-
Frontiers in Immunology 2024Bispecific antibodies (BsAbs) can simultaneously target two epitopes of different antigenic targets, bringing possibilities for diversity in antibody drug design and are...
INTRODUCTION
Bispecific antibodies (BsAbs) can simultaneously target two epitopes of different antigenic targets, bringing possibilities for diversity in antibody drug design and are promising tools for the treatment of cancers and other diseases. T-cell engaging bsAb is an important application of the bispecific antibody, which could promote T cell-mediated tumor cell killing by targeting tumor-associated antigen (TAA) and CD3 at the same time.
METHODS
This study comprised antibodies purification, Elisa assay for antigen binding, cytotoxicity assays, T cell activation by flow cytometry and xenogenic tumor model .
RESULTS
We present a novel bsAb platform named PHE-Ig technique to promote cognate heavy chain (HC)-light chain (LC) pairing by replacing the CH1/CL regions of different monoclonal antibodies (mAbs) with the natural A and B chains of PHE1 fragment of Integrin β2 based on the knob-in-hole (KIH) technology. We had also verified that PHE-Ig technology can be effectively used as a platform to synthesize different desired bsAbs for T-cell immunotherapy. Especially, BCMA×CD3 PHE-Ig bsAbs exhibited robust anti-multiple myeloma (MM) activity and .
DISCUSSION
Moreover, PHE1 domain was further shortened with D14G and R41S mutations, named PHE-S, and the PHE-S-based BCMA×CD3 bsAbs also showed anti BCMA tumor effect and , bringing more possibilities for the development and optimization of different bsAbs. To sum up, PHE1-based IgG-like antibody platform for bsAb construction provides a novel strategy for enhanced T-cell immunotherapy.
Topics: Antibodies, Bispecific; Animals; Humans; T-Lymphocytes; Mice; Immunoglobulin G; Immunotherapy; Cell Line, Tumor; Multiple Myeloma; Xenograft Model Antitumor Assays; Lymphocyte Activation; CD3 Complex; Antigens, Neoplasm
PubMed: 38933272
DOI: 10.3389/fimmu.2024.1415834 -
International Journal of Molecular... Jun 2024Based on the lack of differences in progression-free and overall survival after a median follow-up of 93 months in our HOVON-65/GMMG-HD4 trial (German part; = 395)... (Randomized Controlled Trial)
Randomized Controlled Trial
Molecular Long-Term Analysis of the GMMG-HD4 Trial in Multiple Myeloma-Patterns of Association of Chromosomal Aberrations with Response and Proliferation Determining Survival in Selecting Treatments in View of Limited Resources in Low- and Middle-Income Countries.
Based on the lack of differences in progression-free and overall survival after a median follow-up of 93 months in our HOVON-65/GMMG-HD4 trial (German part; = 395) randomizing VAD induction (vincristin/adriamycin/dexamthasone)/tandem-transplantation/thalidomide-maintenance vs. PAD induction (bortezomib/adriamycin/dexamethasone)/tandem transplantation/bortezomib maintenance, we discern how chromosomal aberrations determine long-term prognosis by different patterns of association with proliferation and treatment-dependent response, whether responses achieved by different regimens are equal regarding prognosis, and whether subpopulations of patients could be defined as treatable without upfront "novel agents" in cases of limited resources, e.g., in low- or middle-income countries. Serum parameters and risk factors were assessed in 395 patients. CD138-purified plasma cells were subjected to fluorescence in situ hybridization ( = 354) and gene expression profiling ( = 204). We found chromosomal aberrations to be associated in four patterns with survival, proliferation, and response: deletion (del) del17p13, del8p21, del13q14, (gain) 1q21+, and translocation t(4;14) (all adverse) associate with higher proliferation. Of these, del17p is associated with an response (pattern 1), and 1q21+, t(4;14), and del13q14 with a treatment-dependent response (pattern 2). Hyperdiploidy associates with lower proliferation without impacting response or survival (pattern 3). Translocation t(11;14) has no association with survival but a treatment-dependent adverse response (pattern 4). Significantly fewer patients reach a near-complete response or better with "conventional" (VAD) vs. bortezomib-based treatment after induction or high-dose melphalan. These patients, however, show significantly median progression-free and overall survival. Molecularly, patients responding to the two regimens differ in gene expression, indicating distinct biological properties of the responding myeloma cells. Patients with normal renal function (89.4%), low cytogenetic risk (72.5%), or low proliferation rate (37.9%) neither benefit in progression-free nor overall survival from bortezomib-based upfront treatment. We conclude that response level, the treatment by which it is achieved, and molecular background determine long-term prognosis. Chromosomal aberrations are associated in four patterns with proliferation and treatment-dependent responses. Associations with faster and deeper responses can be deceptive in the case of prognostically adverse aberrations 1q21+ and t(4;14). Far from advocating a return to "outdated" treatments, if resources do not permit state-of-the-art-treatment, normal renal function and/or molecular profiling identifies patient subpopulations doing well without upfront "novel agents".
Topics: Humans; Multiple Myeloma; Chromosome Aberrations; Female; Male; Middle Aged; Aged; Antineoplastic Combined Chemotherapy Protocols; Cell Proliferation; Prognosis; Adult; Developing Countries; Dexamethasone; Bortezomib; Thalidomide
PubMed: 38928138
DOI: 10.3390/ijms25126431 -
Biomolecules Jun 2024Immunomodulatory imide drugs (IMiDs) play a crucial role in the treatment landscape across various stages of multiple myeloma. Despite their evident efficacy, some...
Immunomodulatory imide drugs (IMiDs) play a crucial role in the treatment landscape across various stages of multiple myeloma. Despite their evident efficacy, some patients may exhibit primary resistance to IMiD therapy, and acquired resistance commonly arises over time leading to inevitable relapse. It is critical to develop novel therapeutic options to add to the treatment arsenal to overcome IMiD resistance. We designed, synthesized, and screened a new class of polyfluorinated thalidomide analogs and investigated their anti-cancer, anti-angiogenic, and anti-inflammatory activity using in vitro and ex vivo biological assays. We identified four lead compounds that exhibit potent anti-myeloma, anti-angiogenic, anti-inflammatory properties using three-dimensional tumor spheroid models, in vitro tube formation, and ex vivo human saphenous vein angiogenesis assays, as well as the THP-1 inflammatory assay. Western blot analyses investigating the expression of proteins downstream of cereblon (CRBN) reveal that Gu1215, our primary lead candidate, exerts its activity through a CRBN-independent mechanism. Our findings demonstrate that the lead compound Gu1215 is a promising candidate for further preclinical development to overcome intrinsic and acquired IMiD resistance in multiple myeloma.
Topics: Multiple Myeloma; Humans; Thalidomide; Drug Resistance, Neoplasm; Antineoplastic Agents; Angiogenesis Inhibitors; Cell Line, Tumor; Anti-Inflammatory Agents; Drug Evaluation, Preclinical
PubMed: 38927128
DOI: 10.3390/biom14060725 -
Biomolecules May 2024Schnitzler syndrome is a rare disorder characterized by a chronic urticarial rash associated with immunoglobulin M (IgM) monoclonal gammopathy. Schnitzler syndrome... (Review)
Review
Schnitzler syndrome is a rare disorder characterized by a chronic urticarial rash associated with immunoglobulin M (IgM) monoclonal gammopathy. Schnitzler syndrome shares strong clinicopathologic similarities with monogenic IL-1-mediated autoinflammatory disorders and is now considered an acquired adult-onset autoinflammatory disease. The spectacular effect of interleukin-1 inhibitors demonstrates the key role of this cytokine in the pathogenesis of the disease. However, the physiopathology of Schnitzler syndrome remains elusive, and the main question regarding the relationship between autoinflammatory features and monoclonal gammopathy is still unanswered. The purpose of this narrative review is to describe what is currently known about the pathogenesis of this peculiar disease, as well as to address its diagnosis and management.
Topics: Schnitzler Syndrome; Humans; Immunoglobulin M; Interleukin-1
PubMed: 38927050
DOI: 10.3390/biom14060646 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2024Multiple myeloma (MM) is an incurable malignant plasma cell diseases, the incidence of which is increasing year by year. The application of immunomodulators drugs,... (Review)
Review
Multiple myeloma (MM) is an incurable malignant plasma cell diseases, the incidence of which is increasing year by year. The application of immunomodulators drugs, proteasome inhibitors, anti-CD38 antibodies, CAR-T, and HSCT have significantly improved the prognosis of patients with MM, however new therapeutic tools need to be developed to improve the prognosis of patients with relapsed/refractory after conventional regimens treatment. Bispecific antibodies are a novel immunotherapeutic approach that generates immune synapses by binding to targets on malignant plasma cells and cytotoxic immune effector cells (T cells/natural killer cells), leading to T/NK cells activation and malignant plasma cell lysis. Several preclinical and phase I clinical studies have shown good efficacy, bringing new possibilities for patients with relapsed/refractory MM to improve their prognosis in the future in combination with the rest of the treatment options. This article summarizes the classification of bispecific antibodies developed in recent years, and the results of preclinical and clinical trials, which will provide some reference for treating MM.
Topics: Humans; Antibodies, Bispecific; Multiple Myeloma; Immunotherapy; Killer Cells, Natural; Prognosis; T-Lymphocytes
PubMed: 38926994
DOI: 10.19746/j.cnki.issn.1009-2137.2024.03.046 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2024To investigate the correlation between the stimulator of interferon genes ( ) promoter polymorphism and the susceptibility to infection after chemotherapy for multiple...
OBJECTIVE
To investigate the correlation between the stimulator of interferon genes ( ) promoter polymorphism and the susceptibility to infection after chemotherapy for multiple myeloma.
METHODS
A total of 102 patients who had undergone chemotherapy for multiple myeloma in our hospital from January 2016 to July 2022 were selected. Depending on the presence or absence of infection after chemotherapy, the enrolled patients were divided into infection group (53 cases) and non-infection group (49 cases). The infection sites and distribution characteristics of pathogenic bacteria of the infection group were analyzed. The genotype distribution of gene promoter rs587777609 was compared between the two groups, and the risk factors of infection after chemotherapy for multiple myeloma were analyzed.
RESULTS
For infection site, digestive system, respiratory system, urinary system, skin and mucous membranes accounted for 43.40%, 26.42%, 20.75%, and 9.43%, respectively. For pathogenic bacteria, Gram-negative bacteria, Gram-positive bacteria and fungi accounted for 57.14%, 26.98%, and 15.87%, respectively. The CC genotype frequency of gene rs587777609 locus in the infection group was lower than that in the non-infection group, while the TT genotype frequency was higher than that in the non-infection group ( < 0.05). The proportions of patients with diabetes, chronic obstructive pulmonary disease, renal insufficiency, serum albumin level< 35 g/L, ISS stage III, mechanical ventilation, and indwelling catheter in the infection group were higher than those in the non-infection group ( < 0.05). Multivariate logistic regression analysis showed that diabetes ( =1.992), serum albumin level< 35 g/L ( =2.782), ISS stage III ( =2.707), mechanical ventilation ( =3.031), and TT genotype ( =2.401) were risk factors of infection after chemotherapy for multiple myeloma ( < 0.05).
CONCLUSION
There is a correlation between promoter polymorphism and the susceptibility to infection after chemotherapy for multiple myeloma, and patients with TT genotype have a higher risk of infection.
Topics: Humans; Multiple Myeloma; Membrane Proteins; Promoter Regions, Genetic; Genotype; Risk Factors; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Male; Infections; Female
PubMed: 38926990
DOI: 10.19746/j.cnki.issn.1009-2137.2024.03.042 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2024To evaluate the clinical and prognostic value of prothrombin time (PT) and activated partial thromboplastin time (APTT) in newly diagnosed patients with multiple myeloma...
OBJECTIVE
To evaluate the clinical and prognostic value of prothrombin time (PT) and activated partial thromboplastin time (APTT) in newly diagnosed patients with multiple myeloma (MM).
METHODS
The clinical data of 116 newly diagnosed MM patients in the Second Hospital and Third Hospital of Shanxi Medical University from October 2014 to March 2022 were analyzed retrospectively, and the patients were divided into two groups: normal PT and APTT group and prolonged PT or APTT group. The differences in sex, age, classification, staging, bleeding events, laboratory indicators [including hemoglobin (Hb), platelet count (PLT), serum calcium, serum albumin (ALB), lactate dehydrogenase (LDH), serum creatinine and β-microglobulin], and cytogenetic characteristics between the two groups of patients were compared. The effect of prolonged PT or APTT on survival of patients with MM was analyzed.
RESULTS
Compared with patients in normal PT and APTT group, patients in prolonged PT or APTT group were more likely to experience bleeding events (=5.087, =0.024), with lower ALB levels (=4.962, =0.026) and PLT levels (=4.309, =0.038), and higher serum calcium levels (=5.056, =0.025). The positive rates of del17p, del13q and 1q21+ in prolonged PT or APTT group were higher than those in normal PT and APTT group, but the difference was not statistically significant ( >0.05). K-M survival analysis showed that the prolonged PT or APTT group had a shorter median progression-free survival (PFS) ( =0.032) and overall survival (OS) ( =0.032). Multivariate Cox analysis showed that prolonged PT or APTT (=2.116, 95% :1.025-4.372, =0.043) and age ≥65 years (=2.403, 95% : 1.195-4.836, =0.014) were independent risk factor for OS in newly diagnosed MM patients. However, prolonged PT or APTT had no significant effect on PFS of newly diagnosed MM patients (=1.162, 95% : 0.666-2.026, =0.597).
CONCLUSION
Newly diagnosed MM patients with prolonged PT or APTT have worse clinical indicators, shorter PFS and OS. Prolonged PT or APTT is an independent risk factor for OS in MM patients.
Topics: Humans; Multiple Myeloma; Partial Thromboplastin Time; Prognosis; Retrospective Studies; Prothrombin Time; Male; Female; Middle Aged
PubMed: 38926971
DOI: 10.19746/j.cnki.issn.1009-2137.2024.03.023 -
[Bone Metabolism of Multiple Myeloma Bone Disease Patients with Different Blood Separation Results].Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2024To investigate the clinical significance of bone metabolic indexes for disease assessment and curative effect monitoring in multiple myeloma (MM) bone disease (MBD)...
OBJECTIVE
To investigate the clinical significance of bone metabolic indexes for disease assessment and curative effect monitoring in multiple myeloma (MM) bone disease (MBD) patients with different blood separation results.
METHODS
A total of 134 newly diagnosed MM patients treated in Cangzhou Hospital of Integrated TCM-WM-Hebei were enrolled and divided into control group [119 cases, serum, colloid and red blood cell (RBC) from top to bottom of sample] and abnormal group (15 cases, serum, mixed layer of RBC and serum, colloid and RBC from top to bottom of sample) according to the results of blood separation. According to the imaging findings, MBD was classified into grade 0-4, grade 0-2 was mild, and grade 3-4 was severe. The MBD grade of patients in the two groups was analyzed. The curative effect of MBD patients after chemotherapy and the changes of blood separation results and bone metabolic indexes before and after treatment were evaluated. The correlation between β-microglobulin (MG) and bone metabolic indexes was analyzed by Pearson correlation analysis.
RESULTS
In the control group, there were 69 cases of grade 0-2 and 50 cases of grade 3-4, while in the abnormal group, there were 5 cases of grade 0-2 and 10 cases of grade 3-4, the difference was statistically significant ( < 0.05). The serum β-MG, β-CTX levels in abnormal group were both significantly higher than those in control group, while the levels of P1NP and osteocalcin (OC) were significantly lower (all < 0.001). In the control group, there were 95 patients with ≥ partial response (PR) and the blood separation results were not changed, while 24 patients with
0.05). Compared with before treatment, the levels of β-CTX and β-MG in the control group with unchanged blood separation results were significantly decreased (both < 0.001), while the levels of P1NP and OC were significantly increased ( < 0.01, < 0.001), and the level of each index in the patients transformed to abnormal blood separation result after treatment did not significantly change ( >0.05); the levels of β-CTX and β-MG in the abnormal group transformed to normal blood separation result were significantly decreased (both < 0.01), while the levels of P1NP and OC were significantly increased ( < 0.001, < 0.01), and the level of each index in patients with unchanged blood separation results did not significantly change (P>0.05). Pearson correlation analysis showed that serum β-MG was positively correlated with β-CTX ( =0.709, < 0.001), and negatively correlated with P1NP and OC ( =-0.410, =-0.412, both < 0.001). CONCLUSION
MBD patients with abnormal blood separation results have higher bone disease grade and poor prognosis, which is closely related to the significant increase of bone resorption index β-CTX level and decrease of bone formation index P1NP and OC levels, leading to more serious bone metabolic homeostasis disorder. The results of blood separation combined with the changes of bone metabolic indexes can be used as one of the comprehensive predictors of disease condition, efficacy monitoring and prognosis evaluation of MBD patients.
Topics: Humans; Multiple Myeloma; Bone and Bones; Bone Diseases; beta 2-Microglobulin; Collagen Type I; Osteocalcin; Male; Middle Aged
PubMed: 38926970
DOI: 10.19746/j.cnki.issn.1009-2137.2024.03.022 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2024To investigate the value of serum free light chain (sFLC) and serum calcium ion in the diagnosis and prognosis of multiple myeloma (MM).
OBJECTIVE
To investigate the value of serum free light chain (sFLC) and serum calcium ion in the diagnosis and prognosis of multiple myeloma (MM).
METHODS
Forty patients with MM treated in Henan Provincial People's Hospital from January 2018 to January 2022 were selected as the observation group, and 40 healthy volunteers were selected as the control group. The differences of sFLC-κ、sFLC-λ、sFLC-κ/λ, serum calcium ions, etc between the two groups were compared. Meanwhile, the differences of sFLC-κ、sFLC-λ、sFLC-κ/λ, serum calcium ions, etc in different international staging systems (ISS), chemotherapy efficacy and prognosis patients were analyzed.
RESULTS
The levels of sFLC-κ[(98.39±21.19) (12.01±4.45) mg/L], sFLC-λ[(210.20±45.54) (14.10±5.11) mg/L] and proportions of hypocalcemia (65% 0) in the observation group were significantly higher than those in the control group ( < 0.05), while sFLC-κ/ λ ratio[(0.44±0.10) (0.87±0.12)] and serum calcium ions [(1.98±0.46) (2.42±0.40)mmol/L] were significantly lower than those in the control group ( < 0.05). The sFLC-κ, sFLC-λ, the proportion of hypocalcemia and the course of hypocalcemia in ISS stage III patients in the observation group were significantly higher than those in stage I and II patients ( < 0.05), while sFLC-κ/λ ratio, and serum calcium ions were significantly lower than those in stage I and II patients ( < 0.05). The levels of sFLC-κ [(107.76±21.22) (94.67±20.11)mg/L], sFLC- λ[(245.54±41.12) (205.54±50.22)mg/L] of patients with hypocalcemia in the observation group was significantly higher than those without hypocalcemia ( < 0.05), while the sFLC-κ/λ ratio was significantly lower than those without hypocalcemia [(0.42±0.04) (0.47±0.06); < 0.05]. The levels of sFLC-κ [(107.29±20.14) ( 91.11±18.92)mg/L], sFLC-λ[(247.98±42.26) (179.29±39.32)mg/L] in patients with ineffective chemotherapy were significantly higher than those in patients with effective chemotherapy ( < 0.05), while the sFLC-κ/λ ratio was significantly lower than those in patients with effective chemotherapy [(0.43±0.10) (0.50±0.09); < 0.05)]. The area under the ROC curve for sFLC-κ, sFLC-λ, sFLC-κ/λ predicting ineffective chemotherapy was 0.803, 0.793 and 0.699 respectively, < 0.05. There was no significant difference in sFLC-κ, sFLC-λ, sFLC-κ/λ ratio, serum calcium ion, hypocalcemia ratio and hypocalcemia course between survival and death patients ( >0.05).
CONCLUSION
sFLC and serum calcium are related to ISS stage of MM patients. sFLC level has a certain value to predict the curative effect of chemotherapy in MM patients. However, the prognostic values of sFLC and serum calcium are not yet confirmed for MM patients.
Topics: Humans; Multiple Myeloma; Calcium; Prognosis; Immunoglobulin kappa-Chains; Immunoglobulin Light Chains; Hypocalcemia; Case-Control Studies; Female; Immunoglobulin lambda-Chains; Male; Middle Aged
PubMed: 38926969
DOI: 10.19746/j.cnki.issn.1009-2137.2024.03.021 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2024To investigate the relative expression level and clinical significance of in serum of patients with multiple myeloma (MM).
OBJECTIVE
To investigate the relative expression level and clinical significance of in serum of patients with multiple myeloma (MM).
METHODS
The expression of in serum of 108 MM patients and five MM cell lines including RPMI 8226, NCI-H929, U266, OPM2 and CAG were detected by real-time fluorescence quantitative PCR. The diagnostic value of in MM was evaluated by receiver operating characteristic (ROC) curve analysis. The correlation of with patients' characteristics was analyzed.
RESULTS
Compared with control groups, the expression of was up-regulated in serum of MM patients and MM cell lines (all < 0.05). ROC curve analysis showed that the optimal cut-off value of was 262.4, the area under curve (AUC) was 0.924(95% : 0.884-0.964), and sensitivity and specificity was 83.3% and 91.7%, respectively, which indicated that had good evaluation value in MM patients. Compared with low- expression group, patients in high- expression group had higher levels of βmicroglobulin (β-MG) and Cystatin C (Cys-C) but lower albumin (ALB) (all < 0.05). Compared with MM patients with International Staging System (ISS) stage I, the expression level of was significantly higher in patients with stage II and III (both < 0.05).
CONCLUSION
is helpful to distinguish MM patients from healthy adults, which is correlated with the prognostic indicators such as β-MG, ALB, and ISS stage.
Topics: Humans; Multiple Myeloma; RNA, Long Noncoding; Cell Line, Tumor; beta 2-Microglobulin; ROC Curve; Clinical Relevance
PubMed: 38926968
DOI: 10.19746/j.cnki.issn.1009-2137.2024.03.020