumab，可使晚期黑色素瘤患者預後得到顯著改善(N Engl J Med 2015；372：320-30和N Engl J Med 2015；372：2521-32)。然而大多數此類研究主要基於抗PD-1藥物在高加索人群中的藥效數據進行分析，黑色素瘤臨床亞型在人群中差異較大，且抗PD-1藥物對疾病的不同亞型響應也有所不同。 Early clinical trials have shown that specific binding to anti-programmed death receptors (anti-PD-1), such as nivolumab and pembrolizumab, can significantly improve outcomes in patients with advanced melanoma ( N Engl J Med 2015;372:320-30 and N Engl J Med 2015;372:2521-32). However, most of these studies are mainly based on the efficacy data of anti-PD-1 drugs in the Caucasian population. different.

A.N.Shoushtari等人(Cancer.2016,122(21)：3354.doi：10.1002/cncr.30259)研究了抗PD-1抗體pembrolizumab對肢端黑色素瘤和黏膜黑色素瘤的療效，他們發現肢端黑色素瘤組的ORR為32%，黏膜黑色素瘤組的ORR為23%，其結果與早期臨床研究數據相當。 ANShoushtari et al. ( Cancer. 2016, 122(21): 3354. doi: 10.1002/cncr. 30259) investigated the efficacy of the anti-PD-1 antibody pembrolizumab in acral and mucosal melanoma, and they found that the acral melanoma group The ORR was 32% in the mucosal melanoma group and 23% in the mucosal melanoma group, a result comparable to earlier clinical data.

T.Maeda等人(Br J Dermatol. 2018 Nov 17.doi：10.1111/bjd.17434)報導納武單抗在不同臨床亞型的黑色素瘤(如肢端黑色素瘤、黏膜黑色素瘤和 皮膚黑色素瘤)亞洲患者的臨床研究數據，在68例患者中，ORR為29.4%，其中2例患者為完成反應，18例患者為部分反應，11例為疾病穩定，37例患者為疾病進展，在細分三種臨床亞型中，皮膚黑色素瘤組的ORR為42.9%，黏膜黑色素瘤組的ORR為20.7%，肢端黑色素瘤組的ORR為18.8%，進一步細分轉移性與非轉移性的，皮膚黑色素瘤組的ORR為41.7%，黏膜黑色素瘤組的ORR為17.6%，肢端黑色素瘤組的ORR只有7.7%。不論是否細分轉移性的，肢端黑色素瘤組均展現差的ORR(7.7% Vs 17.6% Vs 41.7%)。故PD-1抗體單藥用於肢端黑色素瘤的治療仍存在諸多不確定性。 T. Maeda et al. ( Br J Dermatol . 2018 Nov 17. doi: 10.1111/bjd.17434) reported that nivolumab in different clinical subtypes of melanoma (eg acral melanoma, mucosal melanoma and cutaneous melanoma) According to the clinical study data of Asian patients, among 68 patients, the ORR was 29.4%, of which 2 patients had completed responses, 18 patients had partial responses, 11 patients had stable disease, and 37 patients had progressive disease. Among the subtypes, the ORR in the cutaneous melanoma group was 42.9%, the ORR in the mucosal melanoma group was 20.7%, and the ORR in the acral melanoma group was 18.8%. The ORR was 41.7%, compared with 17.6% in the mucosal melanoma group and 7.7% in the acral melanoma group. The acral melanoma group exhibited a poor ORR (7.7% vs 17.6% vs 41.7%) regardless of subdivision metastatic. Therefore, there are still many uncertainties in the use of PD-1 antibody monotherapy for the treatment of acral melanoma.

聯合使用一種以上靶點各異又相互關聯的抗腫瘤藥物，充分發揮各組分優勢，既能提高單藥的抗腫瘤活性又可降低藥物毒性，是一種被普遍接受的抗腫瘤療法。 Combining more than one anti-tumor drug with different but related targets can give full play to the advantages of each component, which can not only improve the anti-tumor activity of a single drug but also reduce the drug toxicity. It is a generally accepted anti-tumor therapy.

阿帕替尼是全球首個晚期胃癌的口服抗血管生成藥物，對VEGFR-2具有高度選擇性，強效抗血管生成。在一項關於阿帕替尼二線以後治療轉移性胃/胃食管結合部癌患者的多中心隨機雙盲安慰劑對照Ⅲ期試驗中，結果顯示與安慰劑相比，阿帕替尼單藥能將中位總生存期延長1.8個月，中位無進展生存期延長0.8個月，且不良事件可控。阿帕替尼的結構式如式(I)所示。 Apatinib is the world's first oral anti-angiogenic drug for advanced gastric cancer, which is highly selective for VEGFR-2 and potently anti-angiogenic. In a multicenter, randomized, double-blind, placebo-controlled phase III trial of apatinib in patients with metastatic gastric/gastroesophageal junction cancer after second-line treatment, the results showed that apatinib monotherapy compared with placebo It can prolong the median overall survival by 1.8 months and the median progression-free survival by 0.8 months, and the adverse events are controllable. The structural formula of apatinib is shown in formula (I).

Figure 110112949-A0101-12-0002-1
Figure 110112949-A0101-12-0002-1

目前已有多個PD-1抗體與VEGFR抑制劑(如舒尼替尼，索拉菲尼等)正處於臨床II/III期，適應症分別為惡性肝癌(索拉菲尼與PD-1抗體聯用)和轉移性腎細胞癌(舒尼替尼與PD-1抗體聯用)，初步結果顯示兩種 藥物聯用效果均優於單藥，但PD-1抗體與VEGF抑制劑聯用具有很多不確定性，值得深入研究，同時尚未見VEGFR抑制劑與PD-1抗體聯於治療肢端黑色素瘤的報告。另一方面，PD-1抗體、VEGF抑制劑與烷基化劑如替莫唑胺三藥聯用是否取得更為優異聯合用藥的藥效也是不能確定性，值得深入研究。 At present, a number of PD-1 antibodies and VEGFR inhibitors (such as sunitinib, sorafenib, etc.) are in clinical phase II/III, and the indications are malignant liver cancer (sorafenib and PD-1 antibodies). combination) and metastatic renal cell carcinoma (sunitinib combined with PD-1 antibody), preliminary results show that both The effect of drug combination is better than that of single drug, but the combination of PD-1 antibody and VEGF inhibitor has many uncertainties, which is worthy of further study. Report. On the other hand, it is uncertain whether the combination of PD-1 antibody, VEGF inhibitor and alkylating agent such as temozolomide can achieve better efficacy, and it is worthy of further study.

本揭露(the disclosure)提供了一種抗PD-1抗體和VEGFR抑制劑聯合在製備治療肢端黑色素瘤(黑色素瘤)的藥物中的用途。 The disclosure provides the use of an anti-PD-1 antibody and a VEGFR inhibitor in combination in the preparation of a medicament for the treatment of acral melanoma (melanoma).

PD-1抗體是已知的，在一些可選實施方案中，該抗PD-1抗體或其抗原結合片段選自：AMP-224、GLS-010、IBI-308、REGN-2810、PDR-001、BGB-A317、匹地利珠單抗(Pidilizumab)、PF-06801591、杰諾單抗(Genolimzumab)、CA-170、MEDI-0680、JS-001、TSR-042、西米普利單抗(Cemiplimab)、卡瑞利珠單抗(Camrelizumab)、帕博利珠單抗(Pembrolizumab)、特瑞普利單抗(Toripalimab)、辛迪利單抗(Sintilimab)、替雷利珠單抗(Tislelizumab)、LZM-009、AK-103和納武單抗(Nivolumab)。 PD-1 antibodies are known, and in some alternative embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is selected from the group consisting of: AMP-224, GLS-010, IBI-308, REGN-2810, PDR-001 , BGB-A317, Pidilizumab, PF-06801591, Genolimzumab, CA-170, MEDI-0680, JS-001, TSR-042, Cemiplimab ), Camrelizumab, Pembrolizumab, Toripalimab, Sintilimab, Tislelizumab, LZM-009, AK-103 and Nivolumab.

在一些實施方案中，該PD-1抗體的輕鏈可變區包含分別如SEQ ID NO：4、SEQ ID NO：5和SEQ ID NO：6所示的LCDR1、LCDR2和LCDR3。 In some embodiments, the light chain variable region of the PD-1 antibody comprises LCDR1, LCDR2 and LCDR3 as set forth in SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6, respectively.

該PD-1抗體的重鏈可變區包含分別如SEQ ID NO：1、SEQ ID NO：2和SEQ ID NO：3所示的HCDR1、HCDR2和HCDR3。 The heavy chain variable region of the PD-1 antibody comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively.

在一些實施方案中，該PD-1抗體或抗原結合片段輕/重鏈中CDR序列如下表所示： In some embodiments, the CDR sequences in the light/heavy chain of the PD-1 antibody or antigen-binding fragment are shown in the following table:

Figure 110112949-A0101-12-0004-2
Figure 110112949-A0101-12-0004-2

在可選實施方案中，該PD-1抗體為人源化抗體。 In alternative embodiments, the PD-1 antibody is a humanized antibody.

在一些可選實施方案中，該抗PD-1抗體或其抗原結合片段選自由Fab、Fab’-SH、Fv、scFv、和(Fab’)2片段組成的組的抗體片段。 In some alternative embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is an antibody fragment selected from the group consisting of Fab, Fab'-SH, Fv, scFv, and (Fab')2 fragments.

免疫球蛋白可以來源於任何通常已知的同種型，包括但不限於IgA、分泌型IgA、IgG和IgM。IgG亞類也是本領域技術人員眾所周知的，包括但不限於IgG1、IgG2、IgG3和IgG4。“同種型”是指由重鏈恆定區基因編碼的Ab種類或亞類(例如，IgM或IgG1)。在一些可選實施方案中，本申請中該抗PD-1抗體或其抗原結合片段包含人源IgG1、IgG2、IgG3或IgG4同種型的重鏈恆定區，較佳包含IgG1或IgG4同種型的重鏈恆定區。 Immunoglobulins can be derived from any commonly known isotype, including but not limited to IgA, secretory IgA, IgG, and IgM. IgG subclasses are also well known to those of skill in the art and include, but are not limited to, IgGl, IgG2, IgG3, and IgG4. "Isotype" refers to the class or subclass of Ab encoded by the heavy chain constant region gene (eg, IgM or IgGl). In some alternative embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof in the present application comprises a heavy chain constant region of human IgG1, IgG2, IgG3 or IgG4 isotype, preferably a heavy chain of IgG1 or IgG4 isotype chain constant region.

在另一些可選實施方案中，該抗PD-1抗體或其抗原結合片段包含κ或λ的輕鏈恆定區。 In other alternative embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a kappa or lambda light chain constant region.

在一些實施方案中，該PD-1抗體或其抗原結合片段包含如SEQ ID NO：10所示的輕鏈可變區或其變體，該變體較佳在SEQ ID NO：10所示的輕鏈可變區序列上有0-10的胺基酸變化，更佳A43S的胺基酸變化；和如SEQ ID NO：9所示的重鏈可變區或其變體，該變體較佳在SEQ ID NO：9所示的重鏈可變區序列上有0-10的胺基酸變化，更佳G44R的胺基酸變化。 In some embodiments, the PD-1 antibody or antigen-binding fragment thereof comprises a light chain variable region as set forth in SEQ ID NO: 10 or a variant thereof, preferably the variant as set forth in SEQ ID NO: 10 There are 0-10 amino acid changes in the light chain variable region sequence, more preferably A43S amino acid changes; and the heavy chain variable region as shown in SEQ ID NO: 9 or a variant thereof, the variant is more Preferably, there are 0-10 amino acid changes in the heavy chain variable region sequence shown in SEQ ID NO: 9, more preferably G44R amino acid changes.

前述PD-1抗體或其抗原結合片段重、輕鏈的可變區序列如下所示： The variable region sequences of the heavy and light chains of the aforementioned PD-1 antibody or its antigen-binding fragment are as follows:

重鏈可變區

Figure 110112949-A0101-12-0005-4
heavy chain variable region
Figure 110112949-A0101-12-0005-4

SEQID NO：9 SEQ ID NO: 9

輕鏈可變區DIQMTQSPSSLSASVGDRVTITCLASQTIGTWLTWYQQKPGKAPKLLIYTATSLADGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQVYSIPWTFGGGTKVEIK light chain variable region DIQMTQSPSSLSASVGDRVTITCLASQTIGTWLTWYQQKPGKAPKLLIYTATSLADGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQVYSIPWTFGGGTKVEIK

SEQID NO：10 SEQ ID NO: 10

在可選實施方案中，該人源化抗體輕鏈序列為如SEQ ID NO：8所示的序列或其變體；該變體較佳在輕鏈可變區有0-10的胺基酸變化；更佳為A43S的胺基酸變化。該人源化抗體重鏈序列為如SEQ ID NO：7所示的序列或其變體；該變體較佳在重鏈可變區有0-10的胺基酸變化；更佳為G44R的胺基酸變化。 In an alternative embodiment, the humanized antibody light chain sequence is the sequence shown in SEQ ID NO: 8 or a variant thereof; the variant preferably has 0-10 amino acids in the light chain variable region change; more preferably amino acid change of A43S. The heavy chain sequence of the humanized antibody is the sequence shown in SEQ ID NO: 7 or a variant thereof; the variant preferably has 0-10 amino acid changes in the variable region of the heavy chain; more preferably G44R Amino acid changes.

在一些實施方案中，該人源化抗體的輕鏈序列為如SEQ ID NO：8所示的序列，重鏈序列為如SEQ ID NO：7所示的序列。 In some embodiments, the light chain sequence of the humanized antibody is the sequence set forth in SEQ ID NO:8 and the heavy chain sequence is the sequence set forth in SEQ ID NO:7.

該人源化抗體重、輕鏈的序列如下所示： The sequences of the humanized antibody heavy and light chains are as follows:

重鏈

Figure 110112949-A0101-12-0005-3
Figure 110112949-A0101-12-0006-5
heavy chain
Figure 110112949-A0101-12-0005-3
Figure 110112949-A0101-12-0006-5

SEQID NO：7 SEQ ID NO: 7

輕鏈

Figure 110112949-A0101-12-0006-6
light chain
Figure 110112949-A0101-12-0006-6

SEQID NO：8 SEQ ID NO: 8

另一方面，PD-1(programmed death 1)，即程序性死亡受體1，是一種重要的免疫抑制分子。當PD-1的開關打開，就會啟動一系列反應，抑制T細胞活性。腫瘤細胞借助PD-L1與T細胞的PD-1結合，“欺騙”T細胞，逃避T細胞的識別，繼續在體內橫行霸道。而PD-L1/PD-1抗體則可以幫助T細胞揭開腫瘤細胞偽善的面紗，恢復其對腫瘤細胞識別和殺傷。在一些可選聯用實施方案中，該抗PD-1抗體或其抗原結合片段為Cemiplimab。在一些可選聯用實施方案中，該抗PD-1抗體或其抗原結合片段為Toripalimab。在一些可選聯用實施方案中，該抗PD-1抗體或其抗原結合片段為Sintilimab。在一些可選聯用實施方案中，該抗PD-1抗體或其抗原結合片段為Tislelizumab。 On the other hand, PD-1 (programmed death 1), the programmed death receptor 1, is an important immunosuppressive molecule. When the switch of PD-1 is turned on, it initiates a series of responses that inhibit T cell activity. Tumor cells use PD-L1 to combine with PD-1 of T cells, "trick" T cells, evade the recognition of T cells, and continue to run rampant in the body. The PD-L1/PD-1 antibody can help T cells uncover the hypocrisy of tumor cells and restore their recognition and killing of tumor cells. In some alternative combination embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is cemiplimab. In some alternative combination embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is Toripalimab. In some alternative combination embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is sintilimab. In some optional combination embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is Tislelizumab.

Figure 110112949-A0101-12-0007-7
Figure 110112949-A0101-12-0007-7

另一方面，在一些實施方案中，其中該VEGFR抑制劑是VEGFR-2抑制劑。 In another aspect, in some embodiments, wherein the VEGFR inhibitor is a VEGFR-2 inhibitor.

在一些實施方案中，其中該VEGFR抑制劑選自阿帕替尼、安羅替尼、他菲替尼、法米替尼、索拉非尼或其可藥用鹽，較佳阿帕替尼或其可藥用鹽。 In some embodiments, wherein the VEGFR inhibitor is selected from apatinib, anlotinib, tavitinib, famitinib, sorafenib or a pharmaceutically acceptable salt thereof, preferably apatinib or a pharmaceutically acceptable salt thereof.

本揭露所述可藥用鹽選自甲磺酸鹽、馬來酸鹽、酒石酸鹽、琥珀酸鹽、醋酸鹽、二氟醋酸鹽、富馬酸鹽、檸檬酸鹽、枸櫞酸鹽、苯磺酸鹽、苯甲酸鹽、萘磺酸鹽、乳酸鹽、蘋果酸鹽、鹽酸鹽、氫溴酸鹽、硫酸鹽、以及磷酸鹽。在一些實施方案中，該阿帕替尼可藥用鹽選自甲磺酸鹽。在一些實施方案中，該安羅替尼可藥用鹽選自鹽酸。本揭露所述聯合抗PD-1抗體和VEGFR抑制劑具有協同藥效作用。 The pharmaceutically acceptable salt of the present disclosure is selected from the group consisting of mesylate, maleate, tartrate, succinate, acetate, difluoroacetate, fumarate, citrate, citrate, benzene Sulfonate, benzoate, naphthalene sulfonate, lactate, malate, hydrochloride, hydrobromide, sulfate, and phosphate. In some embodiments, the pharmaceutically acceptable salt of apatinib is selected from mesylate. In some embodiments, the pharmaceutically acceptable salt of anlotinib is selected from hydrochloric acid. The combined anti-PD-1 antibody and VEGFR inhibitor described in the present disclosure have synergistic pharmacodynamic effects.

進一步地，本揭露中所述患者選自復發的，不能手術切除的或轉移性的。 Further, the patients described in this disclosure are selected from recurrent, unresectable or metastatic.

在一些實施方案中，該復發的為手術後復發的。 In some embodiments, the recurrence is postoperative recurrence.

在可選實施方案中，該患者選自手術後復發的 In alternative embodiments, the patient is selected from postoperative recurrence

在可選實施方案中，該患者選自不能手術切除的。 In an alternative embodiment, the patient is selected from inoperable.

另一方面，前述抗PD-1抗體與VEGFR抑制劑方案中還進一步包含烷基化劑。 On the other hand, the aforementioned anti-PD-1 antibody and VEGFR inhibitor regimen further includes an alkylating agent.

在一些實施方案中，該用途還進一步包括替莫唑胺或其可藥用鹽。 In some embodiments, the use further comprises temozolomide or a pharmaceutically acceptable salt thereof.

在一些實施方案中，該抗PD-1抗體或其抗原結合片段在人類受試者中的施用劑量(按患者體重給藥)選自0.1mg/kg、0.2mg/kg、0.3mg/kg、0.4mg/kg、0.5mg/kg、0.6mg/kg、0.7mg/kg、0.8mg/kg、0.9mg/kg、1.0mg/kg、1.2mg/kg、1.4mg/kg、1.6mg/kg、1.8mg/kg、2.0mg/kg、2.2mg/kg、2.4mg/kg、2.6mg/kg、2.8mg/kg、3.0mg/kg、3.2mg/kg、3.4mg/kg、3.6mg/kg、3.8mg/kg、4.0mg/kg、4.2mg/kg、4.4mg/kg、4.6mg/kg、4.8mg/kg、5.0mg/kg、5.2mg/kg、5.4mg/kg、5.6mg/kg、5.8mg/kg、6.0mg/kg、6.2mg/kg、6.4mg/kg、6.6mg/kg、6.8mg/kg、7.0mg/kg、7.2mg/kg、7.4mg/kg、7.6mg/kg、7.8mg/kg、8.0mg/kg、8.2mg/kg、8.4mg/kg、8.6mg/kg、8.8mg/kg、9.0mg/kg、9.2mg/kg、9.4mg/kg、9.6mg/kg、9.8mg/kg、10.0mg/kg或任意兩數值間任意值，較佳3mg/kg。 In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered in a dose (by patient weight) in a human subject selected from the group consisting of 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4mg/kg, 0.5mg/kg, 0.6mg/kg, 0.7mg/kg, 0.8mg/kg, 0.9mg/kg, 1.0mg/kg, 1.2mg/kg, 1.4mg/kg, 1.6mg/kg, 1.8mg/kg, 2.0mg/kg, 2.2mg/kg, 2.4mg/kg, 2.6mg/kg, 2.8mg/kg, 3.0mg/kg, 3.2mg/kg, 3.4mg/kg, 3.6mg/kg, 3.8mg/kg, 4.0mg/kg, 4.2mg/kg, 4.4mg/kg, 4.6mg/kg, 4.8mg/kg, 5.0mg/kg, 5.2mg/kg, 5.4mg/kg, 5.6mg/kg, 5.8mg/kg, 6.0mg/kg, 6.2mg/kg, 6.4mg/kg, 6.6mg/kg, 6.8mg/kg, 7.0mg/kg, 7.2mg/kg, 7.4mg/kg, 7.6mg/kg, 7.8mg/kg, 8.0mg/kg, 8.2mg/kg, 8.4mg/kg, 8.6mg/kg, 8.8mg/kg, 9.0mg/kg, 9.2mg/kg, 9.4mg/kg, 9.6mg/kg, 9.8mg/kg, 10.0mg/kg or any value between any two values, preferably 3mg/kg.

在另一選實施方案中，該PD-1抗體或其抗原結合片段在人類受試者中的施用劑量為1~600mg，較佳1.0mg、1.2mg、1.4mg、1.6mg、1.8mg、2.0mg、2.2mg、2.4mg、2.6mg、2.8mg、3.0mg、3.2mg、3.4mg、3.6mg、3.8mg、4.0mg、4.2mg、4.4mg、4.6mg、4.8mg、5.0mg、5.2mg、5.4mg、5.6mg、5.8mg、6.0mg、6.2mg、6.4mg、6.6mg、6.8mg、7.0mg、7.2mg、7.4mg、7.6mg、7.8mg、8.0mg、8.2mg、8.4mg、8.6mg、8.8mg、9.0mg、9.2mg、9.4mg、9.6mg、9.8mg、10.0mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、105mg、110mg、115mg、120mg、125mg、130mg、135mg、140mg、145mg、150mg、155mg、160mg、165mg、170mg、175mg、180mg、185mg、190mg、195mg、200mg、205mg、210mg、215mg、220mg、225mg、230mg、235mg、 240mg、245mg、250mg、255mg、260mg、265mg、270mg、275mg、280mg、285mg、290mg、295mg、300mg、305mg、310mg、315mg、320mg、325mg、330mg、335mg、340mg、345mg、350mg、355mg、360mg、365mg、370mg、375mg、380mg、385mg、390mg、395mg、400mg、405mg、410mg、415mg、420mg、425mg、430mg、435mg、440mg、445mg、450mg、455mg、460mg、465mg、470mg、475mg、480mg、485mg、490mg、495mg、500mg、505mg、510mg、515mg、520mg、525mg、530mg、535mg、540mg、545mg、550mg、555mg、560mg、565mg、570mg、575mg、580mg、585mg、590mg、595mg、600mg或任意兩數值間任意值，較佳200mg。 In another embodiment, the dose of the PD-1 antibody or its antigen-binding fragment in a human subject is 1-600 mg, preferably 1.0 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, 2.0 mg mg, 2.2mg, 2.4mg, 2.6mg, 2.8mg, 3.0mg, 3.2mg, 3.4mg, 3.6mg, 3.8mg, 4.0mg, 4.2mg, 4.4mg, 4.6mg, 4.8mg, 5.0mg, 5.2mg, 5.4mg, 5.6mg, 5.8mg, 6.0mg, 6.2mg, 6.4mg, 6.6mg, 6.8mg, 7.0mg, 7.2mg, 7.4mg, 7.6mg, 7.8mg, 8.0mg, 8.2mg, 8.4mg, 8.6mg , 8.8mg, 9.0mg, 9.2mg, 9.4mg, 9.6mg, 9.8mg, 10.0mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, 300mg, 305mg, 310mg, 315mg, 320mg, 325mg, 330mg, 335mg, 340mg, 345mg, 350mg, 355mg, 360mg 365mg, 370mg, 375mg, 380mg, 385mg, 390mg, 395mg, 400mg, 405mg, 410mg, 415mg, 420mg, 425mg, 430mg, 435mg, 440mg, 445mg, 450mg, 455mg, 460mg, 465mg, 470mg, 475mg, 480mg, 485mg 490mg, 495mg, 500mg, 505mg, 510mg, 515mg, 520mg, 525mg, 530mg, 535mg, 540mg, 545mg, 550mg, 555mg, 560mg, 565mg, 570mg, 575mg, 580mg, 585mg, 590mg, 595mg, 600mg or any two values in between Any value, preferably 200 mg.

本揭露所述抗PD-1抗體或其抗原結合片段的給藥頻為一天一次、兩天一次、三天一次、四天一次、五天一次、六天一次、一週一次、二週一次、三週一次、四週一次或一月一次。 The administration frequency of the anti-PD-1 antibody or its antigen-binding fragment described in the present disclosure is once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, and once every three days. Once a week, every four weeks, or once a month.

在一些實施方案中，本揭露所述抗PD-1抗體或其抗原結合片段在人類受試者中的施用劑量為50~600mg/2-3週一次，更佳為200mg/2-3週一次。 In some embodiments, the administration dose of the anti-PD-1 antibody or antigen-binding fragment thereof of the present disclosure in a human subject is 50-600 mg/2-3 weeks, more preferably 200 mg/2-3 weeks .

在另一些實施方案中，該VEGFR抑制劑如阿帕替尼或其可藥用鹽在人類受試者中的施用劑量選自0.1-500mg，可以為0.1mg、0.25mg、0.5mg、0.75mg、1mg、2mg、3mg、4mg、5mg、6mg、7mg、8mg、9mg、10mg、11mg、12mg、12.5mg、15mg、17.5mg、20mg、22.5mg、25mg、30mg、45mg、50mg、60mg、70mg、75mg、80mg、90mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、275mg、300mg、375mg、400mg、500mg，更佳0.25mg、0.5mg、1mg、2mg、3mg、4mg、10mg、15mg、20mg、30mg、45mg、50mg、60mg、75mg、100mg、125mg、150mg、175mg、225mg、250mg、275mg、300mg、325mg、350mg、375mg、400mg、425mg、450mg、475mg、500mg或任意兩數值間任意值，較佳250mg或375mg。 In other embodiments, the administration dose of the VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof in a human subject is selected from 0.1-500 mg, and can be 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg , 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 12.5mg, 15mg, 17.5mg, 20mg, 22.5mg, 25mg, 30mg, 45mg, 50mg, 60mg, 70mg, 75mg, 80mg, 90mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 375mg, 400mg, 500mg, more preferably 0.25mg, 0.5mg, 1mg, 2mg, 3mg, 4mg, 10mg, 15mg, 20mg, 30mg, 45mg, 50mg, 60mg, 75mg, 100mg, 125mg, 150mg, 175mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg or any value in between , preferably 250mg or 375mg.

本揭露所述的用途，該VEGFR抑制劑如阿帕替尼的給藥頻率為一天一次，兩天一次，三天一次，四天一次，五天一次，六天一次，一週一次，每週給藥三天、一天一次，每週給藥四天、一天一次，每週給藥五天、一天一次。 For the purposes described in the present disclosure, the administration frequency of the VEGFR inhibitor such as apatinib is once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, and once a week. Three days, once a day, four days a week, once a day, five days a week, once a day.

在一些實施方案中，該PD-1抗體或其抗原結合片段在人類受試者中的施用劑量選自60至600mg，靜脈輸注，每一至三週一次；VEGFR抑制劑如甲磺酸阿帕替尼在人類受試者中的施用劑量選自250mg至500mg，口服，每一到兩日一次。 In some embodiments, the PD-1 antibody or antigen-binding fragment thereof is administered in a human subject at a dose selected from 60 to 600 mg, intravenous infusion, once every to three weeks; a VEGFR inhibitor such as apatibate mesylate The doses of nisin administered in human subjects are selected from 250 mg to 500 mg, orally, once every to two days.

在一些實施方案中，該PD-1抗體或其抗原結合片段在人類受試者中的施用劑量選自1-5mg/kg，靜脈輸注，每一至三週一次；VEGFR抑制劑如甲磺酸阿帕替尼在人類受試者中的施用劑量選自250mg至500mg，口服，每一到兩日一次。 In some embodiments, the PD-1 antibody or antigen-binding fragment thereof is administered in a human subject at a dose selected from 1-5 mg/kg, intravenous infusion, once every to three weeks; a VEGFR inhibitor such as Patinib is administered in a human subject at a dose selected from 250 mg to 500 mg orally once every to two days.

在一些實施方案中，該PD-1抗體或其抗原結合片段在人類受試者中的施用劑量選自200mg，靜脈輸注，每兩週一次；VEGFR抑制劑如甲磺酸阿帕替尼在人類受試者中的施用劑量選自250mg，口服，每日一次。 In some embodiments, the PD-1 antibody or antigen-binding fragment thereof is administered in a human subject at a dose selected from 200 mg, intravenous infusion, once every two weeks; a VEGFR inhibitor such as apatinib mesylate in humans The administered dose in the subject is selected from 250 mg orally once daily.

在一些實施方案中，該PD-1抗體或其抗原結合片段在人類受試者中的施用劑量選自3mg/kg，靜脈輸注，每兩週一次；VEGFR抑制劑如甲磺酸阿帕替尼在人類受試者中的施用劑量選自250mg，口服，每日一次。 In some embodiments, the PD-1 antibody or antigen-binding fragment thereof is administered in a human subject at a dose selected from 3 mg/kg, intravenous infusion, once every two weeks; a VEGFR inhibitor such as apatinib mesylate The dose administered in human subjects is selected from 250 mg orally once daily.

在一些實施方案中，該PD-1抗體或其抗原結合片段在人類受試者中的施用劑量選自200mg，靜脈輸注，每兩週一次；VEGFR抑制劑如甲磺酸阿帕替尼在人類受試者中的施用劑量選自375mg，口服，每日一次。 In some embodiments, the PD-1 antibody or antigen-binding fragment thereof is administered in a human subject at a dose selected from 200 mg, intravenous infusion, once every two weeks; a VEGFR inhibitor such as apatinib mesylate in humans The administered dose in the subject is selected from 375 mg orally once daily.

進一步地，本揭露所述VEGFR抑制劑為餐後用藥，譬如餐後30分鐘內服藥。 Further, the VEGFR inhibitor described in the present disclosure is administered after meals, for example, within 30 minutes after meals.

另一方面，在另一選實施方案中，該烷基化劑如替莫唑胺在人類受試者中的施用劑量(按體表面積給藥)選自50mg/m2~300mg/m2，包括50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、105mg、110mg、115mg、120mg、125mg、130mg、135mg、140mg、145mg、150mg、155mg、160mg、165mg、170mg、175mg、180mg、185mg、190mg、195mg、200mg、205mg、210mg、215mg、220mg、225mg、230mg、235mg、240mg、245mg、250mg、255mg、260mg、265mg、270mg、275mg、280mg、285mg、290mg、295mg、300mg或任意兩數值間任意值，較佳150mg/m2或200mg/m2。 On the other hand, in another optional embodiment, the administered dose of the alkylating agent such as temozolomide in a human subject (administered by body surface area) is selected from 50 mg/m 2 to 300 mg/m 2 , including 50 mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, 300mg or Any value between any two values, preferably 150 mg/m 2 or 200 mg/m 2 .

本揭露所述烷基化劑如替莫唑胺給藥頻為一天一次、兩天一次、三天一次、四天一次、五天一次、六天一次、一週一次、二週一次、三週一次、四週一次或一月一次。 The alkylating agent of the present disclosure, such as temozolomide, is administered at a frequency of once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, once every three weeks, and once every four weeks or once a month.

在一些實施方案中，該烷基化劑如替莫唑胺在人類受試者中的施用劑量選自150mg/m2或200mg/m2，口服，每日一次。 In some embodiments, such as for the alkylating agent temozolomide administered at a dose in a human subject selected from 150mg / m 2 or 200mg / m 2, orally, once daily.

在一些實施方案中，該烷基化劑如替莫唑胺在人類受試者中的施用劑量選自150mg/m2或200mg/m2，口服，每日一次，共5天。 In some embodiments, the alkylating agent such as temozolomide is administered in a human subject at a dose selected from 150 mg/m 2 or 200 mg/m 2 orally once daily for 5 days.

在一些實施方案中，該烷基化劑如替莫唑胺在人類受試者中的施用劑量選自150mg/m2或200mg/m2，口服，每日一次，共5天，然後停藥23天。 In some embodiments, the alkylating agent such as temozolomide is administered in a human subject at a dose selected from 150 mg/m 2 or 200 mg/m 2 orally once daily for 5 days followed by 23 days off.

在另一些實施方案中，其中該PD-1抗體或其抗原結合片段在人類受試者中的施用劑量選自60至600mg，靜脈輸注，每一至三週一次；VEGFR抑制劑如甲磺酸阿帕替尼在人類受試者中的施用劑量選自250mg至500mg，口服，每一到兩日一次；該烷基化劑如替莫唑胺在人類受試者中的施用劑量選自150mg/m2或200mg/m2，口服，每日一次。 In other embodiments, wherein the PD-1 antibody or antigen-binding fragment thereof is administered in a human subject at a dose selected from 60 to 600 mg, intravenous infusion, once every to three weeks; a VEGFR inhibitor such as Pa erlotinib in human subjects administered dose is selected from 250mg to 500mg, orally, once every one to two days; the alkylating agent temozolomide is administered as a dose in a human subject selected from 150mg / m 2 or 200mg/m 2 , orally, once a day.

在另一些實施方案中，其中該PD-1抗體或其抗原結合片段在人類受試者中的施用劑量選自200mg，靜脈輸注，每兩週一次；VEGFR抑制劑如甲 磺酸阿帕替尼在人類受試者中的施用劑量選自250mg，口服，每日一次；該烷基化劑如替莫唑胺在人類受試者中的施用劑量選自200mg/m2，口服，每日一次，共5天。 In other embodiments, wherein the PD-1 antibody or antigen-binding fragment thereof is administered in a human subject at a dose selected from 200 mg, intravenous infusion, once every two weeks; a VEGFR inhibitor such as apatinib mesylate administered dose in human subjects selected 250mg, orally, once daily; as for the alkylating agent temozolomide administered at a dose in a human subject selected from 200mg / m 2, administered orally, once a day 5 sky.

本揭露另一方面還提供一種抗PD-1抗體、VEGFR抑制劑聯合替莫唑胺或其可藥用鹽在製備治療黑色素瘤的藥物中的用途。 Another aspect of the present disclosure also provides the use of an anti-PD-1 antibody, a VEGFR inhibitor combined with temozolomide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating melanoma.

在一些實施方案中，其中該PD-1抗體或其抗原結合片段在人類受試者中的施用劑量選自60至600mg；VEGFR抑制劑如甲磺酸阿帕替尼在人類受試者中的施用劑量選自0.1mg至500mg；該烷基化劑如替莫唑胺在人類受試者中的施用劑量選自50mg/m2至200mg/m2。 In some embodiments, wherein the PD-1 antibody or antigen-binding fragment thereof is administered in a dose of 60 to 600 mg in a human subject; VEGFR inhibitor such as apatinib mesylate in a human subject The administered dose is selected from 0.1 mg to 500 mg; the administered dose of the alkylating agent such as temozolomide in a human subject is selected from 50 mg/m 2 to 200 mg/m 2 .

在另一些實施方案中，其中該PD-1抗體或其抗原結合片段在人類受試者中的施用劑量選自60至600mg，靜脈輸注，每一至三週一次；VEGFR抑制劑如甲磺酸阿帕替尼在人類受試者中的施用劑量選自0.1至500mg，口服，每一到兩日一次；該烷基化劑如替莫唑胺在人類受試者中的施用劑量選自50mg/m2至200mg/m2，口服，每日一次。 In other embodiments, wherein the PD-1 antibody or antigen-binding fragment thereof is administered in a human subject at a dose selected from 60 to 600 mg, intravenous infusion, once every to three weeks; a VEGFR inhibitor such as Pa erlotinib in human subjects administered dose is selected from 0.1 to 500mg, orally, once every one to two days; administered as the alkylating agent temozolomide in human subjects selected dose 50mg / m 2 to 200mg/m 2 , orally, once a day.

在另一些實施方案中，其中該PD-1抗體或其抗原結合片段在人類受試者中的施用劑量選自200mg，靜脈輸注，每兩週一次；VEGFR抑制劑如甲磺酸阿帕替尼在人類受試者中的施用劑量選自250mg，口服，每日一次；該烷基化劑如替莫唑胺在人類受試者中的施用劑量選自200mg/m2，口服，每日一次，共5天。 In other embodiments, wherein the PD-1 antibody or antigen-binding fragment thereof is administered in a human subject at a dose selected from 200 mg, intravenous infusion, once every two weeks; a VEGFR inhibitor such as apatinib mesylate administered dose in human subjects selected 250mg, orally, once daily; as for the alkylating agent temozolomide administered at a dose in a human subject selected from 200mg / m 2, administered orally, once a day 5 sky.

本揭露還提供了一種抗PD-1抗體和VEGFR抑制劑如阿帕替尼或其可藥用鹽聯合在製備治療黏膜黑色素瘤(黏膜型黑色素瘤)的藥物中的用途，還進一步包含烷基化劑，該烷基化劑較佳替莫唑胺或其可藥用鹽。 The present disclosure also provides the use of an anti-PD-1 antibody in combination with a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of mucosal melanoma (mucosal melanoma), further comprising an alkyl group The alkylating agent is preferably temozolomide or a pharmaceutically acceptable salt thereof.

本揭露提供上述抗PD-1抗體聯合VEGFR抑制劑如阿帕替尼或其可藥用鹽作為治療製備治療肢端黑色素瘤的藥物，還進一步包含烷基化劑，該烷基化劑較佳替莫唑胺或其可藥用鹽。 The present disclosure provides the above-mentioned anti-PD-1 antibody in combination with a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof as a treatment for preparing a drug for the treatment of acral melanoma, further comprising an alkylating agent, and the alkylating agent is preferably Temozolomide or a pharmaceutically acceptable salt thereof.

本揭露還提供一種用於治療黑色素瘤(如肢端黑色素瘤)的抗PD-1抗體，其中抗PD-1抗體與VEGFR抑制劑組合施用。在一些實施方案中，其中還包括烷基化劑，該烷基化劑較佳替莫唑胺或其可藥用鹽。 The present disclosure also provides an anti-PD-1 antibody for the treatment of melanoma, such as acral melanoma, wherein the anti-PD-1 antibody is administered in combination with a VEGFR inhibitor. In some embodiments, an alkylating agent is also included, preferably temozolomide or a pharmaceutically acceptable salt thereof.

另外，本揭露還提供一種用於治療黑色素瘤(如肢端黑色素瘤)的VEGFR抑制劑，其中VEGFR抑制劑與抗PD-1抗體組合施用。在一些實施方案中，其中還包括烷基化劑，該烷基化劑較佳替莫唑胺或其可藥用鹽。 In addition, the present disclosure also provides a VEGFR inhibitor for the treatment of melanoma (eg, acral melanoma), wherein the VEGFR inhibitor is administered in combination with an anti-PD-1 antibody. In some embodiments, an alkylating agent is also included, preferably temozolomide or a pharmaceutically acceptable salt thereof.

本揭露還提供一種用於治療黑色素瘤(如肢端黑色素瘤)的烷基化抑制劑如替莫唑胺或其可藥用鹽，其中該烷基化抑制劑與抗PD-1抗體和VEGFR抑制劑組合施用。本揭露提供上述抗PD-1抗體聯合VEGFR抑制劑如阿帕替尼或其可藥用鹽作為減少藥物不良反應的藥物。在一些實施方案中，該藥物不良反應選自由抗PD-1抗體引起或由VEGFR抑制劑如阿帕替尼或其可藥用鹽引起。 The present disclosure also provides an alkylation inhibitor such as temozolomide or a pharmaceutically acceptable salt thereof for treating melanoma (eg, acral melanoma), wherein the alkylation inhibitor is combined with an anti-PD-1 antibody and a VEGFR inhibitor apply. The present disclosure provides the above-mentioned anti-PD-1 antibody in combination with a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof as a drug for reducing adverse drug reactions. In some embodiments, the adverse drug reaction is selected from an anti-PD-1 antibody or a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof.

另一方面，本揭露提供上述抗PD-1抗體、VEGFR抑制劑如阿帕替尼或其可藥用鹽聯合替莫唑胺或其可藥用鹽作為減少藥物不良反應的藥物。在一些實施方案中，該藥物不良反應選自由抗PD-1抗體引起或由VEGFR抑制劑如阿帕替尼或其可藥用鹽，或者由替莫唑胺或其可藥用鹽引起。 In another aspect, the present disclosure provides the above-mentioned anti-PD-1 antibody, VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof in combination with temozolomide or a pharmaceutically acceptable salt thereof as a drug for reducing adverse drug reactions. In some embodiments, the adverse drug reaction is selected from an anti-PD-1 antibody or a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof, or temozolomide or a pharmaceutically acceptable salt thereof.

本揭露提供上述抗PD-1抗體聯合VEGFR抑制劑如阿帕替尼或其可藥用鹽作為降低抗PD-1抗體單獨施用劑量和/或VEGFR抑制劑如阿帕替尼或其可藥用鹽單獨施用劑量的藥物。 The present disclosure provides the above-mentioned anti-PD-1 antibody in combination with a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof as a dose reduction for the single administration of the anti-PD-1 antibody and/or a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof The salt is administered alone in doses of the drug.

本揭露提供了一種治療肢端黑色素瘤的辦法，包括向患者施用有效量的上述抗PD-1抗體和VEGFR抑制劑如阿帕替尼或其可藥用鹽，還進一步向患者施用有效劑量的烷基化劑如替莫唑胺或其可藥用鹽。 The present disclosure provides a method for treating acral melanoma, comprising administering to a patient an effective amount of the above anti-PD-1 antibody and a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof, and further administering to the patient an effective amount of an anti-PD-1 antibody and a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof Alkylating agents such as temozolomide or a pharmaceutically acceptable salt thereof.

本揭露還提供一種用於治療治療肢端黑色素瘤的組合。在一些實施方案中，該組合中含有抗PD-1抗體和VEGFR抑制劑如阿帕替尼或其可藥用鹽的。在另一些實施方案中，前述組合還包含烷基化劑如替莫唑胺或其可藥用鹽。 The present disclosure also provides a combination for the treatment of acral melanoma. In some embodiments, the combination comprises an anti-PD-1 antibody and a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof. In other embodiments, the aforementioned combinations further comprise an alkylating agent such as temozolomide or a pharmaceutically acceptable salt thereof.

另一方面，本揭露還提供一種用於治療黑色素瘤的、含有抗PD-1抗體、VEGFR抑制劑如阿帕替尼或其可藥用鹽的和烷基化劑如替莫唑胺或其可藥用鹽的組合。該組合中含有有效劑量的抗PD-1抗體、VEGFR抑制劑或烷基化劑。在一些實施方案中，黑色素瘤包括黏膜型黑色素瘤或肢端黑色素瘤。 In another aspect, the present disclosure also provides an anti-PD-1 antibody, a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof, and an alkylating agent such as temozolomide or a pharmaceutically acceptable salt thereof for the treatment of melanoma A combination of salt. The combination contains an effective dose of an anti-PD-1 antibody, a VEGFR inhibitor or an alkylating agent. In some embodiments, the melanoma comprises mucosal melanoma or acral melanoma.

本揭露還提供了一種降低抗PD-1抗體單獨施用劑量和/或VEGFR抑制劑如阿帕替尼或其可藥用鹽單獨施用劑量的方法，包括向患者施用上述抗PD-1抗體聯合VEGFR抑制劑如阿帕替尼或其可藥用鹽，還進一步向患者施用有效劑量的烷基化劑，該烷基化劑較佳替莫唑胺或其可藥用鹽。 The present disclosure also provides a method for reducing the dose of an anti-PD-1 antibody administered alone and/or a dose of a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof alone, comprising administering the above-mentioned anti-PD-1 antibody in combination with VEGFR to a patient Inhibitors such as apatinib or a pharmaceutically acceptable salt thereof, are further administered to the patient an effective dose of an alkylating agent, preferably temozolomide or a pharmaceutically acceptable salt thereof.

在一些實施方案中，與PD-1聯合使用時，該VEGFR抑制劑如阿帕替尼或其可藥用鹽的給藥劑量是其單獨施用劑量的10%~100%，較佳10%~75%，更佳75%、50%、25%、12.5%。在一些實施方案中，與PD-1聯合使用時，該烷基化劑如替莫唑胺或其可藥用鹽的給藥劑量是其單獨施用劑量的10%~100%，較佳10%~75%，更佳75%、50%、25%、12.5%。 In some embodiments, when used in combination with PD-1, the dose of the VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof is 10%-100% of the dose administered alone, preferably 10%-100% 75%, better 75%, 50%, 25%, 12.5%. In some embodiments, when used in combination with PD-1, the alkylating agent such as temozolomide or a pharmaceutically acceptable salt thereof is administered at a dose of 10% to 100%, preferably 10% to 75% of the dose administered alone , better 75%, 50%, 25%, 12.5%.

在一些實施方案中，與VEGFR抑制劑如阿帕替尼或其可藥用鹽聯用時，抗PD-1抗體劑量是抗PD-1抗體單獨施用劑量的10%~100%，較佳10%~50%。在一些實施方案中，與VEGFR抑制劑聯合使用時，該烷基化劑如替莫唑胺或其可藥用鹽的給藥劑量是其單獨施用劑量的10%~100%，較佳10%~75%，更佳75%、50%、25%、12.5%。 In some embodiments, when used in combination with a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof, the dose of anti-PD-1 antibody is 10% to 100% of the dose of anti-PD-1 antibody administered alone, preferably 10% %~50%. In some embodiments, when used in combination with a VEGFR inhibitor, the alkylating agent such as temozolomide or a pharmaceutically acceptable salt thereof is administered at a dose of 10% to 100%, preferably 10% to 75% of the dose administered alone , better 75%, 50%, 25%, 12.5%.

在本揭露實施方案中，當PD-1抗體與VEGFR抑制劑如阿帕替尼或其可藥用鹽或/和烷基化劑如替莫唑胺或其可藥用鹽聯合使用時，可減少由抗PD-1抗體和/或免疫介導的藥物不良反應；較佳地，該不良反應選自血管相關不良反應、腺體機能減退、皮膚不良反應、呼吸系統不良反應、肝臟相關不良反應、內分泌相關不良反應、消化系統不良反應、腎臟相關不良反應、疲勞、發熱；該較佳血管相關不良反應選自血管瘤、血管炎、***瘤、該腺體功能減退選自甲狀腺機能減退、甲狀旁腺功能減退、胰腺功能減退、***功能減退；該皮膚不良反應選自搔癢症、蕁麻疹、皮疹、毒性表皮壞死症；該呼吸系統不良反應選自肺炎、支氣管炎、慢性阻塞性肺病、肺纖維化；該肝臟相關不良反應選自肝炎、肝功能異常；該內分泌相關不良反應選自I型糖尿病、II型糖尿病、低血糖症；腎臟相關不良反應選自腎炎、腎衰竭；該消化系統不良反應選自腹瀉、噁心、嘔吐、腸炎、便秘；更佳的，該藥物不良反應選自血管瘤、甲狀腺機能減退、甲狀旁腺功能減退、搔癢症、肺炎、肝炎、肝功能異常、I型糖尿病、腎炎、腎衰竭。 In an embodiment of the present disclosure, when the PD-1 antibody is used in combination with a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof or/and an alkylating agent such as temozolomide or a pharmaceutically acceptable salt thereof, the reduction of the anti-PD-1 antibody PD-1 antibody and/or immune-mediated adverse drug reactions; preferably, the adverse reactions are selected from vascular-related adverse reactions, hypogonadism, skin adverse reactions, respiratory system adverse reactions, liver-related adverse reactions, and endocrine-related adverse reactions Adverse reactions, digestive system adverse reactions, kidney-related adverse reactions, fatigue, fever; the preferred vascular-related adverse reactions are selected from hemangioma, vasculitis, lymphangioma, and the hypothyroidism is selected from hypothyroidism, parathyroidism Adrenal insufficiency, pancreatic insufficiency, and prostate insufficiency; the skin adverse reactions are selected from pruritus, urticaria, rash, and toxic epidermal necrosis; the respiratory system adverse reactions are selected from pneumonia, bronchitis, chronic obstructive pulmonary disease, and pulmonary fibrosis The liver-related adverse reactions are selected from hepatitis and abnormal liver function; the endocrine-related adverse reactions are selected from type I diabetes, type II diabetes, and hypoglycemia; the kidney-related adverse reactions are selected from nephritis and renal failure; the digestive system adverse reactions Selected from diarrhea, nausea, vomiting, enteritis, constipation; more preferably, the adverse drug reaction is selected from hemangioma, hypothyroidism, hypoparathyroidism, pruritus, pneumonia, hepatitis, abnormal liver function, type I diabetes , nephritis, renal failure.

本揭露還提供了一種藥物組合，其中含有VEGFR抑制劑如阿帕替尼或其可藥用鹽，和抗PD-1抗體或其抗原結合片段，進一步包括烷基化劑，該烷基化劑選自替莫唑胺或其可藥用鹽。 The present disclosure also provides a pharmaceutical combination comprising a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof, and an anti-PD-1 antibody or an antigen-binding fragment thereof, further comprising an alkylating agent, the alkylating agent is selected from temozolomide or a pharmaceutically acceptable salt thereof.

在本揭露實施方案中，該PD-1抗體以注射的方式給藥，例如皮下或靜脈注射，注射前需將PD-1抗體配製成可注射的形式。特別佳的PD-1抗體的可注射形式是注射液或凍乾粉針，其包含PD-1抗體、緩衝劑、穩定劑，任選地還含有表面活性劑。緩衝劑可選自醋酸鹽、檸檬酸鹽、琥珀酸鹽、以及磷酸鹽中的一種或幾種。穩定劑可選自糖或胺基酸，較佳二糖，例如蔗糖、乳糖、海藻糖、麥芽糖。表面活性劑選自聚氧乙烯氫化蓖麻油、甘油脂肪酸酯、聚氧乙烯山梨醇酐脂肪酸酯，較佳該聚氧乙烯山梨醇酐脂肪酸酯為聚山梨酯20、40、60或 80，最佳聚山梨酯20。最為佳的PD-1抗體的可注射形式包含PD-1抗體、醋酸鹽緩衝劑、海藻糖和聚山梨酯20。 In the disclosed embodiment, the PD-1 antibody is administered by injection, such as subcutaneous or intravenous injection, and the PD-1 antibody needs to be formulated into an injectable form before injection. A particularly preferred injectable form of the PD-1 antibody is an injectable solution or a lyophilized powder, which contains the PD-1 antibody, a buffer, a stabilizer, and optionally a surfactant. The buffer can be selected from one or more of acetate, citrate, succinate, and phosphate. Stabilizers may be selected from sugars or amino acids, preferably disaccharides such as sucrose, lactose, trehalose, maltose. Surfactant is selected from polyoxyethylene hydrogenated castor oil, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, preferably the polyoxyethylene sorbitan fatty acid ester is polysorbate 20, 40, 60 or 80, the best polysorbate 20. The most preferred injectable forms of PD-1 antibody comprise PD-1 antibody, acetate buffer, trehalose and polysorbate 20.

本揭露聯合方案任選的還包含其他組分，該其他組分包括但不限於其他抗腫瘤藥等。 The combination scheme of the present disclosure optionally further includes other components, including but not limited to other anti-tumor drugs and the like.

如無相反解釋，本揭露中術語具有如下含義： Unless explained to the contrary, the terms in this disclosure have the following meanings:

本揭露關於“聯合”是一種給藥方式，是指在一定時間期限內給予至少一種劑量的VEGFR抑制劑如阿帕替尼或其可藥用鹽和至少一種劑量的PD-1抗體或其抗原結合片段，其中兩種物質都顯示藥理學作用。該時間期限可以是一個給藥週期內，較佳4週內、3週內、2週內、1週內、或24小時以內，更佳12小時以內。可以同時或依次給予VEGFR抑制劑如阿帕替尼或其可藥用鹽和PD-1抗體或其抗原結合片段。這種期限包括這樣的治療，其中通過相同給藥途徑或不同給藥途徑給予VEGFR抑制劑如阿帕替尼或其可藥用鹽和PD-1抗體或其抗原結合片段。本申請所述聯合的給藥方式選自同時給藥、獨立地配製並共給藥或獨立地配製並相繼給藥。在另一些實施方案中，本揭露“聯合”是指在一定時間期限內給予三種不同種的藥物如VEGFR抑制劑、PD-1抗體以及烷基化劑如替莫唑胺，該時間期限如前述所描述。 In the present disclosure, "combination" is a mode of administration, which refers to the administration of at least one dose of a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof and at least one dose of PD-1 antibody or its antigen within a certain period of time Binding fragments in which both substances exhibit pharmacological effects. The time period can be within one dosing cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours, more preferably within 12 hours. The VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof and the PD-1 antibody or antigen-binding fragment thereof can be administered simultaneously or sequentially. This term includes treatment in which a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof and a PD-1 antibody or antigen-binding fragment thereof are administered by the same route of administration or by different routes of administration. The modes of administration of the combinations described herein are selected from simultaneous administration, separate formulation and co-administration, or separate formulation and sequential administration. In other embodiments, "combination" of the present disclosure refers to the administration of three different drugs, such as a VEGFR inhibitor, a PD-1 antibody, and an alkylating agent, such as temozolomide, for a period of time as described above.

本揭露中所述“有效量”或“有效劑量”包含足以改善或預防醫學病症的症狀或病症的量。有效量還意指足以允許或促進診斷的量。用於特定患者或獸醫學受試者的有效量可依據以下因素而變化：如待治療的病症、患者的總體健康情況、給藥的方法途徑和劑量以及副作用嚴重性。有效量可以是避免顯著副作用或毒性作用的最大劑量或給藥方案。 An "effective amount" or "effective dose" as used in this disclosure includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition being treated, the general health of the patient, the method, route and dosage of administration, and the severity of side effects. An effective amount can be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.

術語“人源化抗體(humanized antibody)”，也稱為CDR移植抗體(CDR-grafted antibody)，是指將小鼠的CDR序列移植到人的抗體可變區框架，即不同類型的人種系抗體構架序列中產生的抗體。可以克服嵌合抗體由於攜帶 大量小鼠蛋白成分，從而誘導的強烈的抗體可變抗體反應。此類構架序列可以從包括種系抗體基因序列的公共DNA數據庫或公開的參考文獻獲得。如人重鏈和輕鏈可變區基因的種系DNA序列可以在“VBase”人種系序列數據庫(在因特網www.mrccpe.com.ac.uk/vbase可獲得)，以及在Kabat，E.A.等人，1991 Sequences of Proteins of Immunological Interest，第5版中找到。在本申請一個較佳的實施方案中，該PD-1人源化抗體的CDR序列選自SEQ ID NO：1、2、3、4、5、6。 The term "humanized antibody", also known as CDR-grafted antibody, refers to the grafting of mouse CDR sequences into a human antibody variable region framework, ie a different type of human germline Antibody produced in antibody framework sequences. can overcome chimeric antibodies due to carrying A large number of mouse protein components, thereby inducing strong antibody-variable antibody responses. Such framework sequences can be obtained from public DNA databases or published references that include germline antibody gene sequences. For example, the germline DNA sequences of human heavy and light chain variable region genes can be found in the "VBase" human germline sequence database (available on the Internet at www.mrccpe.com.ac.uk/vbase), and in Kabat, EA, et al. Human, 1991 Sequences of Proteins of Immunological Interest, 5th ed. In a preferred embodiment of the present application, the CDR sequences of the PD-1 humanized antibody are selected from SEQ ID NOs: 1, 2, 3, 4, 5, and 6.

術語“抗原結合片段”，指具有抗原結合活性的Fab片段、Fab’片段、F(ab’)2片段，以及與人PD-1結合的Fv片段sFv片段；包含本申請該抗體的選自SEQ ID NO：1至SEQ ID NO：6中的一個或多個CDR區。Fv片段含有抗體重鏈可變區和輕鏈可變區，但沒有恆定區，並具有全部抗原結合位點的最小抗體片段。一般地，Fv抗體還包含在VH和VL結構域之間的多肽接頭，且能夠形成抗原結合所需的結構。也可以用不同的連接物將兩個抗體可變區連接成一條多肽鏈，稱為單鏈抗體(single chain antibody)或單鏈Fv(sFv)。本申請的術語“與PD-1結合”，指能與人PD-1相互作用。本申請的術語“抗原結合位點”指抗原上不連續的，由本申請抗體或抗原結合片段識別的三維空間位點。 The term "antigen-binding fragment" refers to Fab fragments, Fab' fragments, F(ab')2 fragments with antigen-binding activity, and Fv fragments sFv fragments that bind to human PD-1; comprising the antibody of the present application selected from the group consisting of SEQ One or more CDR regions of ID NO:1 to SEQ ID NO:6. Fv fragments contain antibody heavy and light chain variable regions, but no constant regions, and are the smallest antibody fragments with all antigen-binding sites. Typically, Fv antibodies also contain a polypeptide linker between the VH and VL domains and are capable of forming the structure required for antigen binding. Different linkers can also be used to link the two antibody variable regions into a single polypeptide chain, called a single chain antibody or single chain Fv (sFv). The term "binding to PD-1" in the present application refers to the ability to interact with human PD-1. The term "antigen-binding site" in the present application refers to a discrete three-dimensional space site on an antigen that is recognized by the antibody or antigen-binding fragment of the present application.

無進展生存期(PFS)：從隨機開始到首次記錄腫瘤客觀進展日期或到任何原因導致死亡的時間，以先出現者為准。 Progression-Free Survival (PFS): Time from randomization to the date of first recording of objective tumor progression or to death from any cause, whichever occurs first.

總生存期(OS)指從隨機期至任何原因導致死亡的期。末次隨訪時仍存活的受試者，其OS以末次隨訪時間計為數據刪失。失訪的受試者，其OS以失訪前末次證實存活時間計為數據刪失。數據刪失的OS定義為從隨機分組到刪失的時間。 Overall survival (OS) refers to the period from randomization to death from any cause. For subjects who were still alive at the last follow-up, their OS was censored at the time of the last follow-up. For subjects lost to follow-up, their OS was censored by the last confirmed survival time before the loss to follow-up. Data-censored OS was defined as the time from randomization to censoring.

客觀緩解率(Objective response rate，ORR)指腫瘤縮小達到一定並且保持一定時間的病人的比例，包含了CR和PR的病例。採用實體瘤緩解評估標準(RECIST 1.1標準)來評定腫瘤客觀緩解。受試者在基線時必須伴有可測 量的腫瘤病灶，療效評定標準根據RECIST 1.1標準分為完全緩解(CR)、部分緩解(PR)、穩定(SD)、進展(PD)。 Objective response rate (ORR) refers to the proportion of patients whose tumor shrinkage reaches a certain level and maintains it for a certain period of time, including cases of CR and PR. Objective tumor response was assessed using Response Evaluation Criteria in Solid Tumors (RECIST 1.1 criteria). Subjects must have measurable According to the RECIST 1.1 criteria, the efficacy evaluation criteria are divided into complete remission (CR), partial remission (PR), stable (SD), and progressive (PD).

疾病控制率(Disease Control Rate，DCR)指經確認的完全緩解、部分緩解和疾病穩定(

Figure 110112949-A0101-12-0018-21
8週)病例數在可評價療效患者中的百分比。 Disease Control Rate (DCR) refers to confirmed complete remission, partial remission and stable disease (
Figure 110112949-A0101-12-0018-21
8 weeks) number of cases in percent of patients evaluable for efficacy.

完全緩解(CR)：所有靶病灶消失，全部病理淋巴結(包括靶結節和非靶結節)短直徑必須減少至<10mm。 Complete remission (CR): All target lesions disappeared, and the short diameter of all pathological lymph nodes (including target and non-target nodules) must be reduced to <10mm.

部分緩解(PR)：靶病灶直徑之和比基線水平減少至少30%。 Partial remission (PR): At least 30% reduction in the sum of target lesion diameters from baseline.

疾病進展(PD)：以整個實驗研究過程中所有測量的靶病灶直徑之和的最小值為參照，直徑和相對增加至少20%(如果基線測量值最小就以基線值為參照)；除此之外，必須滿足直徑和的絕對值增加至少5mm(出現一個或多個新病灶也視為疾病進展)。 Disease progression (PD): At least 20% relative increase in diameter and relative increase in diameter and relative increase of at least 20% with reference to the minimum value of the sum of all measured target lesion diameters during the entire experimental study (reference to baseline value if the baseline measurement value is the smallest); otherwise In addition, the absolute value of the sum of the diameters must increase by at least 5 mm (the appearance of one or more new lesions is also considered as disease progression).

疾病穩定(SD)：靶病灶減小的程度沒達到PR，增加的程度也沒達到PD水平，介於兩者之間，研究時可以直徑之和的最小值作為參考。 Stable disease (SD): The degree of reduction of target lesions does not reach the PR level, and the degree of increase does not reach the level of PD. Between the two, the minimum sum of diameters can be used as a reference in the study.

以下結合實施例用於進一步描述本揭露，但這些實施例並非限制本揭露的範圍。 The following examples are used to further describe the present disclosure, but these examples do not limit the scope of the present disclosure.

實施例1：抗PD-1抗體聯合甲磺酸阿帕替尼治療肢端黑色素瘤的研究 Example 1: Study of anti-PD-1 antibody combined with apatinib mesylate in the treatment of acral melanoma

化合物A：PD-1抗體按照專利申請WO2017054646A中的方法製備，其重、輕鏈的序列如本揭露中SEQID NO：7和SEQID NO：8。200mg/每瓶，配成20mg/ml備用。 Compound A: PD-1 antibody was prepared according to the method in patent application WO2017054646A, and the sequences of its heavy and light chains were as shown in SEQ ID NO: 7 and SEQ ID NO: 8 in the present disclosure. 200 mg/bottle, 20 mg/ml for use.

化合物B：甲磺酸阿帕替尼，可按照專利申請WO2010031266A1中的方法製備。 Compound B: apatinib mesylate, which can be prepared according to the method in patent application WO2010031266A1.

入組標準：(1)經病理組織學證實，手術後復發、不能手術切除或轉移性肢端黑色素瘤患者；(2)3.既往未接受過任何系統抗腫瘤藥物治療 Inclusion criteria: (1) Patients with recurrent, unresectable or metastatic acral melanoma confirmed by histopathology after surgery; (2) 3. Have not received any systemic antitumor drug treatment before

給藥方法： Method of administration:

PD-1抗體：固定劑量200mg，靜脈輸注(無需預防用藥)，或針對基線期體重<50kg的受試者，採用3mg/kg，每2週一次，4週一個週期； PD-1 antibody: fixed dose of 200 mg, intravenous infusion (no preventive medication required), or 3 mg/kg for subjects with baseline body weight < 50 kg, once every 2 weeks for a 4-week cycle;

阿帕替尼：250mg/片，口服，每日一次，一次一片，餐後給藥。 Apatinib: 250 mg/tablet, orally, once a day, one tablet at a time, after meals.

結論： in conclusion:

共計入組20例受試者，可評價18例受試者中，4例患者靶病灶直徑之和比基線水平減少至少30%，9例受試者表現為疾病穩定(SD)，5例患者表現為疾病進展，整體疾病控制率72.2%，疾病緩解率22.2%，而單藥PD-1疾病緩解率為15%，明顯改善患者用藥安全性、有效性。 A total of 20 subjects were enrolled. Of the 18 evaluable subjects, 4 patients had a reduction in the sum of the target lesion diameters by at least 30% from the baseline level, 9 subjects had stable disease (SD), and 5 patients had stable disease (SD). It is manifested as disease progression, the overall disease control rate is 72.2%, and the disease remission rate is 22.2%, while the single-agent PD-1 disease remission rate is 15%, which significantly improves the safety and efficacy of patients' medication.

實施例2：抗PD-1抗體聯合甲磺酸阿帕替尼治療肢端黑色素瘤的研究 Example 2: Anti-PD-1 antibody combined with apatinib mesylate in the treatment of acral melanoma

化合物A：PD-1抗體按照專利申請WO2017054646A中的方法製備，其重、輕鏈的序列如本揭露中SEQID NO：7和SEQID NO：8。200mg/每瓶，配成20mg/ml備用。 Compound A: PD-1 antibody was prepared according to the method in patent application WO2017054646A, and the sequences of its heavy and light chains were as shown in SEQ ID NO: 7 and SEQ ID NO: 8 in the present disclosure. 200 mg/bottle, 20 mg/ml for use.

化合物B：甲磺酸阿帕替尼，可按照專利申請WO2010031266A1中的方法製備。 Compound B: apatinib mesylate, which can be prepared according to the method in patent application WO2010031266A1.

化合物C：替莫唑胺，注射用替莫唑胺(粉針，上海恆瑞)或替莫唑胺膠囊(默沙東)。 Compound C: temozolomide, temozolomide for injection (powder injection, Shanghai Hengrui) or temozolomide capsule (Merck & Co.).

入組標準：(1)經病理組織學證實，手術後復發、不能手術切除或轉移性黑色素瘤患者(包括肢端的)；(2)3.既往未接受過任何系統抗腫瘤藥物治療。 Inclusion criteria: (1) Patients with recurrent, unresectable or metastatic melanoma (including acral ones) confirmed by histopathology after surgery; (2) 3. Have not received any systemic antitumor drug treatment before.

給藥方法： Method of administration:

PD-1抗體：固定劑量200mg，靜脈輸注(無需預防用藥)，或針對基線期體重<50kg的受試者，採用3mg/kg，每2週一次，4週一個週期； PD-1 antibody: fixed dose of 200 mg, intravenous infusion (no preventive medication required), or 3 mg/kg for subjects with baseline body weight < 50 kg, once every 2 weeks for a 4-week cycle;

阿帕替尼：250mg/片，口服，每日一次，一次一片，餐後給藥，每28天為一個週期； Apatinib: 250 mg/tablet, orally, once a day, one tablet at a time, after meals, every 28 days as a cycle;

替莫唑胺：200mg/m2，口服或靜脈注射，每日一次，連續給藥5天，每28天一週期。 Temozolomide: 200 mg/m 2 , orally or intravenously, once a day, for 5 consecutive days, with a cycle every 28 days.

結論： in conclusion:

可評價23例受試者中，1例患者所有靶病灶消失，無新病灶出現，且腫瘤標誌物正常(CR)，11例患者靶病灶直徑之和比基線水平減少至少30%(PR)，10例患者表現為疾病穩定(SD)，1例患者出組，疾病控制率96.65%(22例)，客觀緩解率52.17%(12例)。相比於其他治療方式，如兩藥(ORR22.2%，DCR72.2%)或單藥PD-1(15%)有明顯優勢的。 Among the 23 evaluable subjects, 1 patient disappeared all target lesions, no new lesions appeared, and the tumor markers were normal (CR), and the sum of the target lesion diameters in 11 patients decreased by at least 30% compared with the baseline level (PR), Ten patients showed stable disease (SD), 1 patient was discharged from the group, the disease control rate was 96.65% (22 cases), and the objective response rate was 52.17% (12 cases). Compared with other treatment modalities, such as two-drug (ORR22.2%, DCR72.2%) or single-drug PD-1 (15%), it has obvious advantages.

<110> 江蘇恆瑞醫藥股份有限公司(JIANGSU HENGRUI MEDICINE CO.,LTD.) 蘇州盛迪亞生物醫藥有限公司(SUZHOU SUNCADIA BIOPHARMACEUTICALS CO.,LTD.) <110> JIANGSU HENGRUI MEDICINE CO.,LTD. SUZHOU SUNCADIA BIOPHARMACEUTICALS CO.,LTD.

<120> 一種抗PD-1抗體在製備治療肢端黑色素瘤的藥物中的用途 <120> Use of an anti-PD-1 antibody in the preparation of a medicine for treating acral melanoma

<160> 10 <160> 10

<170> SIPOSequenceListing 1.0 <170> SIPOSequenceListing 1.0

<210> 1 <210> 1

<211> 5 <211> 5

<212> PRT <212> PRT

<213> 鼠源(Mus musculus) <213> Mus musculus

<400> 1 <400> 1

Figure 110112949-A0101-12-0021-9
Figure 110112949-A0101-12-0021-9

<210> 2 <210> 2

<211> 17 <211> 17

<212> PRT <212> PRT

<213> 鼠源(Mus musculus) <213> Mus musculus

<400> 2 <400> 2

Figure 110112949-A0101-12-0021-10
Figure 110112949-A0101-12-0021-10

<210> 3 <210> 3

<211> 7 <211> 7

<212> PRT <212> PRT

<213> 鼠源(Mus musculus) <213> Mus musculus

<400> 3 <400> 3

Figure 110112949-A0101-12-0021-11
Figure 110112949-A0101-12-0021-11

<210> 4 <210> 4

<211> 11 <211> 11

<212> PRT <212> PRT

<213> 鼠源(Mus musculus) <213> Mus musculus

<400> 4 <400> 4

Figure 110112949-A0101-12-0021-12
Figure 110112949-A0101-12-0021-12

<210> 5 <210> 5

<211> 7 <211> 7

<212> PRT <212> PRT

<213> 鼠源(Mus musculus) <213> Mus musculus

<400> 5 <400> 5

Figure 110112949-A0101-12-0021-13
Figure 110112949-A0101-12-0021-13

<210> 6 <210> 6

<211> 9 <211> 9

<212> PRT <212> PRT

<213> 鼠源(Mus musculus) <213> Mus musculus

<400> 6 <400> 6

Figure 110112949-A0101-12-0022-14
Figure 110112949-A0101-12-0022-14

<210> 7 <210> 7

<211> 443 <211> 443

<212> PRT <212> PRT

<213> 人工序列(Artificial Sequence) <213> Artificial Sequence

<220> <220>

<221> 肽 <221> Peptides

<222> (1)..(443) <222> (1)..(443)

<223> 重鏈序列 <223> Heavy chain sequence

<400> 7 <400> 7

Figure 110112949-A0101-12-0022-15
Figure 110112949-A0101-12-0022-15

Figure 110112949-A0101-12-0023-16
Figure 110112949-A0101-12-0023-16

<210> 8 <210> 8

<211> 214 <211> 214

<212> PRT <212> PRT

<213> 人工序列(Artificial Sequence) <213> Artificial Sequence

<220> <220>

<221> 肽 <221> Peptides

<222> (1)..(214) <222> (1)..(214)

<223> 輕鏈序列 <223> light chain sequence

<400> 8 <400> 8

Figure 110112949-A0101-12-0023-17
Figure 110112949-A0101-12-0023-17

Figure 110112949-A0101-12-0024-18
Figure 110112949-A0101-12-0024-18

<210> 9 <210> 9

<211> 116 <211> 116

<212> PRT <212> PRT

<213> 人工序列(Artificial Sequence) <213> Artificial Sequence

<220> <220>

<221> 肽 <221> Peptides

<222> (1)..(116) <222> (1)..(116)

<223> 重鏈可變區 <223> Heavy chain variable region

<400> 9 <400> 9

Figure 110112949-A0101-12-0024-19
Figure 110112949-A0101-12-0024-19

<210> 10 <210> 10

<211> 107 <211> 107

<212> PRT <212> PRT

<213> 人工序列(Artificial Sequence) <213> Artificial Sequence

<220> <220>

<221> 肽 <221> Peptides

<222> (1)..(10) <222> (1)..(10)

<223> 輕鏈可變區 <223> Light chain variable region

<400> 10 <400> 10

Figure 110112949-A0101-12-0024-20
Figure 110112949-A0101-12-0024-20

Figure 110112949-A0101-12-0025-8
Figure 110112949-A0101-12-0025-8

Claims (20)

一種抗PD-1抗體和VEGFR抑制劑聯合在製備治療肢端黑色素瘤的藥物中的用途。 Use of an anti-PD-1 antibody in combination with a VEGFR inhibitor in the preparation of a medicament for treating acral melanoma. 如請求項1所述的用途，其中該VEGFR抑制劑選自阿帕替尼、安羅替尼、他菲替尼、法米替尼、索拉非尼或其可藥用鹽，較佳阿帕替尼或其可藥用鹽。 The use according to claim 1, wherein the VEGFR inhibitor is selected from apatinib, anlotinib, tafitinib, famitinib, sorafenib or a pharmaceutically acceptable salt thereof, preferably a Patinib or a pharmaceutically acceptable salt thereof. 如請求項1或2所述的用途，其中該PD-1抗體或其抗原結合片段選自：AMP-224、GLS-010、IBI-308、REGN-2810、PDR-001、BGB-A317、匹地利珠單抗(Pidilizumab)、PF-06801591、杰諾單抗(Genolimzumab)、CA-170、MEDI-0680、JS-001、TSR-042、西米普利單抗(Cemiplimab)、卡瑞利珠單抗(Camrelizumab)、帕博利珠單抗(Pembrolizumab)、特瑞普利單抗(Toripalimab)、辛迪利單抗(Sintilimab)、替雷利珠單抗(Tislelizumab)、LZM-009、AK-103和納武單抗(Nivolumab)。 The use according to claim 1 or 2, wherein the PD-1 antibody or its antigen-binding fragment is selected from the group consisting of: AMP-224, GLS-010, IBI-308, REGN-2810, PDR-001, BGB-A317, Pidilizumab, PF-06801591, Genolimzumab, CA-170, MEDI-0680, JS-001, TSR-042, Cemiplimab, Carrilizumab Camrelizumab, Pembrolizumab, Toripalimab, Sintilimab, Tislelizumab, LZM-009, AK- 103 and Nivolumab. 如請求項1所述的用途，其中該PD-1抗體或其抗原結合片段的輕鏈可變區包含分別如SEQ ID NO：4、SEQ ID NO：5和SEQ ID NO：6所示的LCDR1、LCDR2和LCDR3，該PD-1抗體的重鏈可變區包含分別如SEQ ID NO：1、SEQ ID NO：2和SEQ ID NO：3所示的HCDR1、HCDR2和HCDR3。 The use of claim 1, wherein the light chain variable region of the PD-1 antibody or antigen-binding fragment thereof comprises LCDR1 as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively , LCDR2 and LCDR3, the heavy chain variable region of the PD-1 antibody comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively. 如請求項4所述的用途，其中該PD-1抗體選自人源化抗體或其抗原結合片段。 The use according to claim 4, wherein the PD-1 antibody is selected from humanized antibodies or antigen-binding fragments thereof. 如請求項4或5所述的用途，其中該抗PD-1抗體或其抗原結合片段包含人源IgG1、IgG2、IgG3或IgG4同種型的重鏈恆定區，較佳包含IgG1或IgG4同種型的重鏈恆定區。 The use according to claim 4 or 5, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain constant region of human IgG1, IgG2, IgG3 or IgG4 isotype, preferably IgG1 or IgG4 isotype Heavy chain constant region. 如請求項4至6中任一項所述的用途，其中該抗PD-1抗體或其抗原結合片段包含κ或λ的輕鏈恆定區。 The use of any one of claims 4 to 6, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain constant region of kappa or lambda. 如請求項4至6中任一項所述的用途，其中該人源化抗體的輕鏈可變區序列為如SEQ ID NO：8所示的序列或其變體，該變體較佳在輕鏈可變區有0-10的胺基酸變化，更佳為A43S的胺基酸變化；重鏈可變區序列為如SEQ ID NO：7所示的序列或其變體，該變體較佳在重鏈可變區有0-10的胺基酸變化，更佳為G44R的胺基酸變化。 The use according to any one of claims 4 to 6, wherein the light chain variable region sequence of the humanized antibody is the sequence shown in SEQ ID NO: 8 or a variant thereof, preferably the variant is The light chain variable region has 0-10 amino acid changes, more preferably A43S amino acid changes; the heavy chain variable region sequence is the sequence shown in SEQ ID NO: 7 or a variant thereof, the variant Preferably there are 0-10 amino acid changes in the heavy chain variable region, more preferably G44R amino acid changes. 如請求項4至6中任一項所述的用途，其中該PD-1抗體或其抗原結合片段包含SEQ ID NO：8所示輕鏈，和如SEQ ID NO：7所示重鏈。 The use according to any one of claims 4 to 6, wherein the PD-1 antibody or antigen-binding fragment thereof comprises a light chain shown in SEQ ID NO:8, and a heavy chain shown in SEQ ID NO:7. 如請求項1至9中任一項所述的用途，其中該患者選自復發的，不能手術切除的或轉移性的，該復發的較佳為手術後復發的。 The use according to any one of claims 1 to 9, wherein the patient is selected from recurrent, unresectable or metastatic, preferably recurrent after surgery. 如請求項1至10中任一項所述的用途，其中該PD-1抗體或其抗原結合片段劑量選自1-10mg/kg，例如3mg/kg。 The use according to any one of claims 1 to 10, wherein the dose of the PD-1 antibody or antigen-binding fragment thereof is selected from 1-10 mg/kg, such as 3 mg/kg. 如請求項1至10中任一項所述的用途，其中該PD-1抗體或其抗原結合片段劑量選自50-600mg，例如200mg。 The use according to any one of claims 1 to 10, wherein the dose of the PD-1 antibody or antigen-binding fragment thereof is selected from 50-600 mg, such as 200 mg. 如請求項1至12中任一項所述的用途，其中該VEGFR抑制劑劑量選自0.1-500mg，例如250mg或375mg。 The use of any one of claims 1 to 12, wherein the VEGFR inhibitor dose is selected from 0.1-500 mg, eg 250 mg or 375 mg. 如請求項1至13中任一項所述的用途，其中還進一步包含烷基化劑，該烷基化劑較佳為替莫唑胺或其可藥用鹽。 The use according to any one of claims 1 to 13, further comprising an alkylating agent, preferably temozolomide or a pharmaceutically acceptable salt thereof. 如請求項14所述的用途，其中該替莫唑胺劑量選自50mg/m2~300mg/m2，例如150mg/m2或200mg/m2。 The use of claim 14, wherein the temozolomide dose is selected from 50 mg/m 2 to 300 mg/m 2 , such as 150 mg/m 2 or 200 mg/m 2 . 如請求項2至15中任一項所述的用途，其中該阿帕替尼可藥用鹽選自甲磺酸鹽、馬來酸鹽、酒石酸鹽、琥珀酸鹽、醋酸鹽、二氟醋酸鹽、富 馬酸鹽、檸檬酸鹽、枸櫞酸鹽、苯磺酸鹽、苯甲酸鹽、萘磺酸鹽、乳酸鹽、蘋果酸鹽、鹽酸鹽、氫溴酸鹽、硫酸鹽和磷酸鹽，較佳甲磺酸鹽。 The use according to any one of claims 2 to 15, wherein the pharmaceutically acceptable salt of apatinib is selected from the group consisting of mesylate, maleate, tartrate, succinate, acetate, difluoroacetic acid salt, rich Maleate, citrate, citrate, benzenesulfonate, benzoate, naphthalenesulfonate, lactate, malate, hydrochloride, hydrobromide, sulfate and phosphate, The mesylate salts are preferred. 一種抗PD-1抗體、VEGFR抑制劑聯合替莫唑胺或其可藥用鹽在製備治療黑色素瘤的藥物中的用途。 Use of an anti-PD-1 antibody, a VEGFR inhibitor combined with temozolomide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating melanoma. 一種用於治療黑色素瘤的抗PD-1抗體，其中抗PD-1抗體與VEGFR抑制劑組合施用，進一步還包括烷基化劑，該烷基化劑較佳為替莫唑胺或其可藥用鹽。 An anti-PD-1 antibody for treating melanoma, wherein the anti-PD-1 antibody is administered in combination with a VEGFR inhibitor, further comprising an alkylating agent, preferably temozolomide or a pharmaceutically acceptable salt thereof. 一種用於治療黑色素瘤的VEGFR抑制劑，其中該VEGFR抑制劑與抗PD-1抗體組合施用，進一步還包括烷基化劑，該烷基化劑較佳為替莫唑胺或其可藥用鹽。 A VEGFR inhibitor for treating melanoma, wherein the VEGFR inhibitor is administered in combination with an anti-PD-1 antibody, further comprising an alkylating agent, preferably temozolomide or a pharmaceutically acceptable salt thereof. 一種藥物組合，其包含有效治療量的PD-1抗體或其抗原結合片段和VEGFR抑制劑，進一步包括烷基化劑，該烷基化劑較佳為替莫唑胺或其可藥用鹽。 A pharmaceutical combination comprising an effective therapeutic amount of a PD-1 antibody or an antigen-binding fragment thereof and a VEGFR inhibitor, further comprising an alkylating agent, preferably temozolomide or a pharmaceutically acceptable salt thereof.
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