Daratumumab is the first CD38 monoclonal antibody drug approved for the treatment of patients with multiple myeloma. It can bind to CD38 expressed by tumor cells, inhibit tumor cell growth and induce myeloma cell apoptosis through a variety of immune-related mechanisms. Meanwhile, CD38 is also expressed in other cells, including regulatory T cells, regulatory B cells and myeloid-derived suppressor cells, which provides a theoretical basis for the treatment of hematological tumor diseases other than non-multiple myeloma diseases. This article reviews the research progress and application of this part.
Humans ; Multiple Myeloma/pathology* ; ADP-ribosyl Cyclase 1 ; Antibodies, Monoclonal/pharmacology* ; Hematologic Neoplasms/drug therapy*

OX40 is a costimulatory receptor that is expressed primarily on activated CD4⁺, CD8⁺, and regulatory T cells. The ligation of OX40 to its sole ligand OX40L potentiates T cell expansion, differentiation, and activation and also promotes dendritic cells to mature to enhance their cytokine production. Therefore, the use of agonistic anti-OX40 antibodies for cancer immunotherapy has gained great interest. However, most of the agonistic anti-OX40 antibodies in the clinic are OX40L-competitive and show limited efficacy. Here, we discovered that BGB-A445, a non-ligand-competitive agonistic anti-OX40 antibody currently under clinical investigation, induced optimal T cell activation without impairing dendritic cell function. In addition, BGB-A445 dose-dependently and significantly depleted regulatory T cells in vitro and in vivo via antibody-dependent cellular cytotoxicity. In the MC38 syngeneic model established in humanized OX40 knock-in mice, BGB-A445 demonstrated robust and dose-dependent antitumor efficacy, whereas the ligand-competitive anti-OX40 antibody showed antitumor efficacy characterized by a hook effect. Furthermore, BGB-A445 demonstrated a strong combination antitumor effect with an anti-PD-1 antibody. Taken together, our findings show that BGB-A445, which does not block OX40-OX40L interaction in contrast to clinical-stage anti-OX40 antibodies, shows superior immune-stimulating effects and antitumor efficacy and thus warrants further clinical investigation.
Mice ; Animals ; Receptors, Tumor Necrosis Factor/physiology* ; Receptors, OX40 ; Membrane Glycoproteins ; Ligands ; Antibodies, Monoclonal/pharmacology* ; Antineoplastic Agents/pharmacology*

Immunotherapies based on immune checkpoint blockade (ICB) have significantly improved patient outcomes and offered new approaches to cancer therapy over the past decade. To date, immune checkpoint inhibitors (ICIs) of CTLA-4 and PD-1/PD-L1 represent the main class of immunotherapy. Blockade of CTLA-4 and PD-1/PD-L1 has shown remarkable efficacy in several specific types of cancers, however, a large subset of refractory patients presents poor responsiveness to ICB therapy; and the underlying mechanism remains elusive. Recently, numerous studies have revealed that metabolic reprogramming of tumor cells restrains immune responses by remodeling the tumor microenvironment (TME) with various products of metabolism, and combination therapies involving metabolic inhibitors and ICIs provide new approaches to cancer therapy. Nevertheless, a systematic summary is lacking regarding the manner by which different targetable metabolic pathways regulate immune checkpoints to overcome ICI resistance. Here, we demonstrate the generalized mechanism of targeting cancer metabolism at three crucial immune checkpoints (CTLA-4, PD-1, and PD-L1) to influence ICB therapy and propose potential combined immunotherapeutic strategies co-targeting tumor metabolic pathways and immune checkpoints.
Humans ; Antibodies, Monoclonal/pharmacology* ; B7-H1 Antigen/antagonists & inhibitors* ; CTLA-4 Antigen/antagonists & inhibitors* ; Immune Checkpoint Inhibitors/pharmacology* ; Neoplasms/drug therapy* ; Programmed Cell Death 1 Receptor ; Tumor Microenvironment

Objective: To explore the differences in the biological effects of different expansion systems on natural killer (NK) cells, as well as the safety and preliminary clinical efficacy in the treatment of patients with recurrence after allogeneic hematopoietic stem cell transplantation (allo-HSCT) . Methods: Peripheral blood cells from healthy donors were stimulated with either CD3 combined with CD52 or K562 feeder cells loaded with IL-21/4-1BB to induce NK cell expansion. Changes in the NK cell phenotype, cytokine secretion, and cytotoxicity before and after expansion were detected. We also evaluated the safety and clinical efficacy of two different expansion strategies for patients received NK infusion. Results: Compared with the CD3/CD52 monoclonal antibody amplification system, the feeder cell expansion group had a higher purity of NK cells and higher expression ratios of NK cell surface activation receptors such as DNAM-1 and NKp30, while inhibitory receptor CTLA-4 expression was low and NKG2D/CD25/CD69/ Trail/PD-1/TIM-3/TIGIT had no statistically significant differences between the groups. Further functional results showed that the expression level of KI67 in NK cells after expansion in the two groups increased significantly, especially in the feeder cell expansion group. Simultaneously, the perforin and granzyme B levels of NK cells in the feeder cell expansion group were significantly higher than in the CD3/CD52 expansion group. A retrospective analysis of eight patients who received monoclonal antibody-expanded NK cell reinfusion and nine patients with trophoblast cell-expanded NK cell reinfusion was done. The disease characteristics of the two groups were comparable, NK cell reinfusion was safe, and there were no obvious adverse reactions. Clinical prognostic results showed that in the CD3/CD52 monoclonal antibody amplification group, the MRD conversion rate was 50% (2/4) , and the feeder cell expansion group was 50% (3/6) . After 5 years of follow-up from allo-HSCT, three patients in the monoclonal antibody expansion group had long-term survival without leukemia, and the remaining five patients had died; two patients died in the feeder cell expansion group, and the other six patients had long-term survival. Six cases had GVHD before NK cell reinfusion, and GVHD did not aggravate or even relieved after NK cell reinfusion. Conclusions: Preliminary results show that the biological characteristics of NK cells with diverse expansion strategies are significantly different, which may affect the clinical prognosis of patients with recurrence or persistent minimal residual disease after HSCT. The two groups of patients treated with NK cells from different expansion strategies had no obvious adverse reactions after NK cell infusion, but efficacy still needs to be further confirmed.
Antibodies, Monoclonal/pharmacology* ; Graft vs Host Disease/metabolism* ; Hematopoietic Stem Cell Transplantation ; Humans ; Killer Cells, Natural ; Retrospective Studies ; Treatment Outcome

OBJECTIVE: To investigate the effectiveness and safety of low concentration dithiothreitol (DTT) in removing the interference of monoclonal anti-CD38 on transfusion compatibility testing, and develop a reasonable clinical transfusion strategy. METHODS: The blood type, direct antiglobulin testing (DAT) and antibody screening were tested according to standard methods. Antibody screening cells and donor's red blood cells were treated by DTT 0.2, 0.1, 0.05, 0.02, 0.01 and 0.005 mol/L, and antibody screening and cross-matching of serums after monoclonal anti-CD38 treatment were performed by anti-human globulin card. RESULTS: The 0.01 mol/L DTT at 37℃ for 30 minutes could remove the effect of monoclonal anti-CD38 on antibody screening and cross-matching, meanwhile retain their effectiveness in detecting anti-K, anti-LW, anti-JMH, anti-Lu^b, anti-e, anti-Di^a and anti-Jk^a alloantibodies. All the 10 patients had no acute or delayed haemolytic transfusion reactions and their routine blood tests showed that the red blood cells transfusion was effective. CONCLUSION The 0.01 mol/L DTT is a safe and effective method for removing the interference of monoclonal anti-CD38 with transfusion compatibility testing, while retaining the ability to detect most alloantibodies.
Antibodies, Monoclonal/pharmacology* ; Blood Grouping and Crossmatching ; Blood Transfusion ; Dithiothreitol/pharmacology* ; Erythrocytes ; Humans ; Isoantibodies/pharmacology*

Animals ; Antibodies, Monoclonal/pharmacology* ; Disease Models, Animal ; Interleukins/antagonists & inhibitors* ; Lupus Erythematosus, Systemic/therapy* ; Mice ; Mice, Inbred MRL lpr

Colorectal cancer (CRC) is a common malignant tumor in the digestive tract, and 30%-85% of CRCs express epidermal growth factor receptors (EGFRs). Recently, treatments using cetuximab, also named C225, an anti-EGFR monoclonal antibody, for CRC have been demonstrated to cause an S492R mutation in EGFR. However, little is known about the biological function of S492R EGFR. Therefore, we attempted to elucidate its biological function in CRC cells and explore new treatment strategies for this mutant form. Our study indicated that EGFR and S492R EGFR accelerate the growth of CRC cells in vitro and in vivo and monoclonal antibody CH12, which specifically recognizes an EGFR tumor-specific epitope, can bind efficiently to S492R EGFR. Furthermore, mAb CH12 showed significantly stronger growth suppression activities and induced a more potent antibody-dependent cellular cytotoxicity effect on CRC cells bearing S492R EGFR than mAb C225. mAb CH12 obviously suppressed the growth of CRC xenografts with S492R EGFR mutations in vivo. Thus, mAb CH12 may be a promising therapeutic agent in treating patients with CRC bearing an S492R EGFR mutation.
Animals ; Antibodies, Monoclonal ; pharmacology ; Antineoplastic Agents, Immunological ; pharmacology ; Caco-2 Cells ; Cell Proliferation ; drug effects ; Colorectal Neoplasms ; therapy ; ErbB Receptors ; genetics ; immunology ; Female ; HT29 Cells ; Humans ; Mice ; Mice, Inbred BALB C ; Mutation ; Xenograft Model Antitumor Assays

The NCCN has recently released its 2017 version 1.0 guideline for colorectal cancer. There are several updates from this new version guideline which are believed to change the current clinical practice. Update one, low-dose aspirin is recommended for patients with colorectal cancer after colectomy for secondary chemoprevention. Update two, biological agents are removed from the neoadjuvant treatment regimen for resectable metastatic colorectal cancer (mCRC). This update is based on lack of evidence to support benefits of biological agents including bevacizumab and cetuximab in the neoadjuvant setting. Both technical criteria and prognostic information should be considered for decision-making. Currently biological agents may not be excluded from the neoadjuvant setting for patients with resectable but poor prognostic disease. Update three, panitumumab and cetuximab combination therapy is only recommended for left-sided tumors in the first line therapy. The location of the primary tumor can be both prognostic and predictive in response to EGFR inhibitors in metastatic colorectal cancer. Cetuximab and panitumumab confer little benefit to patients with metastatic colorectal cancer in the primary tumor originated on the right side. On the other hand, EGFR inhibitors provide significant benefit compared with bevacizumab-containing therapy or chemotherapy alone for patients with left primary tumor. Update four, PD-1 immune checkpoint inhibitors including pembrolizumab or nivolumab are recommended as treatment options in patients with metastatic deficient mismatch repair (dMMR) colorectal cancer in second- or third-line therapy. dMMR tumors contain thousands of mutations, which can encode mutant proteins with the potential to be recognized and targeted by the immune system. It has therefore been hypothesized that dMMR tumors may be sensitive to PD-1 inhibitors.
Antibodies, Monoclonal ; pharmacology ; therapeutic use ; Antibodies, Monoclonal, Humanized ; therapeutic use ; Antineoplastic Agents ; therapeutic use ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Aspirin ; administration & dosage ; therapeutic use ; Bevacizumab ; therapeutic use ; Biological Products ; therapeutic use ; Brain Neoplasms ; drug therapy ; genetics ; Cetuximab ; therapeutic use ; Clinical Decision-Making ; methods ; Colorectal Neoplasms ; drug therapy ; genetics ; pathology ; prevention & control ; therapy ; Contraindications ; Humans ; Mutation ; physiology ; Neoadjuvant Therapy ; standards ; Neoplasm Metastasis ; drug therapy ; Neoplastic Syndromes, Hereditary ; drug therapy ; genetics ; Practice Guidelines as Topic ; Prognosis ; Secondary Prevention ; methods ; standards

OBJECTIVETo investigate the effects of inhibiting TIM-4 function in Kupffer cells (KCs) on liver graft rejection in mice and explore the underlying mechanism.

METHODSMouse models of orthotopic liver transplantation were treated with a control mAb group and TIM-4 mAb. The activated KCs were assayed with immunohistochemistry after operation. The expression of TIM-4 in KCs were assayed with Western blotting and RT-PCR and the levels of AST, ALT, TBIL, TNF-α, IFN-γ and CCL2 were assayed detected. The expression of TIM-4 in KCs was observed with laser confocal microscopy. HE staining was used to observe the microstructure of the liver tissues, and the number of CD25Foxp3T cells was determined using with flow cytometry; the proteins levels of p-P65and p-P38 were assayed with Western blotting. The donor mice were treated with clodronate liposomes to destroy the KCs in the liver before transplantation, and the liver grafts were examined for graft rejection.

RESULTSThe number of activated KCs in the liver graft increased progressively over time. Compared with the sham-operated group, the liver graft showed significantly increased TIM-4 protein and mRNA levels at 1, 3, and 7 days after transplantation (P<0.05) and increased levels of AST, ALT, TBIL, TNF-α, IFN-γ and CCL2 at 7 days (P<0.05). The graft in TIM-4 mAb group showed mild pathological changes with a mean RAI score of 2.67∓0.75, which was significantly lower than that in control mAb group (P<0.05). The mean survival time of the recipient mice was 53.8∓6.4 days in TIM-4 mAb group, significantly longer than that in the control mAB group (14.5∓2.9 days, P<0.05). Donor treatment with clodronate liposomes resulted in comparable RAI scores in TIM-4 mAb and control mAb groups (8.01∓0.64 vs 7.93∓0.56, P>0.05). The protein levels of p-P65 and p-P38 in TIM-4 mAb group were significantly lower than those in control mAb group (P<0.05), and CD25Foxp3T cells in the liver graft increased significantly in TIM-4 mAb group.

CONCLUSIONInhibition of TIM-4 function in KCs reduces the production of inflammatory factors after liver transplantation possibly by inhibiting the NF-κB and MAPK signaling pathways and promoting the proliferation of Foxp3Treg cells to induce allograft tolerance.

Animals ; Antibodies, Monoclonal ; pharmacology ; Graft Rejection ; Immunohistochemistry ; Kupffer Cells ; drug effects ; metabolism ; Liver ; surgery ; Liver Transplantation ; Male ; Membrane Proteins ; antagonists & inhibitors ; Mice ; NF-kappa B ; metabolism ; T-Lymphocytes, Regulatory ; immunology

PURPOSE: Reduced brain glucose metabolism and basal forebrain cholinergic neuron degeneration are common features of Alzheimer's disease and have been correlated with memory function. Although regions representing glucose hypometabolism in patients with Alzheimer's disease are targets of cholinergic basal forebrain neurons, the interaction between cholinergic denervation and glucose hypometabolism is still unclear. The aim of the present study was to evaluate glucose metabolism changes caused by cholinergic deficits. MATERIALS AND METHODS: We lesioned basal forebrain cholinergic neurons in rats using 192 immunoglobulin G-saporin. After 3 weeks, lesioned animals underwent water maze testing or were analyzed by 18F-2-fluoro-2-deoxyglucose positron emission tomography. RESULTS: During water maze probe testing, performance of the lesioned group decreased with respect to time spent in the target quadrant and platform zone. Cingulate cortex glucose metabolism in the lesioned group decreased, compared with the normal group. Additionally, acetylcholinesterase activity and glutamate decarboxylase 65/67 expression declined in the cingulate cortex. CONCLUSION: Our results reveal that spatial memory impairment in animals with selective basal forebrain cholinergic neuron damage is associated with a functional decline in the GABAergic and cholinergic system associated with cingulate cortex glucose hypometabolism.
Acetylcholine/metabolism ; Alzheimer Disease ; Animals ; Antibodies, Monoclonal/*pharmacology ; Basal Forebrain/*drug effects/metabolism ; Cholinergic Agents/administration & dosage/*pharmacology ; Cholinergic Neurons/*drug effects/metabolism ; Fluorodeoxyglucose F18 ; GABAergic Neurons/*drug effects/metabolism ; Glucose/*metabolism ; Gyrus Cinguli/*drug effects/metabolism ; Humans ; Injections ; Maze Learning ; Motor Activity/physiology ; Positron-Emission Tomography ; Rats ; Ribosome Inactivating Proteins, Type 1/*pharmacology