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1.
Sci Immunol ; 8(79): eadd4947, 2023 Jan 13.
Article in English | MEDLINE | ID: mdl-36638191

ABSTRACT

The PD-1 receptor triggers a negative immunoregulatory mechanism that prevents overactivation of immune cells and subsequent inflammatory diseases. Because of its biological significance, PD-1 has been a drug target for modulating immune responses. Immunoenhancing anti-PD-1 blocking antibodies have become a widely used cancer treatment; however, little is known about the required characteristics for anti-PD-1 antibodies to be capable of stimulating immunosuppressive activity. Here, we show that PD-1 agonists exist in the group of anti-PD-1 antibodies recognizing the membrane-proximal extracellular region in sharp contrast to the binding of the membrane-distal region by blocking antibodies. This trend was consistent in an analysis of 81 anti-human PD-1 monoclonal antibodies. Because PD-1 agonist antibodies trigger immunosuppressive signaling by cross-linking PD-1 molecules, Fc engineering to enhance FcγRIIB binding of PD-1 agonist antibodies notably improved human T cell inhibition. A PD-1 agonist antibody suppressed inflammation in murine disease models, indicating its clinical potential for treatment of various inflammatory disorders, including autoimmune diseases.


Subject(s)
Antibodies, Monoclonal , T-Lymphocytes , Animals , Mice , Antibodies, Blocking/metabolism , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal/metabolism , Humans
2.
Oncotarget ; 14: 1-13, 2023 Jan 12.
Article in English | MEDLINE | ID: mdl-36634212

ABSTRACT

Overexpression of CD74, a type II transmembrane glycoprotein involved in MHC class II antigen presentation, has been reported in many B-cell non-Hodgkin lymphomas (NHLs) and in multiple myeloma (MM). STRO-001 is a site-specific, predominantly single-species antibody-drug conjugate (ADC) that targets CD74 and has demonstrated efficacy in xenograft models of MM and tolerability in non-human primates. Here we report results of preclinical studies designed to elucidate the potential role of STRO-001 in B-cell NHL. STRO-001 displayed nanomolar and sub-nanomolar cytotoxicity in 88% (15/17) of cancer cell lines tested. STRO-001 showed potent cytotoxicity on proliferating B cells while limited cytotoxicity was observed on naïve human B cells. A linear dose-response relationship was demonstrated in vivo for DLBCL models SU-DHL-6 and U2932. Tumor regression was induced at doses less than 5 mg/kg, while maximal activity with complete cures were observed starting at 10 mg/kg. In MCL Mino and Jeko-1 xenografts, STRO-001 starting at 3 mg/kg significantly prolonged survival or induced tumor regression, respectively, leading to tumor eradication in both models. In summary, high CD74 expression levels in tumors, nanomolar cellular potency, and significant anti-tumor in DLBCL and MCL xenograft models support the ongoing clinical study of STRO-001 in patients with B-cell NHL.


Subject(s)
Antineoplastic Agents , Immunoconjugates , Lymphoma, Non-Hodgkin , Multiple Myeloma , Animals , Humans , Immunoconjugates/pharmacology , Immunoconjugates/therapeutic use , Antibodies, Monoclonal/pharmacology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Multiple Myeloma/pathology , Lymphoma, Non-Hodgkin/drug therapy , Cell Line, Tumor
3.
Oncoimmunology ; 12(1): 2163784, 2023.
Article in English | MEDLINE | ID: mdl-36632565

ABSTRACT

Primary effusion lymphoma (PEL), an aggressive non-Hodgkin lymphoma caused by Kaposi sarcoma-associated herpesvirus (KSHV), lacks standard therapy and has a median survival of 10-22 months with combination chemotherapy. PEL is a tumor of plasmablast-like B cells generally expressing CD38, the target of daratumumab (Dara). Initially, we assessed PEL cells from eight patients and established that each expressed high levels of CD38 by flow cytometry. PEL cell lines were also evaluated and most had high CD38 expression. We then assessed Dara's effects on complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) of PEL cell lines as well as its clinical benefits on two patients with PEL. Despite high CD38 expression, Dara did not induce CDC of PEL cell lines, due in part to high levels of the complement-inhibitory proteins, CD55 and CD59. However, Dara induced significant and dose-dependent increases in ADCC, particularly in those lines with high CD38 levels. Two FDA-approved drugs, all trans-retinoic acid (ATRA) and pomalidomide (Pom), significantly increased surface CD38 levels in low-CD38 expressing PEL cell lines, resulting in increased Dara-induced ADCC. Two patients with refractory PEL were treated with Dara alone or in combination with Pom. One patient with leptomeningeal PEL had a complete response to Dara and Pom combination treatment. Others had improvement in performance status and resolution of malignant ascites with Dara alone. Together, these data support the use of Dara monotherapy or in combination with ATRA or Pom as a potential therapeutic option for PEL.


Subject(s)
Lymphoma, Primary Effusion , Humans , Lymphoma, Primary Effusion/drug therapy , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Cytotoxicity, Immunologic , Tretinoin/pharmacology , Tretinoin/therapeutic use
4.
Sci Rep ; 13(1): 582, 2023 Jan 11.
Article in English | MEDLINE | ID: mdl-36631511

ABSTRACT

B-cell Non-Hodgkin lymphomas are the malignancies of lymphocytes. CD20 is a membrane protein, which is highly expressed on the cell surface of the B-cells in NHL. Treatments using monoclonal antibodies (mAbs) have resulted in failure in some cases. Nanobodies (NBs), single-domain antibodies with low molecular weights and a high specificity in antigen recognition, could be practical alternatives for traditional mAbs with superior characteristics. To design an optimized NB as a candidate CD20 inhibitor with raised binding affinity to CD20, the structure of anti-CD20 NB was optimized to selectively target CD20. The 3D structure of the NB was constructed based on the optimal templates (6C5W and 5JQH), and the key residues were determined by applying a molecular docking study. After identifying the key residues, some mutations were introduced using a rational protocol to improve the binding affinity of the NB to CD20. The rational mutations were conducted using the experimental design (Taguchi method). Six residues (Ser27, Thr28, Phe29, Ile31, Asp99, and Asn100) were selected as the key residues, and five residues were targeted for rational mutation (Trp, Phe, His, Asp, and Tyr). Based on the mutations suggested by the experimental design, two optimized NB structures were constructed. NB2 showed a remarkable binding affinity to CD20 in docking studies with a binding energy of - 853 kcal/mol. The optimized NB was further evaluated using molecular dynamics simulation. The results revealed that CDR1 (complementarity determining regions1) and CDR3 are essential loops for recognizing the antigen. NB2 could be considered as a potential inhibitor of CD20, though experimental evaluations are needed to confirm it.


Subject(s)
Antibodies, Monoclonal , Single-Domain Antibodies , Molecular Docking Simulation , Antibodies, Monoclonal/pharmacology , Single-Domain Antibodies/pharmacology , B-Lymphocytes , Antigens, CD20
5.
Front Immunol ; 13: 1017780, 2022.
Article in English | MEDLINE | ID: mdl-36605208

ABSTRACT

The use of immune checkpoint inhibitors to treat cancer resulted in unprecedented and durable clinical benefits. However, the response rate among patients remains rather modest. Previous work from our laboratory demonstrated the efficacy of using attenuated bacteria as immunomodulatory anti-cancer agents. The current study investigated the potential of utilizing a low dose of attenuated Salmonella typhimurium to enhance the efficacy of PD-L1 blockade in a relatively immunogenic model of colon cancer. The response of MC38 tumors to treatment with αPD-L1 monoclonal antibody (mAb) was variable, with only 30% of the mice being responsive. Combined treatment with αPD-L1 mAb and Salmonella resulted in 75% inhibition of tumor growth in 100% of animals. Mechanistically, the enhanced response correlated with a decrease in the percentage of tumor-associated granulocytic cells, upregulation in MHC class II expression by intratumoral monocytes and an increase in tumor infiltration by effector T cells. Collectively, these alterations resulted in improved anti-tumor effector responses and increased apoptosis within the tumor. Thus, our study demonstrates that a novel combination treatment utilizing attenuated Salmonella and αPD-L1 mAb could improve the outcome of immunotherapy in colorectal cancer.


Subject(s)
Antineoplastic Agents , Colonic Neoplasms , Animals , Mice , B7-H1 Antigen , Immunotherapy/methods , Antineoplastic Agents/therapeutic use , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Colonic Neoplasms/drug therapy , Salmonella
6.
Antiviral Res ; 210: 105513, 2023 Feb.
Article in English | MEDLINE | ID: mdl-36592670

ABSTRACT

Antibody-based therapy is emerging as a critical therapeutic countermeasure to treat acute viral infections by offering rapid protection against clinical disease. The advancements in structural biology made it feasible to rationalize monoclonal antibodies (mAbs) by identifying key and, possibly, neutralizing epitopes of viral proteins for therapeutic purposes. A critical component in assessing mAbs during pandemics requires the development of rapid but detailed methods to detect and quantitate the neutralization activity. In this study, we developed and optimized two high-content image (HCI)-based assays: one to detect viral proteins by staining and the second to quantify cytopathic viral effects by a label-free phenotypic assay. These assays were employed to screen for therapeutic antibodies against the monkeypox virus (MPXV) using surrogate poxviruses such as vaccinia virus (VACV). Plaque-based neutralization results confirmed the HCI data. The phenotypic assay found pox virus-induced syncytia formation in various cells, and we were able to quantitate and use this phenotype to screen mAbs. The HCI identified several potent VACV-neutralizing antibodies that showed in vitro efficacy against both clades of MPXV. In addition, a combination study of ST-246/tecovirimat/TPOXX a single neutralizing antibody Ab-40, showed synergistic activity against VACV in an in-vitro neutralization assay. This rapid high-content method utilizing state-of-the-art technologies enabled the evaluation of hundreds of mAbs quickly to identify several potent anti-MPXV neutralizing mAbs for further development.


Subject(s)
Antibodies, Viral , Monkeypox virus , Antibodies, Neutralizing , Vaccinia virus/genetics , Viral Proteins , Antibodies, Monoclonal/pharmacology , Neutralization Tests
7.
Pharmacol Res ; 187: 106631, 2023 Jan.
Article in English | MEDLINE | ID: mdl-36586644

ABSTRACT

According to the ß-amyloid (Aß) hypothesis of Alzheimer's disease (AD), brain Aß accumulation is the primary cascade event leading to cognitive deficit and dementia. Numerous anti-Aß drugs either inhibiting production or aggregation of Aß or stimulating its clearance have failed to show clinical benefit in large scale AD trials, with ß- and γ-secretase inhibitors consistently worsening cognitive and clinical decline. In June 2021, the FDA approved aducanumab, an anti-Aß monoclonal antibody for early AD based on its ability to reduce brain amyloid plaques, while two other amyloid-clearing antibodies (lecanemab and donanemab) have recently produced encouraging cognitive and clinical results. We reviewed AD trials using PubMed, meeting abstracts and ClinicalTrials.gov and evaluated the effects of such drugs on cerebrospinal fluid (CSF) Aß levels, correlating them with cognitive effects. We found that ß-secretase and γ-secretase inhibitors produce detrimental cognitive effects by significantly reducing CSF Aß levels. We speculate that monoclonal antibodies targeting Aß protofibrils, fibrils or plaques may improve cognitive performance in early AD by increasing soluble Aß levels through Aß aggregate disassembly and/or stabilization of existing Aß monomers.These findings suggest that the real culprit in AD may be decreased levels of soluble monomeric Aß due to sequestration into brain Aß aggregates and plaques.


Subject(s)
Alzheimer Disease , Humans , Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Amyloid beta-Peptides , Cognition
8.
Expert Opin Drug Metab Toxicol ; 18(11): 755-767, 2022 Nov.
Article in English | MEDLINE | ID: mdl-36582117

ABSTRACT

INTRODUCTION: The introduction of monoclonal antibodies to the chemotherapy backbone treatment has challenged the paradigm of metastatic colorectal cancer (mCRC) treatment. Their mechanism of action and pharmacokinetics are complex but important to understand in order to improve patient selection and treatment outcomes for mCRC population. AREAS COVERED: This review examines the scientific data, pharmacodynamics, and pharmacokinetics of approved monoclonal antibodies used to treat mCRC patients, including agents targeting signaling via VEGFR (bevacizumab and ramucirumab), EGFR (cetuximab and panitumumab), HER2/3 target therapy, and immunotherapy agents such as pembrolizumab or nivolumab. Efficacy and mechanism of action of bispecific antibodies are also covered. EXPERT OPINION: mCRC is a heterogeneous disease and the optimal selection and sequence of treatments is challenging. Monoclonal antibodies have complex pharmacokinetics and pharmacodynamics, with important interactions between them. The arrival of bioequivalent molecules to the market increases the need for the characterization of pharmacokinetics and pharmacodynamics of classic monoclonal antibodies to reach bioequivalent novel molecules.


Subject(s)
Antineoplastic Agents , Colorectal Neoplasms , Humans , Antineoplastic Agents/pharmacology , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , ErbB Receptors/therapeutic use , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Cetuximab/therapeutic use , Immunotherapy
9.
J Hematol Oncol ; 15(1): 177, 2022 12 29.
Article in English | MEDLINE | ID: mdl-36581954

ABSTRACT

Anti-CD38 monoclonal antibodies (mAbs), daratumumab, and isatuximab have represented a breakthrough in the treatment of multiple myeloma (MM). Recently, CD38-based mAbs were expected to achieve increasing potential beyond MM, which encouraged us to develop new anti-CD38 mAbs to meet clinical needs. In this study, we developed a novel humanized anti-CD38 antibody, FTL004, which exhibited enhanced pro-apoptotic ability and negligible binding to red blood cells (RBCs). FTL004 presented a better ability to induce direct apoptosis independent of Fc-mediated cross-linking against lymphoma and MM cell lines as well as primary myeloma cells derived from MM patients. For instance, FTL004 induced RPMI 8226 cells with 55% early apoptosis cells compared with 20% in the isatuximab-treated group. Of interest, FTL004 showed ignorable binding to CD38 on human RBCs in contrast to tumor cells, even at concentrations up to 30 µg/mL. Furthermore, with an engineered Fc domain, FTL004 displayed stronger antibody-dependent cellular cytotoxicity (ADCC) against CD38+ malignant cells. In vivo MM and non-Hodgkin lymphoma tumor xenograft models showed that FTL004 possessed an effective anti-tumor effect. Cryo-electron microscopy structure resolved two epitope centers of FTL004 on CD38: one of which was unique while the other partly overlapped with that of isatuximab. Taken together, FTL004 distinguishes it from other CD38 targeting mAbs and represents a potential candidate for the treatment of MM and non-Hodgkin lymphoma.


Subject(s)
Antineoplastic Agents , Lymphoma, Non-Hodgkin , Multiple Myeloma , Humans , Multiple Myeloma/pathology , Cryoelectron Microscopy , ADP-ribosyl Cyclase 1 , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Lymphoma, Non-Hodgkin/drug therapy , Erythrocytes/pathology
10.
Sci Rep ; 12(1): 22420, 2022 12 27.
Article in English | MEDLINE | ID: mdl-36575233

ABSTRACT

Epidermal growth factor receptor (EGFR) is an effective target for those patients with metastatic colorectal cancers that retain the wild-type RAS gene. However, its efficacy in many cancers, including bladder cancer, is unclear. Here, we studied the in vitro effects of cetuximab monoclonal antibodies (mAbs) targeting EGFR on the bladder cancer cells and role of CD46. Cetuximab was found to inhibit the growth of both colon and bladder cancer cell lines. Furthermore, cetuximab treatment inhibited AKT and ERK phosphorylation in the bladder cancer cells and reduced the expression of CD46 membrane-bound proteins. Restoration of CD46 expression protected the bladder cancer cells from cetuximab-mediated inhibition of AKT and ERK phosphorylation. We hypothesized that CD46 provides protection to the bladder cancer cells against mAb therapies. Bladder cancer cells were also susceptible to cetuximab-mediated immunologic anti-tumor effects. Further, cetuximab enhanced the cell killing by activating both antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in bladder cancer cells. Restoration of CD46 expression protected the cells from both CDC and ADCC induced by cetuximab. Together, CD46 exhibited a cancer-protective effect against both direct (by involvement of PBMC or complement) and indirect cytotoxic activity by cetuximab in bladder cancer cells. Considering its clinical importance, CD46 could be an important link in the action mechanism of ADCC and CDC intercommunication and may be used for the development of novel therapeutic strategies.


Subject(s)
Antineoplastic Agents , Urinary Bladder Neoplasms , Humans , Cetuximab/pharmacology , Leukocytes, Mononuclear/metabolism , Proto-Oncogene Proteins c-akt , Antibodies, Monoclonal, Humanized/pharmacology , Cell Line, Tumor , Antineoplastic Agents/pharmacology , Antibodies, Monoclonal/pharmacology , ErbB Receptors/metabolism , Antibody-Dependent Cell Cytotoxicity , Urinary Bladder Neoplasms/drug therapy , Membrane Cofactor Protein
11.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 34(11): 1194-1199, 2022 Nov.
Article in Chinese | MEDLINE | ID: mdl-36567565

ABSTRACT

OBJECTIVE: To investigate the role of platelets aggregation in the developing process of ductus arteriosus closure of newborn pups, and the effect of platelet membrane glycoprotein IIb-IIIa (GPIIb-IIIa) receptor antagonist (tirofiban). METHODS: Four 24-month-old Beagle bitches were selected and numbered 1, 2, 3, and 4 respectively, and their pups were removed by cesarean section in two batches 1-2 days before the expected date of delivery. Bitches 1 and 2 were the first batch. Eighteen newborn pups were removed after cesarean section as the control group. They were divided into three subgroups: 1-hour subgroup, 4-hour subgroup, and 12-hour subgroup according to postnatal time point, with 6 pups in each subgroup. The newborn pups were injected with normal saline 10 mL/kg via jugular vein immediately after birth. Bitches 3 and 4 were the second batch. Nineteen newborn pups were removed by cesarean section as tirofiban group. They were also divided into three subgroups: 1-hour subgroup (n = 6), 4-hour subgroup (n = 6), and 12-hour subgroup (n = 7) according to the postnatal time point. The newborn pups were injected with tirofiban hydrochloride injection 10 mL/kg (10 mL injection including 2.5 mg of tirofiban) via jugular vein immediately after birth. The diameter of ductus arteriosus was measured by echocardiography. Ductus arteriosus was removed by surgical dissection and divided into two parts. Western blotting and immunohistochemistry were used to detect the expression of platelet membrane GPIIb-IIIa, respectively. RESULTS: In the control group, 1 newborn pup died at 0.5 hour after birth in the 1-hour subgroup. The experiment was completed by 19 in the tirofiban group. Ductus arteriosus of all pups were not closed in 1-hour subgroups of the two groups, and there was no significant difference in the diameter of ductus arteriosus between the control group and the tirofiban group (mm: 1.72±0.08 vs. 1.70±0.11, P > 0.05). Ductus arteriosus of 1 newborn pup in 4-hour subgroup of the control group was closed, but the ductus arteriosus of all the newborn pups in 4-hour subgroup of the tirofiban group were not closed. The diameter of ductus arteriosus of the tirofiban group was significantly larger than that of the control group (mm: 1.52±0.15 vs. 0.95±0.48, P < 0.05). Ductus arteriosus of all pups were closed in 12-hour subgroup of the control group, but the ductus arteriosus of 2 pups of the tirofiban group were still not closed, with the diameter of ductus arteriosus of 1.0 mm and 1.1 mm, respectively. Western blotting showed that at 1-hour, 4-hour and 12-hour after birth, the expression of platelet membrane GPIIb-IIIa was gradually increased in ductus arteriosus of newborn pups of the two groups. The expression of GPIIb-IIIa in 1-hour subgroup of the tirofiban group was significantly lower than that in the control group (GPIIb-IIIa/ß-actin: 0.67±0.07 vs. 0.84±0.16, P < 0.05). The expression of GPIIb-IIIa in 4-hour and 12-hour subgroups of the tirofiban group were slightly lower than those in the control group (GPIIb-IIIa/ß-action: 0.85±0.12 vs. 0.95±0.11 in 4-hour subgroup, 1.04±0.16 vs. 1.09±0.17 in 12-hour subgroup, both P > 0.05). Immunohistochemistry showed that the change trend of platelet membrane GPIIb-IIIa in ductus arteriosus of newborn pups in both groups was similar to the results of Western blotting. CONCLUSIONS: The ductus arteriosus of newborn pups begin to close 1-4 hours after birth, and all closed at 12 hours after birth. The expression of platelet membrane GPIIb-IIIa in ductus arteriosus increase gradually after birth, and the platelet aggregation may participate in and promote ductus arteriosus closure to some extent. Tirofiban, a platelet membrane GPIIb-IIIa receptor antagonist, may delay ductus arteriosus closure of newborn pups to some extent by inhibiting platelet aggregation.


Subject(s)
Ductus Arteriosus , Platelet Aggregation , Dogs , Pregnancy , Animals , Female , Tirofiban/pharmacology , Platelet Aggregation Inhibitors/pharmacology , Animals, Newborn , Ductus Arteriosus/metabolism , Cesarean Section , Tyrosine , Antibodies, Monoclonal/pharmacology , Platelet Glycoprotein GPIIb-IIIa Complex/metabolism , Blood Platelets/metabolism
12.
Front Immunol ; 13: 1060576, 2022.
Article in English | MEDLINE | ID: mdl-36569922

ABSTRACT

Introduction: In de-novo kidney transplantation, the CTLA4-Ig fusion protein belatacept is associated with improved graft function but also an increased risk of acute rejection compared to calcineurin inhibitor therapy. The combination with a second costimulation blocker could potentially improve outcome while avoiding calcineurin inhibitor toxicity. The aim of this study was to define the conditions under which the combination of CTLA4-Ig and CD40L blockade leads to rejection-free permanent graft survival in a stringent murine heart transplantation model. Methods: Naïve wild-type or CD40L (CD154) knock-out mice received a fully mismatched BALB/c cardiac allograft. Selected induction and maintenance protocols for CTLA4-Ig and blocking αCD40L monoclonal antibodies (mAB) were investigated. Graft survival, rejection severity and donor-specific antibody (DSA) formation were assessed during a 100-day follow-up period. Results and Discussion: Administering αCD40L mAb as monotherapy at the time of transplantation significantly prolonged heart allograft survival but did not further improve the outcome when given in addition to chronic CTLA4-Ig therapy (which prolongs graft survival to a median of 22 days). Likewise, chronic αCD40L mAb therapy (0.5mg) combined with perioperative CTLA4-Ig led to rejection in a proportion of mice and extensive histological damage, despite abrogating DSA formation. Only the permanent interruption of CD40-CD40L signaling by using CD40L-/- recipient mice or by chronic αCD40L administration synergized with chronic CTLA4-Ig to achieve long-term allograft survival with preserved histological graft integrity in all recipients without DSA formation. The combination of α-CD40L and CTLA4-Ig works most effectively when both therapeutics are administered chronically.


Subject(s)
Antigens, CD , CD40 Ligand , Animals , Mice , Abatacept/therapeutic use , Calcineurin Inhibitors , Antibodies, Monoclonal/pharmacology , Allografts
13.
Trends Pharmacol Sci ; 44(2): 85-97, 2023 Feb.
Article in English | MEDLINE | ID: mdl-36566131

ABSTRACT

Monoclonal antibodies represent an exciting class of therapeutics against respiratory viral infections. Notwithstanding their specificity and affinity, the conventional parenteral administration is suboptimal in delivering antibodies for neutralizing activity in the airways due to the poor distribution of macromolecules to the respiratory tract. Inhaled therapy is a promising approach to overcome this hurdle in a noninvasive manner, while advances in antibody engineering have led to the development of unique antibody formats which exhibit properties desirable for inhalation. In this Opinion, we examine the major challenges surrounding the development of inhaled antibodies, identify knowledge gaps that need to be addressed and provide strategies from a drug delivery perspective to enhance the efficacy and safety of neutralizing antibodies against respiratory viral infections.


Subject(s)
Antibodies, Neutralizing , COVID-19 , Humans , Antibodies, Neutralizing/pharmacology , Antibodies, Neutralizing/therapeutic use , SARS-CoV-2 , Antibodies, Viral/therapeutic use , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use
14.
Viruses ; 14(12)2022 Nov 29.
Article in English | MEDLINE | ID: mdl-36560681

ABSTRACT

We have recently revealed that the new SARS-CoV-2 Omicron sublineages BA.4 and BA.5 exhibit increased resistance to cilgavimab, a therapeutic monoclonal antibody, and the resistance to cilgavimab is attributed to the spike L452R substitution. However, it remains unclear how the spike L452R substitution renders resistance to cilgavimab. Here, we demonstrated that the increased resistance to cilgavimab of the spike L452R is possibly caused by the steric hindrance between cilgavimab and its binding interface on the spike. Our results suggest the importance of developing therapeutic antibodies that target SARS-CoV-2 variants harboring the spike L452R substitution.


Subject(s)
Antibodies, Monoclonal , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Humans , Antibodies, Monoclonal/pharmacology , COVID-19 , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics
16.
J Am Chem Soc ; 145(1): 322-333, 2023 Jan 11.
Article in English | MEDLINE | ID: mdl-36542493

ABSTRACT

Alternative antibacterial therapies refractory to existing mechanisms of antibiotic resistance are urgently needed. One such attractive therapy is to inhibit bacterial adhesion and colonization. Ser O-heptosylation (Ser O-Hep) on autotransporters of Gram-negative bacteria is a novel glycosylation and has been proven to be essential for bacterial colonization. Herein, we chemically synthesized glycopeptides containing this atypical glycan structure and an absolute C6 configuration through the assembly of Ser O-Hep building blocks. Using glycopeptides as haptens, we generated first-in-class poly- and monoclonal antibodies, termed Anti-SerHep1a and Anti-SerHep1b, that stereoselectively recognize Ser O-heptosylation (d/l-glycero) with high specificity in vitro and in vivo. Importantly, these antibodies effectively blocked diffusely adhering Escherichia coli 2787 adhesion to HeLa cells and in mice in a dose- and Ser O-Hep-dependent manner. Together, these antibodies represent not only useful tools for the discovery of unknown serine O-heptosylated proteins bearing various C6 chiral centers but also a novel class of antiadhesion therapeutic agents for the treatment of bacterial infection.


Subject(s)
Antibodies, Monoclonal , Polysaccharides , Humans , Animals , Mice , HeLa Cells , Glycosylation , Polysaccharides/chemistry , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Escherichia coli , Glycopeptides/chemistry
17.
Sci Transl Med ; 14(676): eabj4221, 2022 12 21.
Article in English | MEDLINE | ID: mdl-36542691

ABSTRACT

Tissue fibrosis is a key driver of end-stage organ failure and cancer, overall accounting for up to 45% of deaths in developed countries. There is a large unmet medical need for antifibrotic therapies. Claudin-1 (CLDN1) is a member of the tight junction protein family. Although the role of CLDN1 incorporated in tight junctions is well established, the function of nonjunctional CLDN1 (njCLDN1) is largely unknown. Using highly specific monoclonal antibodies targeting a conformation-dependent epitope of exposed njCLDN1, we show in patient-derived liver three-dimensional fibrosis and human liver chimeric mouse models that CLDN1 is a mediator and target for liver fibrosis. Targeting CLDN1 reverted inflammation-induced hepatocyte profibrogenic signaling and cell fate and suppressed the myofibroblast differentiation of hepatic stellate cells. Safety studies of a fully humanized antibody in nonhuman primates did not reveal any serious adverse events even at high steady-state concentrations. Our results provide preclinical proof of concept for CLDN1-specific monoclonal antibodies for the treatment of advanced liver fibrosis and cancer prevention. Antifibrotic effects in lung and kidney fibrosis models further indicate a role of CLDN1 as a therapeutic target for tissue fibrosis across organs. In conclusion, our data pave the way for further therapeutic exploration of CLDN1-targeting therapies for fibrotic diseases in patients.


Subject(s)
Antibodies, Monoclonal , Cell Plasticity , Animals , Mice , Humans , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Claudin-1 , Liver Cirrhosis/drug therapy
18.
PLoS One ; 17(12): e0277956, 2022.
Article in English | MEDLINE | ID: mdl-36525420

ABSTRACT

Standard treatment for patients with high-risk neuroblastoma remains multimodal therapy including chemoradiation, surgical resection, and autologous stem cell rescue. Immunotherapy has demonstrated success in treating many types of cancers; however, its use in pediatric solid tumors has been limited by low tumor mutation burdens. Gastrin-releasing peptide receptor (GRP-R) is overexpressed in numerous malignancies, including poorly-differentiated neuroblastoma. Monoclonal antibodies (mAbs) to GRP-R have yet to be developed but could serve as a potential novel immunotherapy. This preclinical study aims to evaluate the efficacy of a novel GRP-R mAb immunotherapy against neuroblastoma. We established four candidate anti-GRP-R mAbs by screening a single-chain variable fragment (scFv) library. GRP-R mAb-1 demonstrated the highest efficacy with the lowest EC50 at 4.607 ng/ml against GRP-R expressing neuroblastoma cells, blocked the GRP-ligand activation of GRP-R and its downstream PI3K/AKT signaling. This resulted in functional inhibition of cell proliferation and anchorage-independent growth, indicating that mAb-1 has an antagonist inhibitory role on GRP-R. To examine the antibody-dependent cellular cytotoxicity (ADCC) of GRP-R mAb-1 on neuroblastoma, we co-cultured neuroblastoma cells with natural killer (NK) cells versus GRP-R mAb-1 treatment alone. GRP-R mAb-1 mediated ADCC effects on neuroblastoma cells and induced release of IFNγ by NK cells under co-culture conditions in vitro. The cytotoxic effects of mAb-1 were confirmed with the secretion of cytotoxic granzyme B from NK cells and the reduction of mitotic tumor cells in vivo using a murine tumor xenograft model. In summary, GRP-R mAb-1 demonstrated efficacious anti-tumor effects on neuroblastoma cells in preclinical models. Importantly, GRP-R mAb-1 may be an efficacious, novel immunotherapy in the treatment of high-risk neuroblastoma patients.


Subject(s)
Neuroblastoma , Receptors, Bombesin , Child , Humans , Mice , Animals , Receptors, Bombesin/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Cell Line, Tumor , Neuroblastoma/metabolism , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use
19.
MAbs ; 15(1): 2156317, 2023.
Article in English | MEDLINE | ID: mdl-36524835

ABSTRACT

Receptor occupancy assays applied in clinical studies provide insights into pharmacokinetic-pharmacodynamic relationships for therapeutic antibodies. When measured by different assays, however, receptor occupancy results can be controversial, as was observed for nivolumab, a monoclonal antibody targeting programmed cell death 1 (PD-1) receptor. We suggested an explanation of results obtained and a mechanistic approach based on specific features of the receptor occupancy assays: measurement of the free or bound receptor, normalized to the baseline or at each time point. The approach was evaluated against controversial clinical data on PD-1 receptor occupancy by nivolumab. It was shown that receptor occupancy measured by different assays might vary substantially if the internalization rate of the bound receptor is higher than the rate of degradation of the free receptor. Equations proposed in this work can be applied in quantitative systems pharmacology models to describe target receptor occupancy by different therapeutic antibodies.


Subject(s)
Network Pharmacology , Nivolumab , Nivolumab/pharmacology , Programmed Cell Death 1 Receptor/metabolism , Antibodies, Monoclonal/pharmacology
20.
J Clin Invest ; 132(24)2022 12 15.
Article in English | MEDLINE | ID: mdl-36519546

ABSTRACT

Fibroblastic reticular cells (FRCs) maintain the architecture of secondary lymphoid organs, which optimize interactions between antigen-presenting dendritic cells and reactive naive T cells. In this issue of the JCI, Zhao, Jung, and colleagues investigated CD4+FoxP3+ regulatory T cell development and long-term heart allograft survival in recipients treated with peritransplant costimulatory blockade to inhibit CD40/CD40 ligand (CD40L) signaling. Treatment with an anti-CD40L monoclonal antibody (mAb) increased the lymph node (LN) population of Madcam1+ FRCs and altered their transcription profile to express immunoregulatory mediators. Administration of nanoparticles, containing the anti-CD40L mAb and a targeting antibody against high endothelial venules, delivered the treatment into LNs of allograft recipients. Direct LN delivery of the costimulatory blockade allowed decreased dosing and increased the efficacy in extending graft survival. The results provide insights into mechanisms by which FRCs can promote donor-reactive tolerance, and establish a strategy for administering costimulation-blocking reagents that circumvent systemic effects and improve allograft outcomes.


Subject(s)
CD40 Ligand , Graft Survival , Mice , Animals , Mice, Inbred BALB C , Mice, Inbred C57BL , T-Lymphocytes , Antibodies, Monoclonal/pharmacology , CD40 Antigens , Graft Rejection
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