Dual fusion protein and use thereof

Abstract

A PD-1 targeted IL15Rα sushi-IL-15 bispecific recombinant protein and a use thereof.

Description

TECHNICAL FIELD The present application belongs to the field of biomedicine, and specifically relates to a PD-1 targeted IL15RaSUSHI-IL15 bispecific recombinant protein and a use thereof. BACKGROUND Two very promising approaches in cancer immunotherapy include cytokine-based therapy and blockade of an immune checkpoint protein such as PD-1. The functions of cytokines such as interleukin 2 (IL2) and interleukin 15 (IL15) contribute to the proliferation and differentiation of B cells, T cells and NK cells. Both cytokines exert their cellular signaling functions by binding to a trimeric complex, wherein the trimeric complex is composed of two shared receptors, namely the common y chain (yc; CD132) and the IL2 receptor P chain (IL2RP; CD122), and an a chain receptor specific to each cytokine: IL2 receptor a (IL2Ra; CD25) or IL15 receptor a (IL15Ra; CD215). Both cytokines are considered to be potentially valuable therapeutic agents in oncology, and IL2 has been approved for the treatment of patients with metastatic renal cell carcinoma and malignant melanoma. Although several clinical trials are ongoing for recombinant IL15, no recombinant IL15 has yet been approved for marketing. However, as potential drugs, both cytokines have a very fast clearance rate, with a half-life of a few minutes. Because of the short half-life, IL2 immunotherapy produces systemic toxicity when administered at a high dose in order to ensure efficacy. In recent clinical trials, such systemic toxicity has also been reported in IL15 immunotherapy (Guo et al., J Immunol, 2015, 195(5): 2353 64). After T cell activation, immune checkpoint proteins (for example, PD-1) are up-regulated to regulate autoimmunity by exhausting activated T cells through binding to immune checkpoint ligands (for example, PD-L1). However, immune checkpoint proteins are also up-regulated in tumor-infiltrating lymphocytes (TILs), and immune checkpoint ligands are overexpressed on tumor cells, thereby contributing to immune escape of tumor cells. Blocking the interaction between immune checkpoint proteins and ligands through drugs such as nivolumab and pembrolizumab eliminates the inhibitory effect on TILs, thereby being highly effective in cancer treatment. Although immune checkpoint blockade therapy such as nivolumab and pembrolizumab is promising, many patients still cannot benefit from an immune checkpoint blocker alone. Although cytokines have been applied in the field of tumor immunotherapy for many years, toxic side effects such as their systemic toxicity prevent them from fully exerting their application in tumor treatment and from meeting unmet clinical needs. Recent studies have shown that "targeted cytokines", such as antibody-cytokine fusion proteins, can deliver cytokines to the desired cell type, while minimizing peripheral exposure and the resulting toxicity. Therefore, developing therapeutic agents based on targeted cytokines will be of great value in treating various diseases such as cancer. WO2019166946A1 discloses variants of human IL15 and fusion proteins comprising the same. It has been confirmed that, in a first aspect, as compared to a wild-type human IL15 polypeptide or a wild-type IL15 receptor a-IL15 fusion polypeptide, the IL15 variant of the application has reduced or no binding activity to IL15 receptor a (CD215), and / or the interaction between IL15 and its signaling receptor (composed of IL2 receptor P (CD122) and the common y chain (CD132)) is reduced. In a second aspect, these affinity-reduced IL15 variants (when presented as antibodycytokine fusion proteins) selectively target the desired cell types (those cells expressing the antibody target). As compared to those cells expressing both components, cell types expressing the IL15 receptor complex (but not expressing the antibody target) are activated to a lesser extent or are not activated. Therefore, the IL15 variants and IL15 fusion proteins disclosed in WO2019166946A1 selectively regulate the activation of cell subsets to effectively and safely promote biological activity, such as antitumor activity. However, the data of the IL15 variants and IL15 fusion proteins disclosed in WO2019166946A1 show that the fusion proteins of the application still exhibit obvious cytokine release; as shown in FIG. 14 of WO2019166946A1, after the PD-1 targeted IL15 fusion protein is administered to mice in vivo, obvious IL-6 and IFNy release is still detected in the serum outside the tumor microenvironment, and an elevated serum IL-6 level is a marker of cytokine storm; it can be seen that, even with the enhanced targeting of the immune checkpoint, IL15, in addition to having an activation effect on tumor-infiltrating lymphocytes (TIL cells), also activates immune cells of non-tumor tissues that do not express the immune checkpoint, thereby releasing cytokines and inducing potential immune safety risks. Existing clinical data have demonstrated that the combination of an anti-PD-1 antibody and IL15 protein confers clinical benefit (Lancet Oncol. 2018 May; 19(5): 694-704), indicating that the combination of an anti-PD-1 antibody and IL15 protein has an antitumor synergistic effect. However, the combination of an anti-PD-1 antibody and IL15 protein has the following drawbacks: the combination of an anti-PD-1 antibody and IL15 is limited by the toxic side effects of IL15, the most common adverse reactions being injection site reaction (90%, 19 / 21) and flu-like symptom (71%); the most common grade 3 adverse reactions occurred in two patients, namely lymphopenia and fatigue, and one patient developed grade 3 myocardial infarction. DESCRIPTION OF DRAWINGS FIG. 1. SDS-PAGE analysis of LC01-7-054-M5 after protein A purification. FIG. 2. SDS-PAGE analysis of LC01-7-054-M5 after refined purification(non-reducing gel). FIG. 3. Proliferative activity of the bispecific recombinant protein on PD-1-negative non-target M-07e cells. FIG. 4. Proliferative activity of LC01-7-054-M5 on PD-1-negative non-target M-07e cells in the range of 1-100 nM. FIG. 5. Proliferative activity of the bispecific recombinant protein on PD-1-positive target M-07e-PD-1 cells. FIG. 6. PD-1 expression on the surface of the CD8+ cell population in unstimulated PBMCs. FIG. 7. PD-1 expression on the surface of the CD8+ cell population in OKT3-activated PBMCs. FIG. 8. PD-1 expression abundance on the surface of different cell subsets. FIG. 9. Proliferative activity of each cell subset on Day 8 after treatment with different dosing groups. FIG. 10. Proliferative activity of the CD8+ cell population on Day 8 after treatment with different dosing groups. FIG. 11. Proliferative activity of LC01-7-054-M5 on each cell subset in cynomolgus monkeys at different time points after a single administration. FIG. 12. Tumor volume (mm3) on Day 35 after treatment of tumor-bearing mice in different dosing groups. FIG. 13. Expansion of LC01-7-054-M5 on tumor-infiltrating immune cells (TILs). FIG. 14. IFN-Y release from PBMCs treated with LC01-7-054-M5 for 72 hours. FIG. 15. IL-6 release from PBMCs treated with LC01-7-054-M5 for 72 hours. FIG. 16. TNF-a release from PBMCs treated with LC01-7-054-M5 for 72 hours. FIG. 17. Structural of LC01-7-054-M5. FIG. 18. Efficacy evaluation of different dosing groups in a subcutaneous xenograft tumor model of human liver cancer Huh-7 cells mixed with PBMCs. FIG. 19. Efficacy evaluation of different dosing groups in a subcutaneous xenograft tumor model of human liver cancer Huh-7 cells mixed with PBMCs. DETAILED DESCRIPTION OF THE INVENTION By designing a highly effective and low-toxicity bispecific recombinant protein, the present application superimposes cytokine therapy with immune checkpoint blockade, preferably as an antibody-cytokine fusion protein, to increase the effective concentration of cytokines in the tumor microenvironment, while reducing potential systemic toxicity induced by cytokines activation of non-target cells . In a first aspect, the present application provides a bispecific recombinant protein, wherein the bispecific recombinant protein comprises an immune checkpoint blocker and a cytokine receptor cytokine portion, wherein the cytokine is an IL15 variant, and compared with wild-type IL15, the IL15 variant has reduced affinity for IL2Rp. In some embodiments, the immune checkpoint blocker is a PD-1 blocker, the cytokine receptor-cytokine is IL15R-IL15; wherein IL15 is an IL15 variant having reduced affinity for IL2RP compared to the wild-type IL15 as set forth in SEQ ID NO: 18; the PD-1 blocker is an anti-PD-1 antibody or an antigen-binding fragment thereof; the N-terminus of the IL15R is linked to the C-terminus of the light chain of the anti-PD-1 antibody or the antigen-binding fragment thereof via a linker; the N-terminus of the IL15 variant is linked to the C-terminus of the IL15R via a linker. In some embodiments, the IL15 variant, as compared to the wild-type IL15, comprises one or more point mutations at position(s) selected from N1, N4, S7, D8, K10, K11, S29, D30, V31, H32, D61, E64, N65, I68, L69, N72, Q108, M109 and I111. In some embodiments, the IL15 variant, as compared to the wild-type IL15, comprises one or more point mutations at position(s) selected from N1, N4 and D61. In some embodiments, the IL15 variant, as compared to the wild-type IL15, comprises one or more point mutations at position(s) selected from N1D, N1A, N1K, N1R, N1E, N1Q, N1G, N4A, N4D, N4E, N4Q, N4G, N4L, N4Y, and D61A. In some embodiments, the IL15 variant, as compared to the wild-type IL15, comprises one or more point mutations at position(s) selected from N1D, N4A, N4D and D61A. In some embodiments, the IL15 variant, as compared to the wild-type IL15, comprises one point mutation of D61A. In some embodiments, the linker linking the IL15R and the IL15 variant is (GGGGS)n, wherein n is an integer selected from 1 to 10, such as n being 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; preferably, the linker is (GGGGS)5. In some embodiments, the IL15R is truncated IL15RaSUSHI; preferably, the sequence of the IL15RaSUSHI comprises SEQ ID NO: 17 or is as set forth in SEQ ID NO: 17, and the sequence of the IL15 variant comprises any one of SEQ ID NOs: 19-22 or is as set forth in any one of SEQ ID NOs: 19-22. In some embodiments, the C-terminus of the IL15 variant is linked directly or via a linker to the N-terminus of the Fc region. In some embodiments, the linker is (GGGGS)n, wherein n is an integer selected from 1-10, for example n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In some embodiments, the C-terminus of the IL15 variant is directly linked to the N-terminus of the Fc region. In some embodiments, the Fc region sequence is an IgG1, IgG2, IgG3 or IgG4 Fc region. In some embodiments, the Fc region sequence is an IgG1 Fc region. In some embodiments, the Fc region sequence is an IgG1 Fc variant. In some embodiments, the IgG1 Fc variant comprises mutations that reduce Fc effects, mutations that prolong half-life and / or knob-into-hole mutations that facilitate purification. In some embodiments, the mutations that reduce Fc effects comprise one or more point mutations selected from L234A and L235A; preferably, the mutations that reduce Fc effects comprise an L234A-L235A mutation combination. In some embodiments, the mutations that prolong half-life comprise one or more point mutations selected from M252Y, S254T and T256E; preferably, the mutations that prolong halflife comprise an M252Y-S254T-T256E mutation combination. In some embodiments, in the knob-into-hole mutations that facilitate purification, the knob mutation is T366W and the hole mutation is T366S-L368A-Y407V. The numbering of amino acids in the Fc variant is according to the EU index numbering. In some embodiments, the Fc region sequence comprises any one of SEQ ID NOs: 11-15 or is as set forth in any one of SEQ ID NOs: 11-15; when the Fc region is a wild type Fc, the Fc region sequence is as set forth in SEQ ID NO: 11; when the Fc region is an Fc variant, it consists of an FcA region and an FcB region, wherein, when the FcA region sequence is SEQ ID NO: 12, the FcB region sequence is SEQ ID NO: 13, and when the FcA region sequence is SEQ ID NO: 14, the FcB region sequence is SEQ ID NO: 15; preferably, the Fc region sequence is as set forth in SEQ ID NO: 13 or SEQ ID NO: 15. In some embodiments, the immune checkpoint blocker is a blocker that blocks the interaction between PD-1 and PD-L1. In some embodiments, the immune checkpoint blocker is a PD-1 blocker; preferably, the PD-1 blocker is an anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments, the anti-PD-1 antibody or the antigen-binding fragment thereof is selected from nivolumab or pembrolizumab or antigen-binding fragments thereof. In some embodiments, the anti-PD-1 antibody or the antigen-binding fragment thereof comprises an anti-PD-1 half antibody composed of one heavy chain and one light chain; in some embodiments, the anti-PD-1 antibody or the antigen-binding fragment thereof is an anti-PD-1 half antibody. In some embodiments, the C-terminus of the anti-PD-1 half antibody light chain is linked to a cytokine receptor-cytokine via a linker; the linker is (GGGGS)n, wherein n is an integer selected from 1-10, for example, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. Preferably, the cytokine receptor-cytokine is IL15R-IL15. In some embodiments, the anti-PD-1 half antibody comprises a heavy chain comprising a heavy chain variable region, and a light chain comprising a light chain variable region; wherein the heavy chain variable region comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, and the light chain variable region comprises a light chain CDR1, a light chain CDR2, and a light chain CDR3; wherein the heavy chain CDR1 sequence comprises SEQ ID NO: 1 or is as set forth in SEQ ID NO: 1, the heavy chain CDR2 sequence comprises SEQ ID NO: 2 or is as set forth in SEQ ID NO: 2, and the heavy chain CDR3 sequence comprises SEQ ID NO: 3 or is as set forth in SEQ ID NO: 3; the light chain CDR1 sequence comprises SEQ ID NO: 4 or is as set forth in SEQ ID NO: 4, the light chain CDR2 sequence comprises SEQ ID NO: 5 or is as set forth in SEQ ID NO: 5, and the light chain CDR3 sequence comprises SEQ ID NO: 6 or is as set forth in SEQ ID NO: 6, wherein the CDR regions are defined by the Kabat numbering scheme. In some embodiments, the heavy chain variable region sequence of the anti-PD-1 half antibody comprises SEQ ID NO: 7 or is as set forth in SEQ ID NO: 7, and the light chain variable region sequence comprises SEQ ID NO: 8 or is as set forth in SEQ ID NO: 8. In some embodiments, the Fc region sequence of the anti-PD-1 half antibody is an IgG1, IgG2, IgG3, or IgG4 Fc region. In some embodiments, the Fc region sequence of the anti-PD-1 half antibody is an IgG1 Fc region. In some embodiments, the Fc region sequence of the anti-PD-1 half antibody is an IgG1 Fc variant. In some embodiments, the IgG1 Fc variant comprises mutations that reduce Fc effects, mutations that prolong half-life and / or knob-into-hole mutations that facilitate purification. In some embodiments, the mutations that reduce Fc effects comprise one or more point mutations selected from L234A and L235A; preferably, the mutations that reduce Fc effects comprise an L234A-L235A mutation combination. In some embodiments, the mutations that prolong half-life comprise one or more point mutations selected from M252Y, S254T and T256E; preferably, the mutations that prolong halflife comprise an M252Y-S254T-T256E mutation combination. In some embodiments, in the knob-into-hole mutations that facilitate purification, the knob mutation is T366W and the hole mutation is T366S-L368A-Y407V. In some embodiments, the Fc region sequence of the anti-PD-1 half antibody is as set forth in any one of SEQ ID NOs: 11-15; when the Fc region is a wild type Fc, the Fc region sequence is as set forth in SEQ ID NO: 11; when the Fc region is an Fc variant, the Fc region sequence of the anti-PD-1 half antibody is as set forth in any one of the sequences of SEQ ID NOs: 12-15; preferably, the Fc region sequence of the anti-PD-1 half antibody is as set forth in SEQ ID NO: 12 or SEQ ID NO: 14. In some embodiments, the bispecific recombinant protein comprises an anti-PD-1 half antibody and an IL15RaSUSHI-(GGGGS)5-IL15 variant, wherein the anti-PD-1 half antibody is composed of one heavy chain and one light chain, and the heavy chain and light chain comprise a heavy chain variable region and a light chain variable region; wherein the heavy chain variable region comprises a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3, and the light chain variable region comprises a light chain CDR1, a light chain CDR2 and a light chain CDR3; wherein the heavy chain CDR1 sequence comprises SEQ ID NO: 1 or is as set forth in SEQ ID NO: 1, the heavy chain CDR2 sequence comprises SEQ ID NO: 2 or is as set forth in SEQ ID NO: 2, the heavy chain CDR3 sequence comprises SEQ ID NO: 3 or is as set forth in SEQ ID NO: 3; the light chain CDR1 sequence comprises SEQ ID NO: 4 or is as set forth in SEQ ID NO: 4, the light chain CDR2 sequence comprises SEQ ID NO: 5 or is as set forth in SEQ ID NO: 5, and the light chain CDR3 sequence comprises SEQ ID NO: 6 or is as set forth in SEQ ID NO: 6; the CDR regions are defined by the Kabat numbering scheme; wherein the IL15 variant, as compared to the wild-type IL15 as set forth in SEQ ID NO: 18, comprises one or more point mutations selected from N1D, N4A, N4D, and D61A, and wherein the C-terminus of the light chain of the anti-PD-1 half antibody is linked to the N-terminus of the IL15RaSUSHI-(GGGGS)5-IL15 variant via a linker. In some embodiments, the bispecific recombinant protein comprises an anti-PD-1 half antibody composed of one heavy chain and one light chain, and an IL15RaSUSHI-(GGGGS)5-IL15 variant; wherein the N-terminus of the IL15R is linked to the C-terminus of the light chain of the anti-PD-1 antibody via a linker; the heavy chain and the light chain of the anti-PD-1 half antibody comprise a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region sequence comprises SEQ ID NO: 7 or is as set forth in SEQ ID NO: 7, and the light chain variable region sequence comprises SEQ ID NO: 8 or is as set forth in SEQ ID NO: 8; the IL15 variant, as compared to the wild-type IL15 as set forth in SEQ ID NO: 18, comprises one or more point mutations selected from N1D, N4A, N4D, and D61A, wherein the C-terminus of the light chain of the anti-PD-1 half antibody is linked to the N-terminus of the IL15RaSUSHI-(GGGGS)5-IL15 variant via a linker. In some embodiments, the bispecific recombinant protein is further linked at the C-terminus of the IL15RaSUSHI-(GGGGS)5-IL15 variant to the N-terminus of an Fc region; preferably, the linkage is direct or via a linker to the N-terminus of the Fc region. In some embodiments, the bispecific recombinant protein comprises an anti-PD-1 half antibody composed of one heavy chain and one light chain, and an IL15RaSUSHI-(GGGGS)5-IL15 variant, wherein the heavy chain and the light chain of the anti-PD-1 half antibody comprise a heavy chain variable region and a light chain variable region; wherein the heavy chain variable region comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, and the light chain variable region comprises a light chain CDR1, a light chain CDR2, and a light chain CDR3; wherein the heavy chain CDR1 sequence comprises SEQ ID NO: 1 or is as set forth in SEQ ID NO: 1, the heavy chain CDR2 sequence comprises SEQ ID NO: 2 or is as set forth in SEQ ID NO: 2, the heavy chain CDR3 sequence comprises SEQ ID NO: 3 or is as set forth in SEQ ID NO: 3; the light chain CDR1 sequence comprises SEQ ID NO: 4 or is as set forth in SEQ ID NO: 4, the light chain CDR2 sequence comprises SEQ ID NO: 5 or is as set forth in SEQ ID NO: 5, the light chain CDR3 sequence comprises SEQ ID NO: 6 or is as set forth in SEQ ID NO: 6; the CDR regions are defined by the Kabat numbering scheme; the IL15 variant, as compared to the wildtype IL15 as set forth in SEQ ID NO: 18, comprises a point mutation of D61A; wherein the C-terminus of the light chain of the anti-PD-1 half antibody is linked to the N-terminus of the IL15RaSUSHI-(GGGGS)5-IL15 variant via a linker. In some embodiments, the bispecific recombinant protein comprises an anti-PD-1 half antibody composed of one heavy chain and one light chain, and an IL15RaSUSHI-(GGGGS)5-IL15 variant, wherein the heavy chain and light chain of the anti-PD-1 half antibody comprise a heavy chain variable region and a light chain variable region; wherein the heavy chain variable region sequence comprises SEQ ID NO: 7 or is as set forth in SEQ ID NO: 7, and the light chain variable region sequence comprises SEQ ID NO: 8 or is as set forth in SEQ ID NO: 8; the IL15 variant, as compared to the wild-type IL15 as set forth in SEQ ID NO: 18, comprises a point mutation of D61A; wherein the C-terminus of the light chain of the anti-PD-1 half antibody is linked to the N-terminus of the IL15RaSUSHI-(GGGGS)5-IL15 variant via a linker. In some embodiments, the bispecific recombinant protein is further linked at the C-terminus of the IL15RaSUSHI-(GGGGS)5-IL15 variant to the N-terminus of an Fc region; preferably, the linkage is direct linkage or via a linker to the N-terminus of the Fc region; more preferably, the linkage is via a (GGGGS)n linker to the N-terminus of the Fc region, wherein n is an integer selected from 1 to 10, such as n being 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, the bispecific recombinant protein comprises an anti-PD-1 half antibody composed of one heavy chain and one light chain, and an IL15RaSUSHI-(GGGGS)5-IL15 variant, wherein the heavy chain and light chain of the anti-PD-1 half antibody comprise a heavy chain variable region and a light chain variable region; wherein the heavy chain variable region sequence comprises SEQ ID NO: 7 or is as set forth in SEQ ID NO: 7, and the light chain variable region sequence comprises SEQ ID NO: 8 or is as set forth in SEQ ID NO: 8; the IL15 variant, as compared to the wild-type IL15 as set forth in SEQ ID NO: 18, comprises a point mutation of D61A; wherein the C-terminus of the light chain of the anti-PD-1 half antibody is linked via a linker to the N-terminus of the IL15RaSUSHI-(GGGGS)5-IL15 variant; wherein the heavy chain constant region of the anti-PD-1 half antibody comprises mutations that reduce Fc effects, mutations that prolong half-life, and / or knob-into-hole mutations that facilitate purification. In some embodiments, the Fc region sequence of the anti-PD-1 half antibody is an IgG1 Fc region. In some embodiments, the Fc region sequence of the anti-PD-1 half antibody is an IgG1 Fc variant. In some embodiments, the IgG1 Fc variant comprises mutations that reduce Fc effects, mutations that prolong half-life and / or knob-into-hole mutations that facilitate purification. In some embodiments, the mutations that reduce Fc effects comprise one or more point mutations selected from L234A, and L235A; preferably, the mutations that reduce Fc effects comprise an L234A-L235A mutation combination. In some embodiments, the mutations that prolong half-life comprise one or more point mutations selected from M252Y, S254T and T256E; preferably, the mutations that prolong halflife comprise an M252Y-S254T-T256E mutation combination. In some embodiments, in the knob-into-hole mutations that facilitate purification, the knob mutation is T366W, and the hole mutation is T366S-L368A-Y407V. In some embodiments, the bispecific recombinant protein comprises an anti-PD-1 half antibody composed of one heavy chain and one light chain and an IL15RaSUSHI-(GGGGS)5-IL15 variant, wherein the heavy chain and the light chain of the anti-PD-1 half antibody comprise a heavy chain and a light chain; wherein the heavy chain sequence comprises SEQ ID NO: 23 or is as set forth in SEQ ID NO: 23, and the light chain sequence comprises SEQ ID NO: 10 or is as set forth in SEQ ID NO: 10; the IL15RaSUSHI-(GGGGS)5-IL15 variant sequence comprises SEQ ID NO: 24 or is as set forth in SEQ ID NO: 24; wherein the C-terminus of the anti-PD-1 half antibody light chain is linked to the N-terminus of the IL15RaSUSHI-(GGGGS)5-IL15 variant via a linker; the C-terminus of the IL15RaSUSHI-(GGGGS)5-IL15 variant is linked directly or via a linker to the N-terminus of an Fc region. In some embodiments, the bispecific recombinant protein comprises an anti-PD-1 half antibody composed of one heavy chain and one light chain, and an IL15RaSUSHI-(GGGGS)5-IL15 variant, wherein the heavy chain sequence of the anti-PD-1 half antibody comprises SEQ ID NO: 23 or is as set forth in SEQ ID NO: 23, and the light chain sequence comprises SEQ ID NO: 10 or is as set forth in SEQ ID NO: 10; the IL15RaSUSHI-(GGGGS)5-IL15 variant sequence comprises SEQ ID NO: 24 or is as set forth in SEQ ID NO: 24; wherein the C-terminus of the light chain of the anti-PD-1 half antibody is linked to the N-terminus of the IL15RaSUSHI-(GGGGS)5-IL15 variant via a (GGGGS)n linker, and the C-terminus of the IL15RaSUSHI-(GGGGS)5-IL15 variant is directly linked to the N-terminus of an Fc region, and n is an integer selected from 1 to 10, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, the bispecific recombinant protein comprises an anti-PD-1 half antibody composed of one heavy chain and one light chain, and an IL15RaSUSHI-(GGGGS)5-IL15 variant; wherein the heavy chain sequence of the anti-PD-1 half antibody comprises SEQ ID NO: 23 or is as set forth in SEQ ID NO: 23, the light chain sequence comprises SEQ ID NO: 10 or is as set forth in SEQ ID NO: 10; the IL15RaSUSHI-(GGGGS)5-IL15 variant sequence comprises SEQ ID NO: 24 or is as set forth in SEQ ID NO: 24; wherein the C-terminus of the anti-PD-1 half antibody light chain is linked to the N-terminus of the IL15RaSUSHI-(GGGGS)5-IL15 variant via a (GGGGS)5 linker, and the C-terminus of the IL15RaSUSHI-(GGGGS)5-IL15 variant is directly linked to the N-terminus of the Fc region. In some embodiments, the bispecific recombinant protein comprises an anti-PD-1 half antibody composed of one heavy chain, and one light chain and an IL15RaSUSHI-(GGGGS)5-IL15 variant; wherein the heavy chain sequence of the anti-PD-1 half antibody comprises SEQ ID NO: 23 or is as set forth in SEQ ID NO: 23, and the light chain sequence comprises SEQ ID NO: 10 or is as set forth in SEQ ID NO: 10; the sequence of the IL15RaSUSHI-(GGGGS)5-IL15 variant comprises SEQ ID NO: 24 or is as set forth in SEQ ID NO: 24; wherein the C-terminus of the light chain of the anti-PD-1 half antibody is linked to the N-terminus of the IL15RaSUSHI-(GGGGS)5-IL15 variant via a (GGGGS)5 linker, and the C-terminus of the IL15RaSUSHI-(GGGGS)5-IL15 variant is directly linked to the N-terminus of an Fc region, and the Fc region sequence comprises SEQ ID NO: 15 or is as set forth in SEQ ID NO: 15. In some embodiments, the bispecific recombinant protein is LC01-7-032-M1, LC01-7-032-M3, LC01-7-032-M4, LC01-7-032-M5, or LC01-7-054-M5; wherein the left arm structure of LC01-7-032-M1 is Nivolumab(H)-Fc1, and the right arm structure is Nivolumab(L)-(GGGGS)5-IL15RaSUSHI-(GGGGS)5-IL15-N1D-Fc2; the left arm structure of LC01-7-032-M3 is Nivolumab(H)-Fc1, and the right arm structure is Nivolumab(L)-(GGGGS)5-IL15RaSUSHI-(GGGGS)5-IL15-N4A-Fc2; the left arm structure of LC01-7-032-M4 is Nivolumab(H)-Fc1, and the right arm structure is Nivolumab(L)-(GGGGS)5-IL15RaSUSHI-(GGGGS)5-IL15-N4D-Fc2; the left arm structure of LC01-7-032-M5 is Nivolumab(H)-Fc1, and the right arm structure is Nivolumab(L)-(GGGGS)5-IL15RaSUSHI-(GGGGS)5-IL15-D61A-Fc2; the left arm structure of LC01-7-054-M5 is Nivolumab(H)-Fc3, and the right arm structure is Nivolumab(L)-(GGGGS)5-IL15RaSUSHI-(GGGGS)5-IL15-D61A-Fc4; wherein Nivolumab(H) refers to a domain composed of a heavy chain VH and CH1, and the amino acid sequence thereof is as set forth in SEQ ID NO: 9; Nivolumab(L) refers to a domain composed of a light chain VL and CL, and the amino acid sequence thereof is as set forth in SEQ ID NO: 10; the amino acid sequence of Fc1 is as set forth in SEQ ID NO: 12; the amino acid sequence of Fc2 is as set forth in SEQ ID NO: 13; the amino acid sequence of Fc3 is as set forth in SEQ ID NO: 14; the amino acid sequence of Fc4 is as set forth in SEQ ID NO: 15; the amino acid sequence of (GGGGS)5 is as set forth in SEQ ID NO: 16; the amino acid sequence of IL15RaSUSHI is as set forth in SEQ ID NO: 17; the amino acid sequence of IL15-N1D is as set forth in SEQ ID NO: 19; the amino acid sequence of IL15-N4A is as set forth in SEQ ID NO: 20; the amino acid sequence of IL15-N4D is as set forth in SEQ ID NO: 21; and the amino acid sequence of IL15-D61A is as set forth in SEQ ID NO: 22. In a second aspect, the present application provides a nucleic acid molecule encoding the above-mentioned bispecific recombinant protein. In a third aspect, the present application provides a vector comprising a nucleic acid molecule encoding the above-mentioned bispecific recombinant protein. In a fourth aspect, the present application provides a host cell comprising the above-mentioned vector. In a fifth aspect, the present application provides a pharmaceutical composition comprising the above-mentioned bispecific recombinant protein. In a sixth aspect, the present application provides a pharmaceutical composition comprising the above-mentioned bispecific recombinant protein and a pharmaceutically acceptable carrier. In a seventh aspect, the present application provides use of the above-mentioned bispecific recombinant protein in the preparation of a medicament for preventing and / or treating cancer. In some embodiments, the present application provides the above-mentioned bispecific recombinant protein for use in preventing and / or treating cancer. In some embodiments, the present application provides a method for preventing and / or treating cancer, comprising administering to a subject in need thereof the above-mentioned bispecific recombinant protein or the pharmaceutical composition. In some embodiments, the cancer is selected from a solid tumor and a hematological tumor; preferably, the cancer is a solid tumor; more preferably, the cancer is melanoma. Definitions Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. For definitions and terms in this field, professionals can refer to Current Protocols in Molecular Biology (Ausubel). The Abbreviations for amino acid residues are the standard 3-letter and / or single-letter codes used in the art to refer to one of the 20 commonly used L-amino acids. The terms "host", "subject" or "individual" used herein refer to mammals, such as humans, but may also be other animals, such as wild animals, livestock or laboratory animals (such as orangutans, monkeys, rats, mice, rabbits, guinea pigs, marmots, ground squirrels, etc.). An intact antibody / full-length antibody is a glycoprotein comprising at least two heavy chains (H) and two light chains (L) interlinked via disulfide bonds. Each heavy chain comprises a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region comprises three domains, CH1, CH2, and CH3. Each light chain comprises a light chain variable region (abbreviated herein as VL) and a light chain constant region. The term "antigen-binding fragment" of an antibody as used herein refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (such as PD-1). It has been demonstrated that the antigen-binding function of an antibody can be performed by certain fragments of a full-length antibody. Examples of binding fragments encompassed by the term "antigen-binding fragment" of an antibody include: (i) a Fab fragment, i.e., a monovalent fragment consisting of the VL, VH, CL and CH1 domains; (ii) an F(ab')2 fragment, i.e., a bivalent fragment consisting of two Fab' fragments linked by a disulfide bond in the hinge region; (iii) an Fd fragment consisting of the VH and CH1 domains; (iv) an Fv fragment consisting of the single-arm VL and VH domains of the antibody; (v) a dAb fragment consisting of a VH domain (Ward et al. (1989) Nature 241: 544-546); and (vi) a CDR. Furthermore, although the two domains VL and VH of an Fv fragment are encoded by different genes, they can be joined together by a synthetic linker through recombinant methods to become a single continuous chain, in which the VL and VH regions pair to form a monovalent molecule (referred to as single-chain Fv (scFv); see, for example, Bird et al. (1988) Science 242: 423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85: 5879-5883). Such single-chain antibodies are also encompassed within the term "antigen-binding fragment" of an antibody. The terms "Fc fragment", "Fc region", "Fc domain", "Fc portion" or similar terms of the present application refer to a part of the heavy chain constant region of an antibody, including a part of the CH1 fragment, the hinge region (hinge), CH2 fragment and CH3 fragment. The Fc region can be engineered or modified, including modifications related to effector function, mutations that prolong half-life and / or knob-into-hole mutations that facilitate purification, for example reducing or eliminating antibody-dependent cell-mediated cytotoxicity (ADCC) and / or complementdependent cytotoxicity (CDC), which can be achieved by introducing one or more amino acid substitutions / mutations in the Fc region of the antibody. FIG. 17 of the description of the present application is merely a brief structural schematic diagram. In fact, the Fc region described in the present application does not contain only the CH2 and CH3 fragments. Unless otherwise stated herein, the numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also referred to as the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th edition, Public Health Service, National Institutes of Health, Bethesda, MD (1991). As used herein, the term "half antibody" refers to a heterodimeric glycoprotein consisting of one light chain (L) and one heavy chain (H) of an antibody, and is the basic structure constituting an immunoglobulin molecule; its molecular weight is half of the molecular weight of the corresponding antibody, about 75,000 daltons, wherein the light chain is connected to the heavy chain through a covalent disulfide bond. The heavy chain and the light chain also have regularly spaced intrachain disulfide bonds. Each heavy chain has a variable region (VH) at one end followed by a plurality of constant regions. Each light chain has a variable region (VL) at one end and a constant region at the other end; the constant region of the light chain is opposite the first constant region of the heavy chain, and the variable region of the light chain is opposite the variable region of the heavy chain. Specific amino acid residues form the interface between the variable regions of the light and heavy chains. The term "IL15" used herein refers to the protein of interleukin 15; the wild-type amino acid sequence of IL15 is as set forth in SEQ ID NO: 18, and the amino acid sequences of IL15 mutants are as set forth in SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, and SEQ ID NO: 22. The term "IL2" used herein refers to the protein of interleukin 2. The M-07e cells used herein are a human megakaryoblastic leukemia cell line, purchased from Nanjing Cobioer Biosciences Co., Ltd. OKT3 used herein is a monoclonal antibody against human mature T-cell common differentiation antigen CD3, which stimulates T-cell activation. The term "Fc effect" used herein refers to a function contributed by the Fc effector domain(s) of IgG (for example, the Fc region of an immunoglobulin). Such functions can be achieved, for example, through the binding of the Fc effector domain(s) to Fc receptors on immune cells having phagocytic or lytic activity, or through the binding of the Fc effector domain(s) to components of the complement system. Examples of typical effector functions include: C1q-mediated complement-dependent cytotoxicity (CDC), Fc receptor binding, antibody-dependent cell-mediated cytotoxicity (ADCC), phagocytosis (ADCP), down-regulation of cell surface receptors (for example, B cell receptors), and B cell activation. The term "Kabat numbering" and similar terms are well-recognized in the art and refer to a system for numbering amino acid residues in the heavy chain and light chain variable regions of an antibody or an antigen-binding fragment thereof. In some aspects, CDRs can be determined according to the Kabat numbering system (see, for example, Kabat EA and Wu TT (1971) Ann NY Acad Sci 190: 382-391; and Kabat EA et al., (1991) Sequences of Proteins of Immunological Interest, 5th edition, U.S. Department of Health and Human Services, NIH Publication No. 913242). Using the Kabat numbering system, the CDRs within an antibody heavy chain molecule are typically present at amino acid positions 31 to 35, and the CDR may optionally include one or two additional amino acids after position 35 (referred to as 35A and 35B in the Kabat numbering scheme) (CDR1); amino acid positions 50 to 65 (CDR2); and amino acid positions 95 to 102 (CDR3). Using the Kabat numbering system, the CDRs within an antibody light chain molecule are typically present at amino acid positions 24 to 34 (CDR1), amino acid positions 50 to 56 (CDR2) and amino acid positions 89 to 97 (CDR3). In a specific example, the CDRs of the antibody described herein are determined according to the Kabat numbering scheme. In describing some embodiments involving mutations of amino acid or nucleic acid sequences, the present application uses the designation "XaaaY" (for example, L234A, etc.), wherein "aaa" represents the sequence position of the amino acid or base (when a specific reference sequence exists, "aaa" represents the sequential position of the residue in the reference sequence; or it may also be according to a position numbering convention commonly used in the art, for example, the EU numbering system, etc.), "X" represents the original amino acid or base at "aaa", and "Y" represents the amino acid or base after change at "aaa". As an example, when describing the L234A mutation of a human heavy chain constant region, it means that leucine (L) at position 234 is mutated to alanine (A) according to the EU numbering system of the human heavy chain constant region. The term "recombinant protein" used herein, in a general context, is a protein consisting of at least two domains, wherein the domains are not associated with each other in the natural state, is encoded by a separate gene, and the genes are linked to each other and, as a whole, are subjected to transcription and translation to produce a single protein. In the technical context of the present application, a "fusion protein" comprising an antibody or an antigen-binding fragment thereof refers to a product obtained by fusing an antibody or an antigen-binding fragment with another biologically active protein using genetic engineering technology; such antibody fusion proteins have both the antigen-binding ability of the antibody and the unique biological characteristics of the biologically active protein fused to the antibody. The term "pharmaceutically acceptable" denotes a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredient. EXAMPLES The present application is further described below with reference to specific examples. It should be understood that these examples are merely used to illustrate the present application and not to limit the scope of the present application. The experimental methods not specified for the specific conditions in the following embodiments are generally carried out in accordance with conventional conditions or in accordance with the conditions recommended by the manufacturer. Example 1. Preparation of bispecific recombinant protein samples The PD-1 targeted IL 15RaSU SHI-IL 15 bispecific recombinant protein was used to specifically recognize PD-1-positive T cells in the tumor microenvironment through the anti-PD-1 half antibody, and to specifically expand and activate such T cells with killing potential through IL15. The heavy chain variable region sequence of the anti-PD-1 half antibody used in the present application is as set forth in SEQ ID NO: 7, and the light chain variable region sequence is as set forth in SEQ ID NO: 8. The C-terminus of the light chain of the anti-PD-1 half antibody is linked via (GGGGS)5 to the N-terminus of the IL15RaSUSHI domain, the C-terminus of the IL15RaSUSHI domain is linked to IL15 via (GGGGS)5, and the light chain-(GGGGS)s-IL15RaSUSHI-(GGGGS)s-IL15 complex is linked to the N-terminus of IgG1 Fc to form the right arm of the PD-1 targeted IL15RaSUSHI-IL15 bispecific recombinant protein, the left arm being the heavy chain of the anti-PD-1 half antibody, and the brief schematic diagram of its structure is as shown in FIG. 17. Point mutations were performed on the IL15 functional fragment in the PD-1 targeted IL15RaSUSHI-IL15 bispecific recombinant protein, and positions N1, N4, D61, E64 and N65 were selected for single-point or combined mutations. The nucleic acid encoding the PD-1 targeted IL15RaSUSHI-IL15 bispecific recombinant protein was directly synthesized by GENEWIZ after codon optimization based on the amino acid sequence (containing a signal peptide at the N-terminus, and the signal peptide sequence as set forth in SEQ ID NO: 25), inserted into the pCDNA3.4 plasmid, and verified by sequencing. Different expression plasmids were mixed and paired to transfect expression cells ExpiCHO-S (Thermo Fisher) to obtain the PD-1 targeted IL15RaSUSHI-IL15 bispecific recombinant protein (see Table 1). All subsequent experimental materials were obtained by extraction after transfecting expression cells with this series of plasmids. Table 1: Molecular structures of PD-1 targeted IL15RaSUSHI-IL15 bispecific recombinant proteins Bispecific recombinant protein number Molecular composition Left arm Right arm LC01-7-032 N ivolumab(H)-F c 1 Nivolumab(L)-(GGGGS)5- IL15RaSUSHI-(GGGGS)5-IL15-Fc2 LC01-7-032-M1 N ivolumab(H)-F c 1 Nivolumab(L)-(GGGGS)5- IL15RaSUSHI-(GGGGS)5-IL 15-N1D-Fc2 LC01-7-032-M3 N ivolumab(H)-F c 1 Nivolumab(L)-(GGGGS)5- IL15RaSUSHI-(GGGGS)5-IL15-N4A-Fc2 LC01-7-032-M4 N ivolumab(H)-F c 1 Nivolumab(L)-(GGGGS)5- IL15RaSUSHI-(GGGGS)5-IL15-N4D-Fc2 LC01-7-032-M5 N ivolumab(H)-F c 1 Nivolumab(L)-(GGGGS)5- IL15RaSUSHI-(GGGGS)5-IL 15-D61A-Fc2 LC01-7-054-M5 Nivolumab(H)-Fc3 Nivolumab(L)-(GGGGS)5- IL15RaSUSHI-(GGGGS)5-IL15-D61A-Fc4 In Table 1, Nivolumab (H) refers to a domain composed of a heavy chain VH and CH1, and the amino acid sequence thereof is as set forth in SEQ ID NO: 9; Nivolumab (L) refers to a domain composed of a light chain VL and CL, and the amino acid sequence thereof is as set forth in SEQ ID NO: 10; the amino acid sequence of Fc1 is as set forth in SEQ ID NO: 12, the amino acid sequence of Fc2 is as set forth in SEQ ID NO: 13, the amino acid sequence of Fc3 is as set forth in SEQ ID NO: 14, and the amino acid sequence of Fc4 is as set forth in SEQ ID NO: 15; the amino acid sequence of (GGGGS)5 is as set forth in SEQ ID NO: 16; and the amino acid sequence of IL15RaSUSHI is as set forth in SEQ ID NO: 17; and the amino acid sequence of IL15 is as set 5 forth in SEQ ID NO: 18; and the amino acid sequence of IL15-N1D is as set forth in SEQ ID NO: 19; the amino acid sequence of IL15-N4A is as set forth in SEQ ID NO: 20; and the amino acid sequence of IL15-N4D is as set forth in SEQ ID NO: 21; and the amino acid sequence of IL15-D61A is as set forth in SEQ ID NO: 22. Table 2: Sequence numbers and corresponding sequences Sequence number and sequence name Specific sequence SEQ ID NO:1 Heavy chain CDR1 NSGMH SEQ ID NO:2 Heavy chain CDR2 VIWYDGSKRYYADSVKG SEQ ID NO:3 Heavy chain CDR3 NDDY SEQ ID NO:4 Light chain CDR1 RASQSVSSYLA SEQ ID NO: 5 Light chain CDR2 DASNRAT SEQ ID NO: 6 Light chain CDR3 QQSSNWPRT SEQ ID NO:7 VH QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGL EWVAVIWYDGSKRYYADSVKGRFTISRDNSKNTLFLQMNSLRAED TAVYYCATNDDYWGQGTLVTVSS SEQ ID NO: 8 VL EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLL IYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWP RTFGQGTKVEIK SEQ ID NO:9 Nivolumab(H) QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGL EWVAVIWYDGSKRYYADSVKGRFTISRDNSKNTLFLQMNSLRAED TAVYYCATNDDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGT AALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSV VTVPSSSLGTQTYICNVNHKPSNTKVDKKV SEQ ID NO:10 Nivolumab(L) EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLL IYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWP RTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE KHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:11 IgG1 wild type Fc EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVV VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLT VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP SRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS PGK SEQ ID NO:12 Fc1 EPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP PSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVL DSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGK SEQ ID NO:13 Fc2 EPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP PSRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGK SEQ ID NO:14 Fc3 EPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYITREPEVTCV VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP PSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVL DSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGK SEQ ID NO:15 Fc4 EPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYITREPEVTCVV VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLT VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP SRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGK SEQ ID NO:16 (GGGGS)5 GGGGSGGGGSGGGGSGGGGSGGGGS SEQ ID NO:17 IL15RaSUSHI ITCPPPMSVEHADIWVKSYSLYSRERYICNSGFKRKAGTSSLTECVL NKATNVAHWTTPSLKCIR SEQ ID NO:18 IL15 NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLE LQVISLESGDASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEK NIKEFLQSFVHIVQMFINTS SEQ ID NO:19 IL15-N1D DWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLE LQVISLESGDASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEK NIKEFLQSFVHIVQMFINTS SEQ ID NO:20 IL15-N4A NWVAVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLE LQVISLESGDASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEK NIKEFLQSFVHIVQMFINTS SEQ ID NO:21 IL15-N4D NWVDVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLE LQVISLESGDASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEK NIKEFLQSFVHIVQMFINTS SEQ ID NO:22 IL15-D61A NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLE LQVISLESGDASIHATVENLIILANNSLSSNGNVTESGCKECEELEEK NIKEFLQSFVHIVQMFINTS SEQ ID NO:23 Nivolumab(H) -Fc3 QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGL EWVAVIWYDGSKRYYADSVKGRFTISRDNSKNTLFLQMNSLRAED TAVYYCATNDDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGT AALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSV VTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPA PEAAGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNW YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLSCA VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDK SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO:24 IL15RaSUSHI -(GGGGS)5-IL15-D61A ITCPPPMSVEHADIWVKSYSLYSRERYICNSGFKRKAGTSSLTECVL NKATNVAHWTTPSLKCIRGGGGSGGGGSGGGGSGGGGSGGGGSN WVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLEL QVISLESGDASIHATVENLIILANNSLSSNGNVTESGCKECEELEEKN IKEFLQSFVHIVQMFINTS SEQ ID NO:25 Signal peptide MRAWIFFLLCLAGRALA Table 3: Control sample information Control sample name Molecular composition Source Nivolumab Anti-PD-1 monoclonal antibody Purchased from Bristol-Myers Squibb, trade name OPDIVO IL15RA / IL15 -Fc Recombinant expression of a fusion protein of human IL15, IL15RaSUSHI and human IgG1 Fc Purchased from Novoprotein, catalog number C15Y The protein expression and purification steps are as follows: 1. Cell transfection and protein expression: After filtering the obtained expression plasmids through a 0.22 pm filter membrane, 50 pg of 5 plasmids (wherein the mass ratio of the left arm and right arm expression plasmids was 2:1 or 3:1) were added to 2 mL of OptiPRO SFM Medium (GIBCO, catalog number 12309050) and mixed well. 160 pL of transfection reagent ExpiFectamine CHO Reagent (GIBCO, catalog number A29129) was aliquoted and added to 2 mL of OptiPRO SFM Medium and mixed well. The obtained transfection reagent mixed solution was added to the mixed solution containing the 10 plasmid and mixed well. The mixture of the plasmid and transfection reagent was slowly and uniformly added to a suspension of host cells ExpiCHO-S (Thermo Fisher, catalog number A29127) with a volume of 50 mL and a cell density of 6*106 viable cells / mL, and the host cells were cultured in an incubator at 37°C and 8% CO2. On Day 1 (after 18-22 hours), 300 pL of ExpiCHO Enhancer (GIBCO, catalog number A29129) and 8 mL of ExpiCHO Feed (GIBCO, 15 catalog number A29129) were added, and the culture temperature was reduced to 32°C; a second feeding was performed on Day 5 by adding 8 mL of ExpiCHO Feed, and harvesting was performed after 12 days of culture. The cell suspension was centrifuged at 8000 rpm for 15 minutes, and the supernatant obtained by centrifugation, i.e., the cell culture harvest, was used for purification of the target protein. 2. Protein purification: (1) Sample capture (protein A affinity capture): the above cell culture harvest was centrifuged at 10,000 rpm for 30 min to remove cells and debris, and then loaded onto a protein A affinity column (GE Healthcare), with the packing material being Mabselect sure (GE, catalog number 17543804), and the target protein was eluted and harvested. Protein purity was detected by SDS-PAGE. The protein A affinity capture method is a conventional protein purification method well known to those skilled in the art, and the specific experimental method can refer to the instructions for use of the GE Healthcare protein A products and the GE antibody purification handbook. (2) Sample fine purification: the target protein obtained by protein A affinity capture of the bispecific recombinant protein LC01-7-054-M5 was subjected to removal of aggregates and other impurities in the sample using Superdex 200pg filler (Cytiva), and the experimental process was as follows: a) Equilibration: the chromatography column was equilibrated with equilibration buffer (50 mM NaAC-HAC, pH 5.5) until the ultraviolet detection line was stable; b) Loading: the sample was loaded with a sample pump, with a retention time of 5 min and a loading capacity of <50 mg / mL; c) Re-equilibration: the chromatography column was washed with equilibration buffer (50 mM NaAC-HAC, pH 5.5) for 5 column volumes; d) Elution: the target protein was eluted with eluent (50 mM NaAC-HAC, 250 mM, pH 5.5), and protein purity was detected by SDS-PAGE. After two-step purification, SEC detection of the sample showed that the purity reached 99% or higher, and reducing SDS-PAGE detection could show two target bands of 50 KD and 75 KD, with no protein breakage or degradation observed. The SDS-PAGE results of one-step purification (protein A affinity capture) and sample fine purification of LC01-7-054-M5 are as shown in FIG. 1-FIG. 2. Example 2. Effects of different bispecific recombinant proteins on the cell proliferation activity of M-07e cells The proliferation activity of different mutants was detected in PD-1-positive and PD-1-negative immune cells. The PD-1-overexpressing M-07e cell line was constructed by infecting M-07e cells (purchased from Nanjing Cobioer Biosciences Co., Ltd.) with lentivirus, and the PD-1-overexpressing cell strain was subsequently abbreviated as M-07e-PD1; the relatively general method for constructing a cell strain by lentivirus infection refers to the reference Elegheert J, et al. Lentiviral transduction of mammalian cells for fast, scalable and high-level production of soluble and membrane proteins. Nat Protoc. 2018 December ; 13(12): 2991-3017. The specific experimental steps for detecting proliferation activity are as follows: 1. M-07e cells and M-07e-PD1 cells were separately collected by centrifugation and resuspended in RPMI1640+20% FBS medium to a density of 2^105 / mL. 2. 50 pL / well of cell suspension was added to a black 96-well plate (Corning Cat. #3904). The cell suspension was incubated in a 37°C, 5% CO2 incubator for 4 hours (without adding GM-CSF). 3. Samples of LC01-7-032 and the different mutants described in Table 1 with an initial concentration of 666 nM (2x) and 3-fold serial dilution were prepared, with a total of 8 concentration points, and the final concentrations were 333, 111, 37, 12.3, 4.1, 1.37, 0.457 and 0.152 nM, respectively. 4. A positive control IL15RA / IL15-Fc (purchased from Novoprotein, catalog number C15Y) with an initial concentration of 20 nM (2x) and 3-fold serial dilution was prepared, with a total of 9 points, and the final concentrations were 10, 3.3, 1.1, 0.37, 0.12, 0.041, 0.014, 0.0046 and 0.0015 nM, respectively. 5. The serially diluted samples or positive control were added to the black 96-well plate at 50 pL / well and mixed well. 6. The 96-well plate was further incubated in a 37°C, 5% CO2 incubator for 72 hours. 7. 3 days later, 40 pL of CellTiter-Glo solution (Promega Cat.#G7573) was added to each well, mixed well, and after 10 minutes, detected with a microplate reader. As shown in FIG. 3, as compared to the bispecific recombinant protein LC01-7-032 fused with wild-type IL15, the bispecific fusion proteins LC01-7-032-M1 (N1D), LC01-7-032-M3 (N4A), LC01-7-032-M4 (N4D) and LC01-7-032-M5 (D61A) fused with IL15 mutants (mutants with reduced affinity for the IL2RP) all showed reduced proliferation activity in PD-1-negative nontarget M-07e cells, and as compared to mutants such as N4A that have weaker affinity for the IL15 receptor (IL2RP or IL15Ra) (see Table 2 of patent US11059876B2), the inventors unexpectedly found that LC01-7-032-M5 (D61A) (D61A is not the IL15 mutant type with the weakest affinity for the IL15 receptor (IL2RP or IL15Ra)) has the best safety in PD-1-negative M-07e cells (the weakest cell proliferation activity of non-target cells). As shown in FIG. 3 and FIG. 4, LC01-7-032-M5 (D61A) and LC01-7-054-M5 (D61A) showed almost no cell proliferation effect on PD-1-negative non-target cells M-07e in the range of 1-100 nM. However, for PD-1-positive target cells M-07e-PD1 cells, within the effective concentration range of the anti-PD-1 antibody (1-100 nM) (Cancer Immunol Res (2014) 2 (9): 846-856), LC01-7-054-M5 fully demonstrated cell proliferation activity in PD-1-positive M-07e-PD1 cells (as shown in FIG. 5). It can be seen that, in the effective concentration range (1-100 nM) of an anti-PD-1 antibody (such as Nivolumab), LC01-7-054-M5 showed almost no cell proliferation activity in non-target cells that do not express PD-1 (PD-1 negative cells), while in target cells that express PD-1 (PD-1 positive cells), it could fully exhibit its cell proliferation activity, unexpectedly demonstrating the balance and perfect match between the safety and efficacy of LC01-7-054-M5, and at the same time, it could also fully exert its effect of blocking PD-1 and PD-L1 in target cells. Example 3. Expression detection of PD-1+ cells in human PBMC in vitro According to literature reports, IL15 can up-regulate the PD-1 expression level on the surface of CD8+ T cells and activate CD8+ T cells. In order to detect the effect of the bispecific recombinant protein LC01-7-054-M5 on the PD-1 expression level on the surface of CD8+ T cells, the inventors detected the PD-1 expression after co-incubation of human PBMCs and the sample in vitro by flow cytometry. The specific experimental steps are as follows: 1. PBMCs were collected by centrifugation and resuspended in RPMI1640+10% FBS medium to a density of 4*106 / 3 mL / well, and plated into a 6-well plate (Corning 3516). The cells were divided into two plates: one plate was directly incubated overnight at 37°C, and OKT3 (Invitrogen 16-0037-85) at a final concentration of 5 ng / mL was added to the other plate, which was incubated at 37°C for 48 h. 2. Cells were collected by centrifugation for 5 minutes (the centrifuge speed was set to 300 g), resuspended in RPMI1640+10% FBS medium to a density of 1*105 / mL, and added to a 96-well plate (Corning 3799) at 100 pL / well. 3. LC01-7-054-M5 with an initial concentration of 400 nM (2x) and 5-fold serial dilution was prepared, with a total of 8 points, and the final concentrations were 200, 40, 8, 1.6, 0.32, 0.064, 0.0128 and 0.00256 nM, respectively. 4. A positive control IL15RA / IL15-Fc with an initial concentration of 100 nM (2x) and 5-fold serial dilution was prepared, with a total of 9 points, and the final concentrations were 50, 10, 2, 0.4, 0.08, 0.016, 0.0032, 0.00064 and 0.000128 nM, respectively. 5. The serially diluted LC01-7-054-M5 or IL15RA / IL15-Fc (purchased from Novoprotein, catalog number C15Y) was added to the 96-well plate at 100 pL / well and mixed well. The plate was incubated in a 37°C, 5% CO2 incubator for 96 hours. 6. After the incubation, cells were collected by centrifugation for 5 minutes (the centrifuge speed was set to 500 g), the supernatant was discarded, and 200 pL / well of FACS buffer (2% BSA / PBS) was added to wash twice. 7. 200 nM of control sample anti-PD-1 antibody Nivolumab (purchased from Bristol-Myers Squibb, trade name OPDIVO) was added to the 96-well plate at a volume of 100 pL well and the plate was incubated at 4°C for 40 minutes. 8. After washing twice with FACS buffer, the supernatant was discarded, 100 p L of antiHuman IgG Fc, FITC Conjugate (Jackson 109-095-098, used at 1:200) was added to each well, and the wells were incubated at 4°C for 40 minutes. 9. After washing twice with FACS buffer, the cells were resuspended in PBS and detected on the machine. The FACS marker was PerCP-Cyanine5.5 anti-human CD8 (eBioscience, 45-008842). FIG. 6 and FIG. 7 are respectively the PD-1 detection results of the CD8+ cell population in unstimulated PBMCs (resting peripheral blood mononuclear cells, PD-1-negative, Rest PBMCs) and OKT3 (a monoclonal antibody against human mature T-cell common differentiation antigen CD3, which can stimulate T-cell activation)-activated PBMC cells (PD-1-positive). The results showed that the control sample IL15RA / IL15-Fc could both up-regulate the PD-1 expression level of CD8+ T cells of Rest PBMCs (PD-1-negative) and up-regulate the PD-1 expression level of CD8+ T cells of OKT3-activated PBMCs (PD-1-positive). However, LC01-7-054-M5, under the effective dose range (1-100 nM) of the anti-PD-1 antibody (such as Nivolumab), had no significant up-regulating effect on PD-1 in the CD8+ T cell subset of Rest PBMCs (unstimulated PBMCs) (PD-1-negative), and at the same time, on CD8+ T cells of OKT3-activated PBMCs (PD-1-positive), LC01-7-054-M5 also demonstrated down-regulation of PD-1. The above results also reveal that the bispecific recombinant protein LC01-7-054-M5 of the present application, within the effective dose range (1-100 nM) of the anti-PD-1 antibody, had almost no effect on the PD-1 expression level on the CD8+ T cell subset in unactivated PBMCs (Rest PBMCs); whereas it had obvious down-regulation of PD-1 expression on the CD8+ T cell subset that had been activated by OKT3, thereby further relieving the immunosuppression caused by tumor cells highly expressing PD-L1 and binding to the activated CD8+ T cell subset highly expressing PD-1 in the tumor microenvironment. The inventors also simultaneously carried out activation experiments of the bispecific recombinant protein and the positive control sample on Rest PBMCs, and the cell activation trend was consistent with the PD-1 up-regulation experimental results (results not shown), that is, within the effective dose range of 1-100 nM of the anti-PD-1 antibody, LC01-7-054-M5 would not cause the CD8+ T cells of Rest PBMCs to be activated, whereas IL15RA / IL15-Fc could significantly activate the CD8+ T cells of Rest PBMCs. The above results show that, within the effective dose range of 1-100 nM of the anti-PD-1 antibody, LC01-7-054-M5 would hardly up-regulate the PD-1 expression level of CD8+ T cells of resting peripheral blood mononuclear cells, that is, within the effective dose range of the anti-PD-1 antibody, LC01-7-054-M5 would not cause systemic toxicity resulting from activation of CD8+ T cells of resting peripheral blood mononuclear cells, whereas the positive control sample had shown obvious activation of CD8+ T cells in this dose range. This indicates that the bispecific recombinant protein LC01-7-054-M5 of the present application has excellent safety within the effective dose range of the anti-PD-1 antibody; at the same time, within the effective dose range of 1-100 nM of the anti-PD-1 antibody, for PD-1-positive CD8+ T cells in the tumor microenvironment, LC01-7-054-M5 would not only fail to up-regulate the PD-1 expression level on CD8+ T cells as the positive control sample or other literature reports do, but could also down-regulate the PD-1 expression level on CD8+ T cells, thereby, while the anti-PD-1 half antibody exerts its effect of relieving immunosuppression, further relieving immunosuppression in the tumor microenvironment caused by PD-1 and PD-L1 binding through downregulation of PD-1 expression. Example 4. Expansion effect of LC01-7-054-M5 on immune cells in a mouse model reconstituted with human hematopoietic stem cells In order to prove that LC01-7-054-M5 achieves the same effect in preclinical animal models, the expansion effect of LC01-7-054-M5 on PD-1-negative and PD-1-positive immune cells was evaluated in a mouse model reconstituted with human hematopoietic stem cells. The specific experimental steps are as follows: human CD34+ hematopoietic stem cells were transplanted into NCG mice via the tail vein to construct mice reconstituted with human hematopoietic stem cells; when the percentage of hCD45+hCD3+ cells in the peripheral blood among live cells reached a mean value of 21.82%, the mice were randomly grouped according to body weight, wherein the mean value herein refers to the average value of the percentage of hCD45+hCD3+ cells among live cells of all mice. On the day of grouping (D0), the drug was administered via i.v. at a dosing volume of 10 pL / g x mouse body weight (g). On Day 8 (D8), peripheral blood was collected for flow cytometry detection to detect the proportion of the proliferation marker Ki67 in different cell subsets such as CD4+ T (CCR7± and CD45RA±), CD8+ T (CCR7± and CD45RA±), ydT (TCRyST) and NK (CD56+). As shown in FIG. 8, in the mouse model reconstituted with human hematopoietic stem cells, the PD-1 expression abundance of human CD8 (hCD8) cells and human TCRydT cells was relatively high, while the PD-1 expression abundance of NK cells (CD56+) was low or negative; among human CD8 (hCD8) cells, the PD-1 expression abundance of CD8 effector cells (hCD8 Effector, CD8+CD45RA+CCR7-) and CD8 effector memory cells (hCD8 Effector Memory, CD8+CD45RA-CCR7-) was relatively high, and the PD-1 expression abundance of hCD8 naive cells (CD8+CD45RA+CCR7+) was low or negative. In the mouse model reconstituted with human hematopoietic stem cells, LC01-7-054-M5 had a significant expansion effect on hCD8+ cells and hTCRvoT cells with relatively high PD-1 expression abundance. As shown in FIG. 9, on Day 8 after administration, LC01-7-054-M5 could significantly increase the Ki67 proportion of hCD8+ cells and hTCRvoT cells at different doses (0.3 mg / kg, 1 mg / kg, and 3 mg / kg); LC01-7-054-M5 at 0.3 mg / kg (the dose at which the anti-PD-1 antibody achieves complete PD-1 occupancy) could significantly maintain the expression of the proliferation marker Ki67 in hCD8+ cells (still maintaining a relatively high Ki67 proportion on Day 8), whereas the control sample IL15RA / IL15-Fc had no significant proliferation activity on Day 8. Furthermore, on Day 8 after administration, LC01-7-054-M5 showed no proliferation activity in NK cells (CD56+) with relatively low PD-1 expression abundance. As shown in FIG. 10, on Day 8 after administration, proliferation activity detection was performed in different PD-1 expression abundance subsets in CD8+ cells at different doses (0.3 mg / kg, 1 mg / kg, and 3 mg / kg) of LC01-7-054-M5, and the results found that LC01-7-054-M5 showed no expansion effect in PD-1-negative CD8+ naive cells, whereas it had a very significant expansion effect in PD-1-positive CD8+ effector cells (hCD8 Effector). The above results show that LC01-7-054-M5 showed almost no cell proliferation activity in non-target cells that do not express PD-1 (PD-1-negative cells) in in vivo animal models, while it could fully demonstrate its cell proliferation activity in target cells that express PD-1 (PD-1-positive cells), and this activity had a certain persistence. Example 5. Expansion effect of LC01-7-054-M5 on immune cells in a cynomolgus monkey model To verify the expansion activity of LC01-7-054-M5 on PD-1-negative and PD-1-positive immune cells in a cynomolgus monkey model, the experimental scheme is as follows: Cynomolgus monkeys were administered a single dose of 0.2 mg / kg, and peripheral blood was collected before administration, at Day 1-4 h (i.e., 1-4 hours after administration, with the administration time counted as Day 0), Day 5, Day 7, Day 10, Day 15, Day 22 and Day 29, respectively. The cell proliferation of cell subsets CD45+CD3+ (total T cells), CD45+CD3+CD4+ (CD4+ T), CD45+CD3+CD8+ (CD8+ T), CD45+CD3-CD56+ (NK), CD45+CD3+CD56+ (NKT) and CD45+CD3+CD4-CD8- (y8T) in the samples was detected. The flow cytometry antibodies used were: FITC Mouse Anti-NHP CD45 (Becton Dickinson 557803), Percp Mouse Anti-Human CD3 (BD 552851), BUV395 Mouse Anti-Human CD4 (BD 564107), BV605 Mouse Anti-Human CD8 (BD 564116), BV421 Mouse Anti-Human CD56 (Biolegend 318328), and PE-eFluor 610 Ki67 (eBioscience 61-5698-82). The results are as shown in FIG. 11: in the cynomolgus monkey model, LC01-7-054-M5 had a significant expansion effect on PD-1-positive (PD-1 highly expressing) y^t cells (CD45+CD3+CD4-CD8-), and the effective dose (0.2 mg / kg) matched the clinical dosage of the anti-PD-1 antibody Nivolumab; at this dose concentration, LC01-7-054-M5 had a very weak expansion effect on other groups of immune cells (T cells, NK cells, NKT cells) that are PD-1-negative or PD-1-low-expressing. Example 6. Efficacy evaluation in a subcutaneous xenograft tumor model of human melanoma A375 cells mixed with PBMCs In order to further verify the tumor inhibition effect of LC01-7-054-M5, the antitumor effect of LC01-7-054-M5 was evaluated in an A375 tumor model of humanized mice. The specific experimental scheme is as follows: 1. A375 cells (human malignant melanoma cells, derived from the Cell Bank of the Chinese Academy of Sciences, catalog number SCSP-533) were cultured in DMEM medium containing 10% fetal bovine serum (FBS). A375 cells in the logarithmic growth phase were collected, resuspended in HBSS, and used for subcutaneous tumor inoculation of NCG mice. 2. The revived frozen PBMCs were co-cultured with A375 cells for 5 days. After 5 days, the PBMCs were collected. PBMCs at 4*105 cells / mouse and A375 cells at 4*106 cells / mouse, in 0.2 mL PBS / mouse (containing 50% Matrigel (a substance that promotes tumor formation)), were inoculated subcutaneously on the right side of NCG mice. On the day of inoculation, the mice were randomly divided into 6 groups according to body weight, with 6 mice per group. The day of grouping and administration was Day 0. 3. The detailed administration method, dose and route are shown in Table 4: Table 4. Grouping and administration Group Dosing group N Dose (mg / kg) Administration regimen Administration route 1 Control group (PBS) 6 — QW*4W i.v. 2 Nivolumab 6 1 QW*4W i.v. 3 LC01-7-054-M5 6 0.3 QW*4W i.v. 4 LC01-7-054-M5 6 1 QW*4W i.v. 5 IL15RA / IL15-Fc 6 0.02 QW*4W i.v. 6 LC01-7-054-M5 6 1 Single administration (Day 0) i.v. Note: N: number of animals used; i.v.: tail vein injection; QW*4W: once a week for 4 weeks, a total of 4 times; dosing volume: the dosing volume was adjusted according to the body weight of tumor-bearing mice (0.1 mL / 10 g). Tumor volume was measured twice a week with a vernier caliper, and tumors were collected at the experimental endpoint for analysis of tumor-infiltrating lymphocytes (TILs); the FACS markers were APC anti-human CD45 (BD, catalog number 555485), FITC anti-human CD3 (BD, catalog number 555339), BV605 anti-human CD4 (Biolegend, catalog number 317438) and APC / Cy7 anti-human CD8 (Biolegend, catalog number 300926). As shown in FIG. 12, LC01-7-054-M5 had significant antitumor effects at dose concentrations of 0.3 mg / kg (QW*4W), 1 mg / kg (QW*4W) and 1 mg / kg (single), and the tumor inhibition effect was better than that of the anti-PD-1 antibody Nivolumab and IL15RA / IL15-Fc; moreover, as compared to the anti-PD-1 antibody Nivolumab, LC01-7-054-M5 had a significant expansion effect on tumor-infiltrating immune cells (FIG. 13). The above results show that LC01-7-054-M5 has significant antitumor effects and effects of expanding tumor-infiltrating immune cells, and the effective dose matches the clinical dosage of the anti-PD-1 antibody. Example 7. Safety evaluation of LC01-7-054-M5 in a cynomolgus monkey model In order to prove the safety of LC01-7-054-M5 at an effective dose (1-100 nM) matched with the dosage of the anti-PD-1 antibody Nivolumab, a safety evaluation of LC01-7-054-M5 was performed in a cynomolgus monkey pre-toxicology model. LC01-7-054-M5 was administered to cynomolgus monkeys at doses of 1 mg / kg and 5 mg / kg by i.v. administration for 4 weeks, once a week, a total of 5 times. The last administration was on Day 29, and necropsy was performed on Day 30. During this period, clinical observation, monitoring of body weight and food intake, blood biochemistry, coagulation detection and cytokine detection were performed on the cynomolgus monkeys. After the experimental endpoint, necropsy was performed, and gross examination and histopathological detection were carried out. Table 5. Pre-toxicology results Group and dosage Medium dose group 1 mg / kg High dose group 5 mg / kg Experiment design i.v., once a week, a total of 5 times. Last administration on D29, necropsy on D30. Clinical observation No abnormality observed On Day 29, 1 monkey (female) showed decreased activity and cold skin sensation (decreased body temperature) Body weight and food intake No abnormality observed From Day 11 to Day 29, food intake of 2 monkeys (2 / 2) was reduced; Cytokines IFN-Y, IL-10, TNF-a and IL2 showed no abnormality, and IL-6 showed a transient increase at a very low concentration (<20 ng / mL) IFN-Y, IL-10, TNF-a and IL2 showed no abnormality, and IL-6 showed a transient increase at a very low concentration (<40 ng / mL) Gross examination No abnormality observed Spleen enlargement was observed in 2 monkeys (2 / 2), and ascites was observed in 1 monkey (1 / 2). Histopathology Spleen enlargement was observed in 2 monkeys (2 / 2), and ascites was observed in 1 monkey (1 / 2). In the spleen, moderate red pulp cell proliferation and severe white pulp cell reduction; in the liver, moderate intrasinusoidal cell proliferation and mild to moderate mononuclear cell infiltration; in the heart and lung (1 / 2), mild mononuclear cell infiltration; and in the kidney, mild mononuclear cell infiltration. In the toxicology test with repeated administration of LC01-7-054-M5 at doses of 1 mg / kg and 5 mg / kg for 4 weeks, the cynomolgus monkeys were in good overall condition, with no death or moribund state, and the highest non-severely toxic dose (HNSTD) was 5 mg / kg. The specific parameters are shown in Table 5. Example 8. In vitro cytokine release experiment of human PBMCs In order to prove the safety of LC01-7-054-M5 at an effective dose matched with the dosage of the anti-PD-1 antibody Nivolumab, we evaluated the safety of LC01-7-054-M5 by an in vitro cytokine release experiment of human PBMCs. The specific experimental steps are as follows: 1. PBMCs were collected by centrifugation and resuspended in RPMI1640+10% FBS medium to a density of 1x106 mL. 2. 100 pL / well of cell suspension was added to a round-bottom 96-well plate (Corning Cat. #3799). 3. A positive control sample IL15RA / IL15-Fc and LC01-7-054-M5 with an initial concentration of 100 nM and 10-fold serial dilution were prepared, with a total of 6 points. 4. 100 pL of serially diluted LC01-7-054-M5 or IL15RA / IL15-Fc was added to each well and mixed well. 5. The 96-well plate was incubated in a 37°C, 5% CO2 incubator for 72 hours. 6. After 3 days, the supernatant was collected by centrifugation, and IL-6, TNF-a, and IFN-y in the supernatant were detected according to the HTRF (homogeneous time-resolved fluorescence) instructions (Cisbio, catalog numbers 62HIL06PEG, 62HTNFAPEH and 62HIFNGPEH, respectively). The results are as shown in FIG. 14-FIG. 16: in the cytokine release experiment of human PBMCs (peripheral blood mononuclear cells), after treatment with LC01-7-054-M5 for 72 hours, at the dose concentration (1-100 nM) at which the drug effect is exerted, no release of the cytokine IFN-Y was detected in the culture supernatant of PBMCs, and only very small amounts of IL-6 and TNF-a release were detected; whereas for IL15RA / IL15-Fc, obvious release of IL-6 and IFN-y was detected at a concentration of 1 nM, and obvious release of TNF-a was detected at a concentration of 0.01 nM, and the cytokine release increased in a dose-dependent manner. The above results show that the safety of LC01-7-054-M5 is significantly better than that of IL15RA / IL15-Fc. Example 9. Effect of a high dose LC01-7-054-M5 (300 nM) on cytokine release from healthy human PBMCs. Methods: Peripheral blood mononuclear cells (PBMCs) from 3 donors were seeded into a 96-well plate at 2x105 cells / well; LC01-7-054-M5 was co-incubated with PBMCs by solid-phase and liquidphase methods, respectively (300 nM in duplicate); the positive control wells contained 2 pg / mL CD3 (Thermo, catalog number 16-0037-85), CD28 (BD, catalog number 555725) and 100 ng / mL LPS (Sigma, catalog number L2880); the negative control wells contained only PBMCs; and 300 nM isotype antibody control wells (HulgGl) were also set. After incubation in an incubator for 24 h or 48 h, the supernatant was collected to detect the concentrations of IFN-y, IL-ip, IL-2, IL-4, IL-6, IL-8, IL-10 and TNF-a using the MSD kit method, and the cell survival of cells in the liquidphase method was detected by CTG. Results: Under the current in vitro experimental conditions, as compared to the negative control group and the isotype control HulgGl group, the LPS and CD3 / CD28 positive control groups could significantly promote the release of IFN-y, IL-ip, IL-2, IL-4, IL-6, IL-8, IL-10 and TNF-a in human PBMCs, while LC01-7-054-M5 did not promote the release of any of the cytokines in either the solid-phase or liquid-phase method, and did not affect the survival of PBMCs. LC01-7-054-M5 has no risk of inducing CRS in vitro. Example 10. Efficacy evaluation of the test drug in a subcutaneous xenograft tumor model of human liver cancer Huh-7 cells mixed with PBMCs Cell strain: Huh-7 cells, derived from the Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences (SIBS, catalog number SCSP-526). Experimental animals: NCG mice, female, 6-8 weeks old, weighing approximately 20-22 g. Purchased from Gempharmatech Co., Ltd. Rearing environment: SPF grade. Before the formal experiment, adaptive feeding was carried out for at least 3 days. Method 1: PBMCs co-cultured with Huh-7 cells in vitro and freshly digested Huh-7 cells were inoculated subcutaneously on the right side of the back of NCG mice, at 4x105 PBMCs, 4x106 Huh-7 cells and 0.2 mL / mouse (containing 50% Matrigel). After inoculation, when the tumors grew to about 90-115 mm3, 26 mice were selected and randomly divided into 4 groups according to tumor volume, with 8 mice in the vehicle group (0.9% sodium chloride injection) and 6 mice in each of the other groups; the day of grouping and administration was Day 0. The experiment was divided into G1: vehicle control group; G2: LC01-7-054-M5, 0.1 mg / kg dosing group; G3: LC01-7-054-M5, 0.3 mg / kg dosing group; G4: Keytruda (purchased from Merck Sharp & Dohme), 10 mg / kg dosing group. The G1-G4 groups were administered by tail vein injection starting from the day of grouping (D0), and the body weight and tumor volume of mice were measured twice a week during the administration and observation period, with the measured values recorded. After the administration was ended on Day 18, the observation was continued, and the experiment was ended on Day 22. The tumors were weighed and photographed, and the tumor growth inhibition rate TGI (%) was calculated. Table 6. Group and administration Group Dosing group Number of mice Dose (mg / kg) Administration route Administration frequency G1 Vehicle control group 8 — i.v. BIW*5 times G2 LC01-7-054-M5 6 0.1 mg / kg i.v. QW*3 times G3 LC01-7-054-M5 6 0.3 mg / kg i.v. QW*3 times G4 Keytruda 6 10mg / kg i.v. BIW*5 times Note: BIW: twice a week; QW: once a week. Results: On Day 21, the mean tumor volume of the G1 vehicle control group was 1081.80±97.01 mm3; the mean tumor volumes of the G2 (LC01-7-054-M5, 0.1 mg / kg) dosing group, the G3 (LC01-7-054-M5, 0.3 mg / kg) dosing group and the G4 (Keytruda, 10 mg / kg) dosing group were 790.04±79.69 mm3, 583.20±173.04 mm3 and 960.57±137.34 mm3, respectively. As compared to the G1 vehicle control group, the tumor growth inhibition rates (TGI) of the G2-G4 groups were 29.82%, 50.91% and 12.35%, respectively, as shown in FIG. 18. The experiment was ended on Day 22, and all mice were euthanized, with their tumors dissected, weighed and photographed. The mean tumor weight of the G1 vehicle control group was 1.140±0.098 g; the mean tumor weights of the G2 (LC01-7-054-M, 0.1 mg / kg) dosing group, the G3 (LC01-7-054-M, 0.3 mg / kg) dosing group and the G4 (Keytruda, 10 mg / kg) dosing group were 0.839±0.093 g, 0.566±0.170 g and 1.009±0.146 g, respectively. LC01-7-054-M5 can effectively inhibit the growth of Huh-7 subcutaneous xenograft tumors in mice in vivo in a dose-dependent manner, with efficacy better than that of Keytruda. Method 2: PBMCs co-cultured with Huh-7 cells in vitro and freshly digested Huh-7 cells were inoculated subcutaneously on the right side of the back of NCG mice, at 4*105 PBMCs, 4*106 Huh-7 cells and 0.2 mL / mouse (containing 50% Matrigel). After inoculation, when the tumors grew to about 90-100 mm3, 18 mice were selected and randomly divided into 3 groups according to tumor volume, with 6 mice in each group; the day of grouping and administration was Day 0. The experiment was divided into: G1: vehicle control group; G2: LC01-7-054-M5, 1 mg / kg dosing group; and G3: Camrelizumab (provided by Shanghai Lide Biotech Co., Ltd.) 10 mg / kg dosing group. The G1-G3 groups were administered by tail vein injection starting from the day of grouping (D0), and the body weight and tumor volume of mice were measured twice a week during the administration and observation period, with the measured values recorded. After the administration was ended on Day 16, the observation was continued, and the experiment was ended on Day 23; the tumor-bearing mice were euthanized, and the tumors were dissected, weighed and photographed, and the tumor growth inhibition rate TGI (%) was calculated. Table 7. Group and administration Group Dosing group Number of mice Dose (mg / kg) Administration route Administration frequency G1 Vehicle control group 6 — i.v. BIW*5 times G2 LC01-7-054-M5 6 1 mg / kg i.v. QW*3 times G3 Camrelizumab 6 10 mg / kg i.v. BIW*3 times Note: BIW: twice a week; QW: once a week. Results: On Day 23, the mean tumor volume of the G1 vehicle control group was 684.26±102.60 mm3; the mean tumor volumes of the G2 (LC01-7-054-M5, 1 mg / kg) dosing group and the G3 (Camrelizumab, 10 mg / kg) dosing group were 371.54±105.24 mm3 and 67.57±25.26 mm3, respectively. As compared to the G1 vehicle control group, the tumor growth inhibition rates (TGI) of the G2-G3 groups were 105.65% and 53.58%, respectively; as compared to the G3 group, the TGI of the G2 group increased by 52.07%, and the tumor volume was significantly reduced (p<0.05), as shown in FIG. 19. The experiment was ended on Day 23, and all mice were euthanized, with their tumors dissected, weighed and photographed. The mean tumor weight of the G1 vehicle control group was 0.693±0.111 g; the mean tumor weights of the G2 (LC01-7-054-M51 mg / kg) group and the G3 (Camrelizumab 10 mg / kg) group were 0.066±0.024 g and 0.371±0.102 g, respectively. The efficacy of LC01-7-054-M5 at 1 mg / kg was significantly better than that of Camrelizumab at 10 mg / kg. CLAIMS 1. A bispecific recombinant protein, comprising PD-1 blocker and IL15R-IL15 moiety, wherein the IL15 is an IL15 variant having reduced affinity for IL2RP compared to wild-type IL15 as set forth in SEQ ID NO: 18, and the PD-1 blocker is an anti-PD-1 antibody or an antigen-binding fragment thereof; the N-terminus of the IL15R is linked to the C-terminus of a light chain of the anti-PD-1 antibody or the antigen-binding fragment thereof via a linker; the N-terminus of the IL15 variant is linked to the C-terminus of the IL15R via a linker. 2. The bispecific recombinant protein according to claim 1, wherein the IL15 variant, as compared to the wild-type IL15, comprises one or more point mutations at position(s) selected from N1, N4 and D61. 3. The bispecific recombinant protein according to claim 2, wherein the IL15 variant, as compared to the wild-type IL15, comprises a point mutation at position D61; preferably, the IL15 variant, as compared to the wild-type IL15, comprises a point mutation of D61A. 4. The bispecific recombinant protein according to any one of claims 1-3, wherein the linker linking the IL15R and the IL15 variant is (GGGGS)n, wherein n is an integer selected from 1 to 10, for example, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; preferably, the linker is (GGGGS)5. 5. The bispecific recombinant protein according to any one of claims 1-4, wherein the IL15R is a truncated IL15RaSUSHI; preferably, the IL15RaSUSHI comprises an amino acid sequence as set forth in SEQ ID NO: 17. 6. The bispecific recombinant protein according to any one of claims 1-5, wherein the anti-PD-1 antibody or the antigen-binding fragment thereof comprises an anti-PD-1 half antibody composed of one heavy chain and one light chain; wherein the heavy chain and light chain comprise a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises heavy chain CDR1, heavy chain CDR2 and heavy chain CDR3, and the light chain variable region comprises light chain CDR1, light chain CDR2 and light chain CDR3; wherein the heavy chain CDR1 sequence comprises SEQ ID NO: 1 or is as set forth in SEQ ID NO: 1, the heavy chain CDR2 sequence comprises SEQ ID NO: 2 or is as set forth in SEQ ID NO: 2, the heavy chain CDR3 sequence comprises SEQ ID NO: 3 or is as set forth in SEQ ID NO: 3; the light chain CDR1 sequence comprises SEQ ID NO: 4 or is as set forth in SEQ ID NO: 4, the light chain CDR2 sequence comprises SEQ ID NO: 5 or is as set forth in SEQ ID NO: 5, the light chain CDR3 sequence comprises SEQ ID NO: 6 or is as set forth in SEQ ID NO: 6, and the CDR regions are defined by the Kabat numbering scheme. 7. The bispecific recombinant protein according to claim 6, wherein the heavy chain variable region sequence comprises SEQ ID NO: 7 or is as set forth in SEQ ID NO: 7, and the light chain variable region sequence comprises SEQ ID NO: 8 or is as set forth in SEQ ID NO: 8. 8. The bispecific recombinant protein according to any one of claims 1-7, wherein the C-terminus of the IL15 variant is further linked to the N-terminus of an Fc sequence. 9. The bispecific recombinant protein according to claim 8, wherein the Fc region of the anti-PD-1 antibody or the antigen-binding fragment thereof and the Fc region linked to the IL15 variant are each an IgG1 Fc region or an IgG1 Fc variant sequence; preferably, the IgG1 Fc variant comprises mutations that reduce Fc effects, mutations that prolong half-life, and / or knob-into-hole mutations that facilitate purification, wherein the mutations that reduce Fc effects comprise one or more point mutations of L234A and L235A; preferably, the mutations that reduce Fc effects comprise an L234A-L235A mutation combination; the mutations that prolong half-life comprise one or more point mutations of M252Y, S254T and T256E; preferably, the mutations that prolong half-life comprise an M252Y-S254T-T256E mutation combination; in the knob-into-hole mutations that facilitate purification, the knob mutation is T366W, and the hole mutations are T366S-L368A-Y407V; the amino acid numbering is according to the EU index numbering. 10. A bispecific recombinant protein, comprising an anti-PD-1 half antibody and an IL15RaSUSHI-(GGGGS)5-IL15 variant; wherein the anti-PD-1 half antibody is composed of one heavy chain and one light chain, and the N-terminus of the IL15R is linked to the C-terminus of the light chain of the anti-PD-1 antibody via a linker; wherein the anti-PD-1 half antibody comprises a heavy chain comprising a heavy chain variable region and a light chain comprising a light chain variable region, wherein the heavy chain variable region comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, and the light chain variable region comprises a light chain CDR1, a light chain CDR2, and a light chain CDR3; wherein the heavy chain CDR1 sequence comprises SEQ ID NO: 1 or is as set forth in SEQ ID NO: 1, the heavy chain CDR2 sequence comprises SEQ ID NO: 2 or is as set forth in SEQ ID NO: 2, and the heavy chain CDR3 sequence comprises SEQ ID NO: 3 or is as set forth in SEQ ID NO: 3; the light chain CDR1 sequence comprises SEQ ID NO: 4 or is as set forth in SEQ ID NO: 4, the light chain CDR2 sequence comprises SEQ ID NO: 5 or is as set forth in SEQ ID NO: 5, and the light chain CDR3 sequence comprises SEQ ID NO: 6 or is as set forth in SEQ ID NO: 6, wherein the CDR regions are defined by the Kabat numbering scheme; the IL15 variant, as compared to the wild-type IL15 as set forth in SEQ ID NO: 18, comprises one or more point mutations selected from N1D, N4A, N4D and D61A; wherein the C-terminus of the light chain of the anti-PD-1 half antibody is linked to the N-terminus of the IL15RaSUSHI-(GGGGS)5-IL15 variant via a linker; preferably, the heavy chain variable region sequence is as set forth in SEQ ID NO: 7, and the light chain variable region sequence is as set forth in SEQ ID NO: 8. 11. The bispecific recombinant protein according to claim 10, wherein the C-terminus of the IL15RaSUSHI-(GGGGS)5-IL15 variant is further linked to an Fc region; wherein the C-terminus of the IL15RaSUSHI-(GGGGS)5-IL15 variant is linked to the N-terminus of the Fc region; preferably, the C-terminus of the IL15RaSUSHI-(GGGGS)5-IL15 variant is linked directly to the N-terminus of the Fc region. 12. The bispecific recombinant protein according to claim 10 or 11, wherein the Fc region of the anti-PD-1 antibody or the antigen-binding fragment thereof and the Fc region linked to the IL15 variant are each an IgG1 Fc region or an IgG1 Fc variant sequence; preferably, the IgG1 Fc variant comprises mutations that reduce Fc effects, mutations that prolong half-life, and / or knob-into-hole mutations that facilitate purification, wherein the mutations that reduce Fc effects comprise one or more point mutations of L234A and L235A; preferably, the mutations that reduce Fc effects comprise an L234A-L235A mutation combination; the mutations that prolong half-life comprise one or more point mutations of M252Y, S254T, and T256E; preferably, the mutations that prolong half-life comprise an M252Y-S254T-T256E mutation combination; in the knob-into-hole mutations that facilitate purification, the knob mutation is T366W, and the hole mutation is T366S-L368A-Y407V; the amino acid numbering is according to the EU index numbering. 13. The bispecific recombinant protein according to claim 12, wherein the heavy chain sequence is as set forth in SEQ ID NO: 23, and the light chain sequence is as set forth in SEQ ID NO: 10; the IL15RaSUSHI-(GGGGS)5-IL15 variant sequence is as set forth in SEQ ID NO: 24; wherein the C-terminus of the light chain of the anti-PD-1 half antibody is linked to the N-terminus of the IL15RaSUSHI-(GGGGS)5-IL15 variant via (GGGGS)5, and the C-terminus of the IL15RaSUSHI-(GGGGS)5-IL15 variant is directly linked to the N-terminus of the Fc region, and the Fc region sequence is as set forth in SEQ ID NO: 15. 14. A bispecific recombinant protein, wherein the bispecific recombinant protein is selected from the group consisting of LC01-7-032-M1, LC01-7-032-M3, LC01-7-032-M4, LC01-7-032-M5 and LC01-7-054-M5; wherein the left arm structure of LC01-7-032-M1 is Nivolumab(H)-Fc1, and the right arm structure of LC01-7-032-M1 is Nivolumab(L)-(GGGGS)5-IL15RaSUSHI-(GGGGS)5-IL15-N1D-Fc2; the left arm structure of LC01-7-032-M3 is Nivolumab(H)-Fc1, and the right arm structure of LC01-7-032-M3 is Nivolumab(L)-(GGGGS)5-IL15RaSUSHI-(GGGGS)5-IL15-N4A-Fc2; the left arm structure of LC01-7-032-M4 is Nivolumab(H)-Fc1, and the right arm structure of LC01-7-032-M4 is Nivolumab(L)-(GGGGS)5-IL15RaSUSHI-(GGGGS)5-IL15-N4D-Fc2; the left arm structure of LC01-7-032-M5 is Nivolumab(H)-Fc1, and the right arm structure of LC01-7-032-M5 is Nivolumab(L)-(GGGGS)5-IL 15RaSUSHI-(GGGGS)5-IL 15-D61A-Fc2; the left arm structure of LC01-7-054-M5 is Nivolumab(H)-Fc3, and the right arm structure of LC01-7-054-M5 is Nivolumab(L)-(GGGGS)5-IL 15RaSUSHI-(GGGGS)5-IL 15-D61A-Fc4; wherein the Nivolumab(H) refers to a domain composed of a heavy chain VH and CH1, and the amino acid sequence thereof is as set forth in SEQ ID NO: 9; Nivolumab(L) refers to a domain composed of a light chain VL and CL, and the amino acid sequence thereof is as set forth in SEQ ID NO: 10; the amino acid sequence of Fc1 is as set forth in SEQ ID NO: 12; the amino acid sequence of Fc2 is as set forth in SEQ ID NO: 13; the amino acid sequence of Fc3 is as set forth in SEQ ID NO: 14; the amino acid sequence of Fc4 is as set forth in SEQ ID NO: 15; the amino acid sequence of (GGGGS)5 is as set forth in SEQ ID NO: 16; the amino acid sequence of IL15RaSUSHI is as set forth in SEQ ID NO: 17; the amino acid sequence of IL15-N1D is as set forth in SEQ ID NO: 19; the amino acid sequence of IL15-N4A is as set forth in SEQ ID NO: 20; the amino acid sequence of IL15-N4D is as set forth in SEQ ID NO: 21; and the amino acid sequence of IL15-D61A is as set forth in SEQ ID NO: 22. 15. A nucleic acid molecule encoding the bispecific recombinant protein according to any one of claims 1-14. 16. A vector comprising the nucleic acid molecule according to claim 15. 17. A host cell comprising the nucleic acid molecule according to claim 15 or the vector according to claim 16. 18. A pharmaceutical composition comprising the bispecific recombinant protein according to any one of claims 1-14 and a pharmaceutically acceptable carrier. 19. Use of the bispecific recombinant protein according to any one of claims 1-14 or the pharmaceutical composition according to claim 18 in the preparation of a medicament for preventing and / or treating cancer. 20. The use according to claim 19, wherein the cancer is selected from a solid tumor and a hematological tumor, preferably, the cancer is a solid tumor, and more preferably, the cancer is melanoma. 21. A method for preventing and / or treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of the bispecific recombinant protein according to any one of claims 1-14 or the pharmaceutical composition according to claim 18. 22. The method according to claim 21, wherein the cancer is selected from a solid tumor and a hematological tumor; preferably, the cancer is a solid tumor; more preferably, the cancer is melanoma. ABSTRACT A PD-1 targeted IL15Ra sushi-IL-15 bispecific recombinant protein and a use thereof. FIGURES 12 3 -250 1  LC01-7-054-M5 Non-reducing 2 Marker — 150 3 LCO1—7—054—M5 Reducing -100 -  ”-75 “ -         -50 -37 - —         -25 -20 -15 -10 Standard FIG. 1 250 — 150 — 100- 1 Marker 2 LC01-7-054-M5 Non-reducing 50 37 — 25 — 20 — 15 — 10- FIG. 3 101 Sample concentration (nM) 101       102 t—i 1i irn[‘“ 10° LC01 -7-032 LC01-7-054-M5(D61A) 300-1 PD-1-negative M-07e cell proliferation Sample concentration (nM) 200 PD-1 -negative M-07e ceil proliferation effective concentration' range of an anti-PD-L antibody               ■ IL-15RA / IL-15-FC LC01-7-032 LC01-7-032-M1(N1D) LC01-7-032-M3(N4A) LC01-7-032-M4(N4D) LC01-7-032-M5(D61A) 10-4 1—I 11 mil— 10-2 200- 100- 150 100 50 .......I 102 mi 104 FIG. 4 Unstimulated PBMCs LC01-7-032 LC01-7-054-M5(D61 A) LC01-7-054-M5 IL-15RA / IL-15-Fc 150 100- 50- i i miq "i rmni| 10-3 Sample concentration (nM) effective concentration range of an anti-PD-1 antibody limn 102 i i ■ miq—i i i iniq— 10-2     10-1 200 M-07e-PDl cell proliferation 400 300 200 100 s OJ = U = © FIG. 6 10-6 ni| iiii i ni|    i i i 111ii| 104      10-2      10° Sample concentration (nM) ™1 102 FIG. 5 OKT3-activated PBMCs LC01-7-054-M5 (1000 ug / kg) LC01-7-054-M5 (300 ug / kg) Nivolumab (3000 ug / kg) vehicle LCO1-7-054-M5 (300 ug / kg) LC01-7-054-M5 (1000 ug / kg) LC01-7-054-M5 (3000 ug / kg) Nivolumab (3000 ug / kg) IL-15RA / IL-15-FC (235 ug / kg) FIG. 10 O Vehicle IL-15RA / IL-15-Fc (235 ug / kg) Tumor volume (mm3)                                               Proliferation fold CD45+CD3+ CD45+CD3+CD4+ CD45+CD3+CD8+ CD45+CD3+CD4-CD8- vehicle CD45+CD3-CD56+ CD45+CD3+CD56+ 1000- IL-15RA / IL-15-FC, 0.02 mg / kg, QW*4 Nivolumab, 1 mg / kg, QW*4 LC01-7-054-M5, 0.3 mg / kg, QW*4 LC01-7-054-M5, 1 mg / kg, QW*4 LC01-7-054-M5,1 mg / kg, once Proportion analysis of tumor-infiltrating immune cells (TILs) Vehicle Nivolumab, 1 mg / kg LC01-7-054-M5, 1 mg / kg FIG. 13 IFN-y 15000-1 a 100nM HTRF ratio 10000- □ 10nM a 1nM ESI 0.1nM m 0.01nM O.OOInM a 100nM a 10nM a 1nM ED 0.1nM D 0.01nM 1=1 O.OOInM HTRF ratio □ 100nM 1=1 10nM □ 1nM □ 0.1nM 1=1 0.01nM a O.OOInM IL15Ra sushi Vehicle control group LC01-7-054-M5,0.1 mg / kg -A- LC01-7-054-M5,0.3 mg / kg ~Keytmda. 10 mg / kg Vehicle control group Camrelizumab, 10 mg / kg LC01-7-054-M5, 1 mg / kg .                                  Tumor volume (m m 3) Tumor volume (mmJ) Drug withdrawal

Claims

1. A bispecific recombinant protein, comprising PD-1 blocker and IL15R-IL15 moiety, wherein the IL15 is an IL15 variant having reduced affinity for IL2RP compared to wild-type IL15 as set forth in SEQ ID NO: 18, and the PD-1 blocker is an anti-PD-1 antibody or an antigen-binding fragment thereof;the N-terminus of the IL15R is linked to the C-terminus of a light chain of the anti-PD-1 antibody or the antigen-binding fragment thereof via a linker; the N-terminus of the IL15 variant is linked to the C-terminus of the IL15R via a linker.

2. The bispecific recombinant protein according to claim 1, wherein the IL15 variant, as compared to the wild-type IL15, comprises one or more point mutations at position(s) selected from N1, N4 and D61.

3. The bispecific recombinant protein according to claim 2, wherein the IL15 variant, as compared to the wild-type IL15, comprises a point mutation at position D61; preferably, the IL15 variant, as compared to the wild-type IL15, comprises a point mutation of D61A.

4. The bispecific recombinant protein according to any one of claims 1-3, wherein the linker linking the IL15R and the IL15 variant is (GGGGS)n, wherein n is an integer selected from 1 to 10, for example, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; preferably, the linker is (GGGGS)5.

5. The bispecific recombinant protein according to any one of claims 1-4, wherein the IL15R is a truncated IL15RaSUSHI; preferably, the IL15RaSUSHI comprises an amino acid sequence as set forth in SEQ ID NO: 17.

6. The bispecific recombinant protein according to any one of claims 1-5, wherein the anti-PD-1 antibody or the antigen-binding fragment thereof comprises an anti-PD-1 half antibody composed of one heavy chain and one light chain; wherein the heavy chain and light chain comprise a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises heavy chain CDR1, heavy chain CDR2 and heavy chain CDR3, and the light chain variable region comprises light chain CDR1, light chain CDR2 and light chain CDR3; wherein the heavy chain CDR1 sequence comprises SEQ ID NO: 1 or is as set forth in SEQ ID NO: 1, the heavy chain CDR2 sequence comprises SEQ ID NO: 2 or is as set forth in SEQ ID NO: 2, the heavy chain CDR3 sequence comprises SEQ ID NO: 3 or is as set forth in SEQ ID NO: 3; the light chain CDR1 sequence comprises SEQ ID NO: 4 or is as set forth in SEQ ID NO: 4, the light chain CDR2 sequence comprises SEQ ID NO: 5 or is as set forth in SEQ ID NO: 5, the light chain CDR3 sequence comprises SEQ ID NO: 6 or is as set forth in SEQ ID NO: 6, and the CDR regions are defined by the Kabat numbering scheme.

7. The bispecific recombinant protein according to claim 6, wherein the heavy chain variable region sequence comprises SEQ ID NO: 7 or is as set forth in SEQ ID NO: 7, and the light chain variable region sequence comprises SEQ ID NO: 8 or is as set forth in SEQ ID NO: 8.

8. The bispecific recombinant protein according to any one of claims 1-7, wherein the C-terminus of the IL15 variant is further linked to the N-terminus of an Fc sequence.

9. The bispecific recombinant protein according to claim 8, wherein the Fc region of the anti-PD-1 antibody or the antigen-binding fragment thereof and the Fc region linked to the IL15 variant are each an IgG1 Fc region or an IgG1 Fc variant sequence; preferably, the IgG1 Fc variant comprises mutations that reduce Fc effects, mutations that prolong half-life, and / or knob-into-hole mutations that facilitate purification, wherein the mutations that reduce Fc effects comprise one or more point mutations of L234A and L235A; preferably, the mutations that reduce Fc effects comprise an L234A-L235A mutation combination; the mutations that prolong half-life comprise one or more point mutations of M252Y, S254T and T256E; preferably, the mutations that prolong half-life comprise an M252Y-S254T-T256E mutation combination; in the knob-into-hole mutations that facilitate purification, the knob mutation is T366W, and the hole mutations are T366S-L368A-Y407V; the amino acid numbering is according to the EU index numbering.

10. A bispecific recombinant protein, comprising an anti-PD-1 half antibody and an IL15RaSUSHI-(GGGGS)5-IL15 variant; wherein the anti-PD-1 half antibody is composed of one heavy chain and one light chain, and the N-terminus of the IL15R is linked to the C-terminus of the light chain of the anti-PD-1 antibody via a linker;wherein the anti-PD-1 half antibody comprises a heavy chain comprising a heavy chain variable region and a light chain comprising a light chain variable region, wherein the heavy chain variable region comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, and the light chain variable region comprises a light chain CDR1, a light chain CDR2, and a light chain CDR3; wherein the heavy chain CDR1 sequence comprises SEQ ID NO: 1 or is as set forth in SEQ ID NO: 1, the heavy chain CDR2 sequence comprises SEQ ID NO: 2 or is as set forth in SEQ ID NO: 2, and the heavy chain CDR3 sequence comprises SEQ ID NO: 3 or is as set forth in SEQ ID NO: 3; the light chain CDR1 sequence comprises SEQ ID NO: 4 or is as set forth in SEQ ID NO: 4, the light chain CDR2 sequence comprises SEQ ID NO: 5 or is as set forth in SEQ ID NO: 5, and the light chain CDR3 sequence comprises SEQ ID NO: 6 or is as set forth in SEQ ID NO: 6, wherein the CDR regions are defined by the Kabat numbering scheme;the IL15 variant, as compared to the wild-type IL15 as set forth in SEQ ID NO: 18, comprises one or more point mutations selected from N1D, N4A, N4D and D61A; wherein the C-terminus ofthe light chain of the anti-PD-1 half antibody is linked to the N-terminus of the IL15RaSUSHI-(GGGGS)5-IL15 variant via a linker;preferably, the heavy chain variable region sequence is as set forth in SEQ ID NO: 7, and the light chain variable region sequence is as set forth in SEQ ID NO: 8.

11. The bispecific recombinant protein according to claim 10, wherein the C-terminus of the IL15RaSUSHI-(GGGGS)5-IL15 variant is further linked to an Fc region; wherein the C-terminus of the IL15RaSUSHI-(GGGGS)5-IL15 variant is linked to the N-terminus of the Fc region; preferably, the C-terminus of the IL15RaSUSHI-(GGGGS)s-IL15 variant is linked directly to the N-terminus of the Fc region.

12. The bispecific recombinant protein according to claim 10 or 11, wherein the Fc region of the anti-PD-1 antibody or the antigen-binding fragment thereof and the Fc region linked to the IL15 variant are each an IgG1 Fc region or an IgG1 Fc variant sequence; preferably, the IgG1 Fc variant comprises mutations that reduce Fc effects, mutations that prolong half-life, and / or knob-into-hole mutations that facilitate purification, wherein the mutations that reduce Fc effects comprise one or more point mutations of L234A and L235A; preferably, the mutations that reduce Fc effects comprise an L234A-L235A mutation combination; the mutations that prolong half-life comprise one or more point mutations of M252Y, S254T, and T256E; preferably, the mutations that prolong half-life comprise an M252Y-S254T-T256E mutation combination; in the knob-into-hole mutations that facilitate purification, the knob mutation is T366W, and the hole mutation is T366S-L368A-Y407V; the amino acid numbering is according to the EU index numbering.

13. The bispecific recombinant protein according to claim 12, wherein the heavy chain sequence is as set forth in SEQ ID NO: 23, and the light chain sequence is as set forth in SEQ ID NO: 10; the IL15RaSUSHI-(GGGGS)s-IL15 variant sequence is as set forth in SEQ ID NO: 24; wherein the C-terminus of the light chain of the anti-PD-1 half antibody is linked to the N-terminus of the IL15RaSUSHI-(GGGGS)5-IL15 variant via (GGGGS)5, and the C-terminus of the IL15RaSUSHI-(GGGGS)5-IL15 variant is directly linked to the N-terminus of the Fc region, and the Fc region sequence is as set forth in SEQ ID NO: 15.

14. A bispecific recombinant protein, wherein the bispecific recombinant protein is selected from the group consisting of LC01-7-032-M1, LC01-7-032-M3, LC01-7-032-M4, LC01-7-032-M5 and LC01-7-054-M5;wherein the left arm structure of LC01-7-032-M1 is Nivolumab(H)-Fc1, and the right arm structure of LC01-7-032-M1 is Nivolumab(L)-(GGGGS)5-IL15RaSUSHI-(GGGGS)5-IL15-N1D-Fc2;the left arm structure of LC01-7-032-M3 is Nivolumab(H)-Fc1, and the right arm structure of LC01-7-032-M3 is Nivolumab(L)-(GGGGS)5-IL15RaSUSHI-(GGGGS)5-IL15-N4A-Fc2;the left arm structure of LC01-7-032-M4 is Nivolumab(H)-Fc1, and the right arm structure of LC01-7-032-M4 is Nivolumab(L)-(GGGGS)5-IL15RaSUSHI-(GGGGS)5-IL15-N4D-Fc2;the left arm structure of LC01-7-032-M5 is Nivolumab(H)-Fc1, and the right arm structure of LC01-7-032-M5 is Nivolumab(L)-(GGGGS)5-IL15RaSUSHI-(GGGGS)5-IL15-D61A-Fc2;the left arm structure of LC01-7-054-M5 is Nivolumab(H)-Fc3, and the right arm structure of LC01-7-054-M5 is Nivolumab(L)-(GGGGS)5-IL15RaSUSHI-(GGGGS)5-IL15-D61A-Fc4;wherein the Nivolumab(H) refers to a domain composed of a heavy chain VH and CH1, and the amino acid sequence thereof is as set forth in SEQ ID NO: 9; Nivolumab(L) refers to a domain composed of a light chain VL and CL, and the amino acid sequence thereof is as set forth in SEQ ID NO: 10; the amino acid sequence of Fc1 is as set forth in SEQ ID NO: 12; the amino acid sequence of Fc2 is as set forth in SEQ ID NO: 13; the amino acid sequence of Fc3 is as set forth in SEQ ID NO: 14; the amino acid sequence of Fc4 is as set forth in SEQ ID NO: 15; the amino acid sequence of (GGGGS)5 is as set forth in SEQ ID NO: 16; the amino acid sequence of IL15RaSUSHI is as set forth in SEQ ID NO: 17; the amino acid sequence of IL15-N1D is as set forth in SEQ ID NO: 19; the amino acid sequence of IL15-N4A is as set forth in SEQ ID NO: 20; the amino acid sequence of IL15-N4D is as set forth in SEQ ID NO: 21; and the amino acid sequence of IL15-D61A is as set forth in SEQ ID NO: 22.

15. A nucleic acid molecule encoding the bispecific recombinant protein according to any one of claims 1-14.

16. A vector comprising the nucleic acid molecule according to claim 15.

17. A host cell comprising the nucleic acid molecule according to claim 15 or the vector according to claim 16.

18. A pharmaceutical composition comprising the bispecific recombinant protein according to any one of claims 1-14 and a pharmaceutically acceptable carrier.

19. Use of the bispecific recombinant protein according to any one of claims 1-14 or the pharmaceutical composition according to claim 18 in the preparation of a medicament for preventing and / or treating cancer.

20. The use according to claim 19, wherein the cancer is selected from a solid tumor and a hematological tumor, preferably, the cancer is a solid tumor, and more preferably, the cancer is melanoma.

21. A method for preventing and / or treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of the bispecific recombinant protein according to any one of claims 1-14 or the pharmaceutical composition according to claim 18.

22. The method according to claim 21, wherein the cancer is selected from a solid tumor and a 5 hematological tumor; preferably, the cancer is a solid tumor; more preferably, the cancer is melanoma.

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