Multiple myeloma, immunotherapy, monoclonal antibodies, immunomodulators, bone marrow microenvironment, target targets, drugs, growth factors, bone metabolism, immune response” were searched for as search terms. Articles were selected if their content was related to multiple myeloma, and recent articles published in refereed journals in the same field. The final 52 articles were selected for review.
RESULTS AND CONCLUSIONS: Monoclonal antibody immunotherapy differs from conventional multiple myeloma treatment in that it has important clinical applications with mild toxic side effects and a wide range of population indications. The current research mainly involves monoclonal antibodies related to myeloma cell adhesion proteins such as CS1, multiligand proteoglycan 1, CD56 monoclonal antibody, monoclonal antibodies related to neutralizing growth factors or inhibiting pro-growth receptors such as interleukin 6, insulin-like growth factor 1 receptor, vascular endothelial growth factor, etc., monoclonal antibodies related to activating death receptors, monoclonal antibodies related to enhancing anti-tumor immune response, and monoclonal antibodies related to bone disease regulators. These monoclonal antibodies are used to regulate the bone marrow microenvironment associated with the development of multiple myeloma, promote apoptosis of myeloma cells, and enhance the immune response to tumors.
Introduction
Multiple myeloma is a plasma cell disease that occurs in B-lymphocytes and is the second most common malignancy of the hematological system. It occurs in middle-aged and elderly people aged 50-60 years old, and seriously affects the quality of life of patients. At present, the main treatment methods are chemotherapy based on thalidomide (reaction stop), ralidomide, bortezomib and dexamethasone, treatment for bone destruction and transplantation of own hematopoietic stem cells, marrow clearing and allogeneic stem cell transplantation, etc. These methods have greatly improved the remission rate of multiple myeloma treatment and significantly prolonged the survival time, but relapse and refractory to treatment are still a huge clinical challenge today. However, relapse and refractory to treatment are still huge clinical problems. With the increasing understanding of multiple myeloma, monoclonal antibodies have gradually attracted the attention of experts and scholars. In this paper, we systematically summarize the mechanism of action and research progress related to immunotherapy of multiple myeloma involving monoclonal antibodies, and discuss their limitations in order to promote their clinical application.
1. Materials and methods
1.1 Data sources: “multiple myeloma, immunotherapy, monoclonal antibody,immunomodulatory drugs, bone marrow micro-environment, target, drugs, growthfactor, bone metabolism, immunological response” as English keywords and “multiple myeloma, immunotherapy, monoclonal antibody, immunomodulatory agent, bone marrow microenvironment, target, drug, growth factor, bone metabolism, immunological response” as Chinese keywords. “The PubMed database, China Journal Full Text Database (CNKI), Vipshop database and Wanfang database were searched from 1997 to 2012 for the Chinese keywords.
1.2 Inclusion criteria
Inclusion criteria: the contents described in the literature need to be closely related to monoclonal antibodies and multiple myeloma.
Exclusion criteria: duplicate studies or literature with old content
1.3 Quality assessment 364 papers were obtained from the initial review, and the titles and abstracts were read for the initial screening. 146 papers with irrelevant research purposes and 166 papers with backward and repetitive views were excluded, and 52 papers were retained for further analysis.
2 , Results
2.1 Myeloma cell adhesion protein-associated monoclonal antibodies
Myeloma cells can interact with a variety of cellular and non-cellular components of the bone marrow microenvironment, such as adhesion, which facilitates the growth of myeloma cells and protects them from antitumor drugs, leading to bone destruction and decreased immunity in patients with multiple myeloma. Activation of specific cell membrane receptors on myeloma cells and stromal cells and their downstream related signaling pathway molecules can regulate adhesion, inhibit apoptosis of myeloma cells, and further promote the production of myeloma growth factors such as interleukin 6, insulin growth factor 1, and vascular endothelial growth factor. With the increasing research in recent years, a variety of monoclonal antibodies targeting adhesion proteins on myeloma cells have shown promising applications.
antibodies targeting adhesion proteins on myeloma cells have shown promising applications.
2.1.1 CS1 monoclonal antibodies
CS1, as a cell surface glycoprotein, is expressed at high levels in myeloma cells, and the expression of related mRNA molecules is higher than 97%, while the expression of related mRNAs in normal tissues or cells cannot be detected or is low. CS1 is involved in regulating the mutual adhesion between myeloma cells and bone marrow stromal cells. On the other hand, CS1 upregulates mitogen-activated protein kinase 1/2, protein kinase and related signaling of signal transduction factor and transcriptional activator 3, thereby inhibiting apoptosis of myeloma cells and promoting the progression of multiple myeloma disease [3]. It is easy to see that CS1 can be considered as a novel target for immunotherapy of multiple myeloma.Elotuzumab is a CS1 monoclonal antibody that acts directly on
Plasma cell surface highly expressed glycoprotein CS1 inhibits intercellular adhesion, thereby attenuating the growth stimulating effect of stromal cells on myeloma cells. elotuzumab was found to induce myeloma cell death through antibody-dependent cell-mediated cytoxicity (ADCC) by Van Rhee et al. death. In animal studies, the natural killer cell activity was enhanced by the pretreatment of effector cells with ralidomide, which further promoted the apoptogenic effect of elotuzumab. On the other hand, the ADCC effect of elotuzumab on myeloma cells can also be enhanced by other multiple myeloma therapeutic agents such as bortezomib, dexamethasone, and the Akt protease inhibitor perifosine. Lonial et al. investigated the toxic effects of elotuzumab combination therapy. In a phase I clinical trial, when 5, 10 and 20 mg of elotuzumab were combined with ralidomide and dexamethasone, respectively, no non-dose limiting toxic effects (DLT) were observed, and 82% of patients with ralidomide-resistant multiple myeloma achieved partial remission without serious adverse effects. When elotuzumab was combined with bortezomib, at least 48%, including some bortezomib-refractory or recurrent cases, achieved partial remission with fair results. elotuzumab adverse reactions included dizziness, headache, nausea and vomiting, but all were mild and tolerated by patients. It can be seen that CS1 monoclonal antibody can be combined with other classical anti-myeloma drugs for the treatment of multiple myeloma.
2.1.2 Multiligand proteoglycan 1 (Syndecan-1/CD138) monoclonal antibody
Syndecan-1/CD138, a member of the integrin family, is a transmembrane acetyl heparan sulfate proteoglycan molecule expressed mainly on the surface of normal and malignant plasma cells and is involved in the maintenance of normal cell morphology and the development of cell differentiation, as well as in the regulation of normal physiological and pathological processes of the body. CD138 is a receptor for collagen and fibronectin in the extracellular matrix, and can also be expressed by acetyl heparan sulfate in the outer segment of its own molecular membrane with intrinsic components of the extracellular matrix, such as type I, III, V collagen, antithrombin, fibronectin or free molecules CD138 also plays a role in the migration and homing of tumor cells, as it is a low-affinity receptor for basic fibroblast growth factor, allowing basic fibroblast growth factor to bind to high-affinity receptors on the cell surface, thereby mediating the regulation of relevant cellular behaviors such as proliferation and migration. Soluble CD138 molecules are also involved in the regulation of pathological processes in the organism, by promoting osteoblast differentiation and inhibiting osteoclast activity, thus affecting the bone marrow microenvironment in which myeloma cells grow. nBT062, a CD138-associated immunotoxic monoclonal antibody, showed anti-myeloma cell activity in both in vitro experiments and animal models after binding to specific alkaloids. Among them, the complex nBT062-SPBD-DM4 covalent binding mode is more common, which makes the performance of nBT062 more stable and synergistic with ralidomide and bortezomib. However, nBT062 can cause mucositis with a maximum tolerated dose of 160 mg/m2. Therefore, novel nBT062 covalent binding modalities can be further explored for better clinical use.
2.1.3 CD56 monoclonal antibody, a neural cell adhesion molecule
CD56, also known as neural cell adhesion molecule, is mainly expressed in cells, tissues and tumors of neuroectodermal origin, but also in some mesoderm-derived tumors, natural killer cell lymphomas. Lorvotuzumab (IMGN901), a common CD56 monoclonal antibody, was found by Chanan et al. to inhibit adhesion to tumor cell lines in the presence of stromal cells in a murine myeloma model. Synergistic effects with ralidomide were seen in in vitro experiments and animal models. In combination with bortezomib, which is effective in human myeloma-transplanted mice, the opposite effect was shown in in vitro experiments. Phase I studies treating patients with relapsed, refractory CD56-positive myeloma showed Lorvotuzumab to be biocompatible with a maximum tolerated dose of 112 mg/m2 and adverse effects including malaise and renal failure. They also studied the effect of Lorvotuzumab in combination with ralidomide and dexamethasone, and at the first dose level, no serious adverse reactions were observed, and 2/3 of patients achieved more satisfactory partial remission and 1/3 partial remission. For the specific method of combination, more studies are needed to prove it.
2.1.4 CD38 monoclonal antibody
CD38 molecules are single-chain type II transmembrane glycoproteins that catalyze the synthesis and degradation of cyclic adenosine diphosphate ribose, are involved in calcium mobilization, and are closely associated with receptor-regulated adhesion. Kong et al. demonstrated that the novel murine anti-human CD38 monoclonal antibody daratumumab can kill CD38+ myeloma cells by complement-mediated cytotoxicity (CDC) or antibody-dependent cytotoxicity in the presence or absence of bone marrow stromal cells. cells. In addition, the combination of daratumumab and anti-immunoglobulin G antibody induced apoptosis of myeloma cells. Studies in a murine multiple myeloma model found that the antibody-dependent cytotoxic effect of daratumumab on killing was enhanced by pretreatment of tumor cells with ralidomide. However, there are fewer reports on the combination with other classes of drugs.
2.1.5 Intercellular adhesion molecule 1 (ICAM-1/CD54) monoclonal antibody
ICAM-1/CD54, a member of the immunoglobulin superfamily, is a transmembrane single-chain glycoprotein with a wide distribution, such as expression in vascular endothelial cells, peripheral blood lymphocytes, a variety of tumor cells and thyroid epithelial cells. It can regulate the adhesion of myeloma cells to stromal cells, and therefore can also be a target for the treatment of multiple myeloma. CD54 is highly expressed on the surface of plasma cells in most patients with multiple myeloma, but it is also partially expressed in normal cells such as some endothelial cells, epithelial cells, fibroblasts, and some leukocytes, and Veitonmaki et al. found that CD54 expression was often increased after chemotherapy in patients with multiple myeloma. High levels of CD54 also predicted low patient responsiveness to chemotherapy. i-505, a CD54-specific antibody, inhibited the growth of murine myeloma and killed tumor cell lines and induced apoptosis in in vitro experiments. However, CD54 monoclonal antibody is not well studied and its suitability for combination drug therapy and associated adverse effects remains to be demonstrated.
2.2 Neutralizing growth factors or inhibiting growth-promoting receptor-related monoclonal antibodies
Bone marrow stromal cells, osteoblasts, and osteoclasts can produce some multiple myeloma growth factors, such as interleukin 6, insulin-like growth factor 1, vascular endothelial growth factor, and B-lymphocyte activating factor, etc. After binding to specific receptors, regulatory tumor growth-related signaling pathways are activated and inhibitory effects are produced by antitumor drugs. Neutralizing growth factors or inhibiting pro-growth receptor-related monoclonal antibodies are under continuous development.
2.2.1 Interleukin 6 monoclonal antibodies
Interleukin 6 is mainly produced and secreted by bone marrow stromal cells and activates the JAK/STAT3, Ras/MAPK and PI3K/Akt signaling pathways. It is a major growth, proliferation and survival promoter in multiple myeloma, protects multiple myeloma from antitumor drugs such as dexamethasone, and prevents Dex and chemotherapy-mediated apoptosis. Investigators have demonstrated that anti-interleukin 6 monoclonal antibody blocks the proliferation of multiple myeloma cell lines and primary multiple myeloma cells. Mouse anti-human interleukin 6 antibodies have been used in the treatment of multiple myeloma with no clinical evidence to support the development of serious adverse effects. One of the antibodies, B-E8, has been shown to be ineffective in patients undergoing secondary hematopoietic stem cell transplantation. siltuximab (CNTO 328) potentiates the cytotoxic effects of the proteasome enzyme inhibitor bortezomib by inhibiting interleukin 6. Treatment of interleukin-6-dependent multiple myeloma cell lines with Siltuximab resulted in dose-limiting inhibition of tumor cell proliferation and differentiation with or without stromal cell involvement. However, non-interleukin-6-dependent cell lines were virtually unaffected. It can be seen that Siltuximab monotherapy is limited and needs to be considered in combination. Interleukin 6 is involved in the transcriptional regulation of the anti-apoptotic protein Mcl-1 and heat shock proteins 70/90. Bortezomib is associated with a variety of pro-apoptotic systems in multiple myeloma cells, but also activates Mcl-1, heat shock proteins 70/90 . This is the rationale for the combination of Siltuximab with bortezomib. When combined, the cytotoxic effect on both interleukin-6-dependent and non-dependent cell lines is stronger than both alone, resulting in partial remission in at least 57% of patients in clinical trials. In addition, Siltuximab may also enhance the cytotoxic effect of dexamethasone. Siltuximab may also synergistically enhance the antitumor effect of melphalan by inhibiting the interleukin-6 pathway. However, it is easy to see that other monoclonal antibody drugs can also be designed using interleukin 6 specific receptors or other downstream signaling molecules as target targets.
2.2.2 Insulin-like growth factor 1 receptor monoclonal antibodies
Insulin-like growth factor 1 is another major pro-myeloma cell growth factor. A variety of tumors, including multiple myeloma, occur when the insulin-like growth factor signaling pathway is aberrantly activated. Activation of the insulin-like growth factor signaling pathway can promote tumor growth through multiple signaling cascades such as PI3K/Akt and Ras/MAPK signaling pathways against multiple myeloma cell apoptosis. Overexpression of insulin-like growth factor 1, insulin-like growth factor 1 receptor and insulin receptor substrates in the pathway is associated with promoting tumor cell proliferation and inhibiting apoptosis, increasing the behavior of multiple myeloma infiltrating surrounding tissues. Among these, multiple myeloma occurs mainly with significantly increased levels of insulin-like growth factor 1. Insulin-like growth factor 1 overexpression is mainly related to insulin-like growth factor 1 and methylation of the gene. Normal B cells or plasma cells do not express the insulin-like growth factor 1 receptor gene, but 31%-50% of plasma cells in untreated multiple myeloma patients do. Moreover, insulin-like growth factor 1 does not favor the antitumor drug bortezomib against multiple myeloma.Descamps et al [22] found that the humanized insulin-like growth factor 1 receptor monoclonal antibody AVE1642 inhibited tumor growth and significantly increased bortezomib-induced apoptosis in CD45-negative tumor cell lines, but not in CD45-positive ones. This synergistic effect may be related to the upregulation of apoptosis gene Bax expression. Moreover, AVE1642 was better tolerated except in patients with concomitant grade 3 hyperglycemic diabetes. However, this combination achieved partial remission in only 18% of patients. figitumumab (CP-751,871) monoclonal antibody blocked insulin
(CP-751,871) monoclonal antibody blocks insulin-like growth factor 1 signaling and inhibits tumor growth either as monotherapy or in combination with chemotherapeutic agents. Monotherapy resulted in stable disease in some patients with no significant dose-limiting toxic effects, and the addition of dexamethasone resulted in partial remission in 33% of patients [23]. Therefore, insulin-like growth factor 1 receptor-related monoclonal antibodies have a greater potential application.
2.2.3 Vascular endothelial growth factor monoclonal antibodies
Vascular endothelial growth factor is the most potent angiogenesis-stimulating factor and is upregulated in most tumors, including multiple myeloma. Investigators have demonstrated that VEGF may
serve as a prognostic determinant in multiple myeloma, with poor overall survival at higher tissue levels. VEGF is mainly produced by multiple myeloma cells and bone marrow stromal cells. In addition to promoting bone marrow angiogenesis to provide nutrition, VEGF stimulates stromal cells to secrete interleukin 6, which inhibits dendritic cell maturation and contributes to tumor cell migration. There is a relationship between the development of multiple myeloma and the level of vascular endothelial growth factor: (1) VEGF is highly expressed in multiple myeloma. (ii) This high expression is associated with complications in advanced stages, the level of cell proliferation and the level of tumor differentiation. (iii) Activation of the vascular endothelial growth factor pathway may be a predictor of survival prognosis in patients with multiple myeloma. ④Vascular endothelial growth factor plays an important role in the development of multiple myeloma. Therefore, VEGF may also be a therapeutic target for multiple myeloma. Studies have shown that bevacizumab, a VEGF monoclonal antibody, inhibits the activation of the signaling cascade in multiple myeloma cells, suppresses capillary angiogenesis, and reduces the proliferation of multiple myeloma cells and stromal cells, either as a single agent or in combination, in patients with multiple myeloma. Monoclonal bevacizumab is well tolerated, with adverse effects mainly including bleeding, hypertension, proteinuria, and thromboembolism [24]. Immunomodulators also have anti-angiogenic effects by downregulating the expression of vascular endothelial growth factor and tumor necrosis factor alpha and basic fibroblast growth factor. Therefore, it is reasonable to consider the combination of bevacizumab, ralidomide and dexamethasone [25]. Preclinical studies showed that the combination led to partial remission in 70% of patients and was not superior to the use of the three drugs alone. Linifanib (ABT-869) is a novel oral potent selective vascular endothelial growth factor, platelet-derived growth factor receptor tyrosine kinase inhibitor. A phase II study on Linifanib in 44 patients with advanced multiple myeloma showed a response rate of up to 7%, a median progression-free survival of 3.7 months, and a median overall survival of 9.3 months, and was within acceptable safety limits [26]. However, it can be seen that more experimental support is needed for the use of vascular endothelial growth factor monoclonal antibody for monotherapy or in combination.
2.2.4 B lymphocyte activating factor monoclonal antibody
B-lymphocyte activating factor (B-lymphocyte activating factor) is a member of the tumor necrosis factor superfamily.
B-lymphocyte activating factor is a member of the tumor necrosis factor superfamily and is produced by monocytes, osteoblasts, and neutrophils in the bone marrow microenvironment. When it binds to tumor necrosis factor-related receptors such as TACI, BCMA, and BAFF-R, it activates the NF-κB, PI3K, and MAPK pathways, thereby maintaining the survival of multiple myeloma cells, promoting B-cell differentiation and maturation, enhancing the ability of B cells to differentiate into antibody-secreting plasma cells, and maintaining resistance to dexamethasone. B-lymphocyte-activating factor also improves adhesion between tumor cells and stromal cells. The anti-B-lymphocyte activating factor monoclonal antibody LY2127399 has anti-multiple myeloma activity and inhibits osteoclastogenesis.
2.2.5 CD74 monoclonal antibody
CD74 is a constant chain that is associated with the major histocompatibility of antibody II α and β chains and directs the transport of these complexes to endonucleosomes and lysosomes. CD74 also acts as a receptor for macrophage migration inhibitory factor, and upon binding to it, activates the NF-κB pathway and promotes the proliferation of multiple myeloma cells. Stein et al. found that Milatuzumab (hLL1, IMMU-115) monoclonal antibody blocked CD74 activity and NF-κB signaling, leading to growth inhibitory effects and apoptosis of multiple myeloma cell lines. Clinical studies have demonstrated that milatuzumab has no significant adverse effects on relapsed and refractory multiple myeloma patients on monotherapy and has stabilized some patients for more than 12 weeks. Other mechanisms of action of the antitumor properties of milatuzumab are not known.
2.2.6 CD40 monoclonal antibody
CD40 is also a member of the tumor necrosis factor receptor family and is generally expressed in B cells, dendritic cells, and some epithelial and endothelial cells. The stimulation of CD40 has a significant effect on the adhesion of tumor cells to stromal cells and increases the production of the pro-growth factors interleukin 6 and vascular endothelial growth factor. investigated the antibody-dependent cell-mediated cytotoxic effects of Dacetuzumab (SGN-40) monoclonal antibody on CD40-positive multiple myeloma cells, which upregulated cytotoxic receptors and downregulated the expression of interleukin 6 receptors, although it did not affect CD40L-related signaling pathways. Moreover, the cytotoxic effect was significantly enhanced by the addition of ralidomide, which was achieved through direct anti-proliferative and anti-apoptotic effects and indirect enhancement of antibody-dependent cell-mediated cytotoxicity of multiple myeloma cells against natural killer effector cells. Phase I clinical studies have demonstrated a maximum toxicity dose of 12 mg/kg per week in combination with ralidomide and dexamethasone, resulting in partial remission in at least 39% of patients.HCD122 is a fully humanized CD40 monoclonal antibody that blocks the CD40L downstream pathway, inhibits CD40L-induced secretion of interleukin 6 and vascular endothelial growth factor in multiple myeloma cells and stromal cells, and reduces CD40L induced adhesion of multiple myeloma cells to fibronectin and stromal cells, thus successfully inhibiting tumor growth. Monotherapy was well tolerated, with 1/9 patients in phase I clinical studies in partial remission and 2/9 in stable disease. Adverse reactions included chills, nausea, fever, and arthralgia, which occurred especially with the first dose. Thus, CD40 monoclonal antibody may inhibit myeloma activity in multiple ways.
2.3 Activation of death receptor-associated monoclonal antibodies
Apoptosis of multiple myeloma cells occurs once the tumor necrosis factor family members FASL and TRAIL bind to the related death receptors FAS, TRAIL-R1/-R2, respectively. inhibition of TRAIL-R expression by RNA interference method suppresses the apoptotic effect. The TRAIL-R monoclonal antibodies that entered the study were mapatumumab, lexatumumab, the latter with relatively weaker antitumor effects. Moreover, their antitumor effect is not affected by other cells in the bone marrow microenvironment, even though these cells protect multiple myeloma cells from TRAIL-induced apoptosis. DR4 and DR5 are tumor necrosis factor-related apoptosis-inducing ligand receptors, and binding of monoclonal antibodies to the receptors induces apoptosis in myeloma cells. DR5 monoclonal antibody is able to induce apoptosis or growth inhibition in tumor necrosis factor-related apoptosis-inducing ligand-sensitive multiple myeloma cell lines in vitro and in vivo. Therefore, the effect of multiple myeloma cell killing can be enhanced by combining bortezomib with mapatumumab.
2.4 Enhancement of antitumor immune response-related monoclonal antibodies
2.4.1 Changes in the immune response in multiple myeloma
Natural killer cells are not only important antibody-dependent effector cells for cell-mediated cytotoxic effects, but also kill multiple myeloma cells in an antibody non-dependent manner. The function of natural killer cells is regulated by several types of activating and inhibiting receptors. In pathological conditions, the expression of MHC class I molecules on the surface of tumor cells is reduced, absent or structurally altered, and the recognition of killer cell inhibitory receptors is blocked, allowing natural killer cells to activate and kill target cells. In addition, patients with multiple myeloma have severely damaged dendritic cells and reduced expression of co-stimulatory molecules. The suppression of myeloma-specific cytotoxic T cells by cytokines and the recruitment of regulatory T cells leads to the phenomenon of tumor escape.
2.4.2 Killer cell inhibitor receptor (KIR) monoclonal antibody
The ligand for the killer cell inhibitor receptor is its own MHC class I molecule or its own peptide-MHC class I antigen complex, which, when bound to the ligand, initiates an inhibitory signal that blocks the activation of natural killer cells and inhibits their killing activity.Benson et al. found that KIR2DL1/2/3 fully humanized antibody 1-7F9 enhances natural killer cell activity by interacting with the HLA-C ligand. Clinical use was well tolerated, and some patients with multiple myeloma could reach a stable state of disease. Ralidomide also inhibited KIR, and in combination with 1-7F9, the cytotoxicity of natural killer cells against multiple myeloma cells was significantly enhanced, which may be related to enhanced migration of natural killer cells to multiple myeloma cells, upregulation of some killer cell activation receptors, and increased natural killer cell γ-interferon and granzyme B. It follows that the combination of KIR monoclonal antibody with ralidomide can be considered.
2.4.3 PD-1 monoclonal antibodies
Dual signaling plays a very important role for the effective activation of the immune response. The B7 family of co-stimulatory signals is widely used in tumor immunotherapy, among which PD-L1 is a newly discovered member of the B7 family. PD-L1 is expressed by plasma cells in most patients with multiple myeloma, and its expression can be detected in a variety of tumor tissues such as liver, gastric and ovarian cancers, and its ligand is PD-1. PD-1 is an immunoglobulin superfamily with a relative molecular mass of 55 000 u The PD-1/PD-L1 axis downregulates the tumor immune response of natural killer cells, thereby reducing the killing effect on multiple myeloma cells, and regulation of this signaling axis is an important way to enhance the tumor immune response. Natural killer cells in healthy individuals do not express PD-1, but can be upregulated to some extent by exogenous leukocyte
interleukin 2 is upregulated to some extent. In contrast, natural killer cells in multiple myeloma patients express PD-1, and natural killer cell function is inhibited by interaction with PD-L1 on myeloma cells. The humanized IgG1 monoclonal antibody CT-011 is a newly developed PD-1 monoclonal antibody that enhances the migration ability of natural killer cells, improves the function of natural killer cells against their own multiple myeloma cells, and promotes the formation of immune complexes. Benson et al. demonstrated that ralidomide not only activated natural killer cells, but also down-regulated PD-L1 expression on myeloma cells, enhancing the killing function of natural killer cells, and therefore had a synergistic effect with CT-011. In addition to the effect on natural killer cells, CT-011 also blocked PD-1/PD-L1 interaction and enhanced myeloma-specific T cell immunity in both in vivo and in vitro experiments. Moreover, CT-011 enhanced the responsiveness of autologous dendritic cell-myeloma cell fusion vaccine to T cells. The percentage of CD4-positive T cells in peripheral blood was elevated and better tolerated in patients treated with CT-011. Host immunity against multiple myeloma was further enhanced by the combination of immunomodulatory drugs. Alternatively, PD-L1 monoclonal antibodies could be designed to act on the PD-1/PD-L1 axis to exert antitumor effects.
2.4.4 CD200 monoclonal antibodies
B/T lymphocytes, epithelial cells, dendritic cells, and neuronal cells all express CD200 to varying degrees, but lack it in normal plasma cells. Multiple myeloma cells can express CD200, inhibit T-cell responses, and lead to tumor escape.Mahadevan et al. found that samalizumab (ALXN6000), a murine anti-human CD200 monoclonal antibody, blocked the interaction of CD200 with the corresponding receptor. Animal model studies found that this monoclonal antibody enhanced peripheral blood monocyte-mediated growth inhibition of CD200-positive tumor cells, decreased regulatory T cells, and increased activated T cells.The drug combination of samalizumab needs to be further explored.
2.5 Bone disease-modifying factor-associated monoclonal antibodies
More than half of the patients with multiple myeloma have other bone diseases at the same time. Enhanced osteoclast and osteogenic cell activity and reduced osteoblast activity contribute to the osteolytic lesion
The development of osteolytic lesions. Moreover, osteoclast activity contributes to the survival and growth of multiple myeloma cells, while osteoblast activity does the opposite. The osteoporosis treatment drug bisphosphonates reduce skeletal complications by inhibiting osteoclast activity. For example, zoledronic acid sodium 4 mg monthly intravenous drip reduces pain but does not completely stop multiple myeloma progression and does not promote bone formation, with bone repair occurring in only some patients. Myeloma cells may express the NF-κB ligand RANKL or induce corresponding expression in stromal cells, and osteoclastic activity is enhanced upon binding to RANK. Osteoprotegerin, in turn, inhibits RANK/RANKL action. The anti-RANKL monoclonal antibody denosumab not only inhibits osteolysis and reduces the level of bone transformation index, but also reduces tumor burden. denosumab was shown by Vanderkerken et al. through clinical trials to impede or delay the effect of skeletal lesions in patients with solid tumors and multiple myeloma not inferior to the effect of zoledronic acid on bone lesions. bHQ880 is a Dkk-1 monoclonal antibody. The DKK family is involved in the formation of embryonic structures and is closely related to bone metabolism and tumorigenesis, and consists of Dkk-1, 2, 3, 4 and Dkk-3 related genes soggy. Among them, DKK1 contains two cysteine-rich structural domains that bind to LRP5 and LRP6 co-receptors to form endocytic vesicles, which in turn prevent the formation of the Wnt-Frizzled complex, or directly bind to LRP5/6 to form trimers and then promote its internalization, block Wnt pathway signaling, inhibit the Wnt/β-linked protein classical transduction pathway, and increase osteoclastogenesis. Therefore, the level of Dkk-1 is higher in osteolytic lesions. The main targets of drug research to inhibit the action of Dkk-1 include antisense oligonucleotides that inhibit Dkk-1 expression and Dkk-1 monoclonal antibodies. The anti-Dkk-1 monoclonal antibody BHQ880 promotes bone formation, inhibits the adhesion of multiple myeloma cells to stromal cells, and reduces the production of interleukin 6 by stromal cells, so it is detrimental to tumor growth. In animal experiments, BHQ880 inhibited the development of osteolytic lesions in rats with multiple myeloma and increased bone density at key sites when combined with zoledronic acid. This shows that the combination of bortezomib with denosumab or BHQ880 is a good choice because bortezomib not only inhibits bone resorption but also promotes bone formation.
2.6 RAS/RAF/MEK/ERK signaling pathway-related immunotherapy
2.6.1 RAS/RAF/MEK/ERK signaling process The RAS/RAF/MEK/ERK signaling pathway is one of several pathways of mitogen-activated protein kinase (MAPK), which is highly conserved and essential for cell proliferation and differentiation, and is usually upregulated in neoplastic diseases such as multiple myeloma. The specific signaling process can be summarized as follows: upon cell stimulation by growth factors or other factors, EGFR forms a dimer with a conformational change, protein tyrosine kinase (PTK) activity is enhanced, and multiple tyrosine residues in the intracellular region are autophosphorylated by kinase action. Tyrosine phosphorylated EGFR is activated by the production of growth factor binding protein (Grb2) as a bridging molecule leading to GDP release and GTP binding of Ras protein. Activated Ras causes the recruitment of the downstream molecule Raf from the cytoplasm to the cell membrane, which is the first molecule in the MAPK cascade phosphorylation reaction, acting on MEK, which in turn acts on ERK, completing the three-stage MAPK phosphorylation and activation program. The activated ERK translocates to the nucleus and phosphorylates some transcription factors such as Elk-1, CREB, Fos, and bead protein transcription factor 1 (Gata-1), changing the expression status of intracellular growth factors and other cytokine genes, regulating cell growth and differentiation status, and inhibiting apoptosis.
2.6.2 RAS/RAF/MEK/ERK pathway-related monoclonal antibodies
Ras oncogene and its signaling pathway play an important role in the development of multiple myeloma, and patients with Ras mutation in vivo have shorter survival and are not sensitive to chemotherapy. Sorafenib, onafarnib, egorafenib, and AZD6244 are all monoclonal antibodies related to the RAS pathway and are in phase I/II clinical studies. Sorafenib (sorafenib) is currently the most promising immune-related molecular targeting agent for multiple myeloma, inhibiting a variety of kinases, including VEGFR-2/-3, PDGFR-β, Flt-3, and c-Kit in addition to Raf kinase. sorafenib has gradually begun to be used in the treatment of multiple myeloma. llovet et al. in a phase III clinical trial found that the median overall survival was 7.9 months in the control group and up to 10.7 months in the sorafenib group. The median time to disease progression changed from 2.8 months in the control group to 5.5 months. Although sorafenib is well tolerated, there are still adverse effects such as diarrhea and skin rashes on the hands and feet, and it is currently used mainly as an adjuvant therapy to prevent relapse after the rest of the treatment methods.MEK inhibitors can also inhibit tumorigenesis and myeloma cell proliferation.O’Neil et al [52] showed that treatment of human multiple myeloma transplanted mice with the selective MEK inhibitor AZD6244 impede the activation of ERK1/2, slow down tumor growth and induce apoptosis in vivo. The inhibitor D0325901 had a pharmacopreventive effect on tumor development. Moreover, the combination of AZD6244 and multiple conventional anti-myeloma effects such as thalidomide increased antitumor activity relative to each alone. However, a phase II multicenter clinical study was unsuccessful in demonstrating the benefit of AZD6244 as monotherapy in patients with advanced multiple myeloma, suggesting a possible limited effect of MEK signaling inhibition alone.
3. Summary and outlook
The treatment of multiple myeloma continues to evolve, but relapse and refractory to treatment are always inevitable clinical challenges. Monoclonal antibody immunotherapy has gradually emerged in recent years, and some monoclonal antibodies have shown clear antitumor effects in preclinical and phase I and II clinical trials, but it is important to further search for myeloma cell-specific targets. The discovery of cytokines, microenvironment in bone marrow and effector molecules of signaling pathways in cell membranes related to the mechanism of multiple myeloma development has provided many new targets for the treatment of multiple myeloma. However, there are still many problems in the development of monoclonal antibodies, such as optimization of drug delivery, improvement of biocompatibility, and rational combination with traditional therapeutic drugs, which need to be further solved. In particular, monoclonal antibodies have many problems such as high cost and tolerance. At the same time, the secondary antibodies generated in the body after the application of monoclonal antibodies make the original monoclonal antibodies useless is also one of the current problems. However, it is reasonable to believe that with the further research, monoclonal antibodies can be better used in clinical practice and bring new hope for the treatment of multiple myeloma. Further development of new monoclonal antibodies, mastering the key points of clinical application, and extending their clinical application will be the research direction and development trend of monoclonal antibodies in the field of medical treatment.