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941.
《Clinical therapeutics》2020,42(1):108-120.e1
PurposeGantenerumab, a fully human anti–amyloid-β IgG1 monoclonal antibody that binds to aggregated forms of amyloid-β, is being investigated as a potential disease-modifying treatment for early (prodromal to mild) Alzheimer disease (AD). Our study compared the pain associated with 5- and 15-s subcutaneous injections of gantenerumab and evaluated the tolerability and pharmacokinetic properties of subcutaneous gantenerumab.MethodsThis randomized, open-label, single-active-dose, placebo-controlled crossover study was conducted in 50 healthy volunteers aged 40–80 years with no history of clinically significant disorders, drug or alcohol abuse, familial history of early-onset AD, or prior gantenerumab exposure. Eligible participants were randomized to a sequence of one 300-mg SC gantenerumab injection into the abdomen and 2 SC placebo injections (1 into the abdomen and 1 into the thigh) during 5 or 15 s. All injections were administered at least 90 min apart. Participants were assessed for local pain by visual analog scale (VAS) and verbal rating scale; safety profiles were assessed by recording adverse events (AEs), and plasma pharmacokinetic properties were also evaluated.FindingsImmediately after the subcutaneous gantenerumab injection, the pain VAS score was numerically higher without reaching statistical significance in the 5-s versus 15-s injection group (VAS least-squares mean difference, 7.492 mm; 95% CI, −4.439–19.423 mm). In both injection speed groups, the mean pain VAS score was comparable after subcutaneous gantenerumab and placebo injections into the abdomen. Pain was reported after needle insertion and immediately after dosing, subsiding within 5 min after the dose. The pain VAS score was numerically higher after SC placebo injection into the thigh versus abdomen (5-s injection group: mean [SD] VAS score, 26.68 [27.83] vs 19.20 [25.60] mm; 15-s injection group: mean [SD] VAS score, 14.16 [20.62] vs 9.48 [12.04] mm). No serious AEs were reported; no participants withdrew because of an AE. All AEs were of mild intensity, were transient, and had resolved without sequelae at follow-up. The most common AEs were injection site reactions; redness was the most frequently observed skin reactivity event after subcutaneous gantenerumab administration (5-s injection group: 36%; 15-s injection group: 32%). After subcutaneous administration, gantenerumab reached a peak plasma concentration at a median time of 119 h (approximately 5 days); plasma concentrations declined in a monoexponential manner. Comparable pharmacokinetic profiles were observed between the injection speed groups.ImplicationsSubcutaneous gantenerumab injections at speeds of 5 and 15 s were well tolerated in healthy volunteers and could enable at-home administration by patients with AD or their caregivers. ClinicalTrials.gov identifier: NCT02882009. 相似文献
942.
《Clinical therapeutics》2020,42(8):1612-1616
PurposeThe purpose of this case report was to investigate the clinical efficacy and tolerability of anti–programmed cell death protein (PD)-1 antibody combined with iodine (I)-125 seed brachytherapy in lung cancer treatment.MethodsThree patients with advanced PD-L1–positive non–small-cell lung cancer were treated first with I-125 seed brachytherapy and then with anti–PD-1 antibody. Clinical efficacy was evaluated with Response Evaluation Criteria in Solid Tumors.FindingsAll 3 patients had complete response or partial response. None of the 3 patients had reported obvious adverse events.ImplicationsEncouraging preliminary results provide important support for further clinical treatment of lung cancer using anti–PD-1 antibody combined with I-125 seed brachytherapy. 相似文献
943.
Chien-Han Kao Jaw-Yuan Wang Kuo-Hsiang Chuang Chih-Hung Chuang Ta-Chun Cheng Yuan-Chin Hsieh Yun-long Tseng Bing-Mae Chen Steve R. Roffler Tian-Lu Cheng 《Biomaterials》2014
Methoxy PEGylated nanoparticles (mPEG-NPs) are increasingly used for cancer imaging and therapy. Here we describe a general and simple approach to confer tumor tropism to any mPEG-NP. We demonstrate this approach with humanized bispecific antibodies (BsAbs) that can bind to both mPEG molecules on mPEG-NPs and to EGFR or HER2 molecules overexpressed on the surface of cancer cells. Simple mixing of BsAbs with mPEG-NPs can mediate preferential binding of diverse mPEG-NPs to cancer cells that overexpress EGFR or HER2 under physiological conditions and significantly increase cancer cell killing by liposomal doxorubicin to EGFR+ and HER2+ cancer cells. BsAbs modification also enhanced accumulation of fluorescence-labeled NPs and significantly increased the anticancer activity of drug-loaded NPs to antigen-positive human tumors in a mouse model. Anti-mPEG BsAbs offer a simple one-step method to confer tumor specificity to mPEG-NPs for enhanced tumor accumulation and improved therapeutic efficacy. 相似文献
944.
945.
Beata Mierzejewska Paul M. Schroder Caitlin E. Baum Annette Blair Connie Smith Rene J. Duquesnoy Marilyn Marrari Amira Gohara Deepak Malhotra Dinkar Kaw Robert Liwski Michael A. Rees Stanislaw Stepkowski 《Human immunology》2014
Donor-specific alloantibodies (DSA) to HLA-DP may cause antibody-mediated rejection (AMR), especially in re-transplants. We describe the immunization history of a patient who received 3 kidney transplants; the 3rd kidney was completely matched except at DPA1 and DPB1. Prior to the 3rd transplant, single antigen bead analysis (SAB) showed DSA reactivity against DPA1 shared by the 1st and 3rd donors, but B and T flow crossmatch (FXM) results were negative. Within 11 days the 3rd transplant underwent acute C4d+ AMR which coincided with the presence of complement (C1q)-binding IgG1 DSA against donor DPA1 and DPB1. Using HLAMatchmaker and SAB, we provide evidence that eplet (epitope) spreading on DPA1 and eplet sharing on differing DPB1 alleles of the 1st and 3rd transplants was associated with AMR. Since weak DSA to DPA1/DPB1 may induce acute AMR with negative FXM, donor DPA1/DPB1 high resolution typing should be considered in sensitized patients with DP-directed DSA. 相似文献
946.
Monoclonal antibodies to molecular targets important for bone formation and bone resorption are being investigated for treatment of postmenopausal osteoporosis. Postmenopausal osteoporosis is characterized by increased bone turnover, with bone resorption typically exceeding bone formation. These pathophysiological changes cause decreased bone mineral density and disruption of bone microarchitecture which lead to low-trauma fractures. 相似文献
947.
948.
Norma Segovia-Gamboa Martha Eunice Rodríguez-Arellano Rafael Rangel-Cruz Moisés Sánchez-Díaz Julio César Ramírez-Reyes Raquel Faradji Érika González-Domínguez Carmen Sánchez-Torres 《Clinical immunology (Orlando, Fla.)》2014,154(1):72-83
Tolerogenic dendritic cells (tDC) constitute a promising therapy for autoimmune diseases, since they can anergize T lymphocytes recognizing self-antigens. Patients with type 1 diabetes mellitus (T1D) have autoreactive T cells against pancreatic islet antigens (insulin, glutamic acid decarboxylase 65 -GAD65-). We aimed to determine the ability of tDC derived from T1D patients to inactivate their insulin- and GAD65-reactive T cells. CD14 + monocytes and CD4 + CD45RA- effector/memory lymphocytes were isolated from 25 patients. Monocyte-derived DC were generated in the absence (control, cDC) or presence of IL-10 and TGF-β1 (tDC), and loaded with insulin or GAD65. DC were cultured with T lymphocytes (primary culture), and cell proliferation and cytokine secretion were determined. These lymphocytes were rechallenged with insulin-, GAD65- or candidin-pulsed cDC (secondary culture) to assess whether tDC rendered T cells hyporesponsive to further stimulation. In the primary cultures, tDC induced significant lower lymphocyte proliferation and IL-2 and IFN-γ secretion than cDC; in contrast, tDC induced higher IL-10 production. Lymphocytes from 60% of patients proliferated specifically against insulin or GAD65 (group 1), whereas 40% did not (group 2). Most patients from group 1 had controlled glycemia. The secondary cultures showed tolerance induction to insulin or GAD65 in 14 and 10 patients, respectively. A high percentage of these patients (70–80%) belonged to group 1. Importantly, tDC induced antigen-specific T-cell hyporesponsiveness, since the responses against unrelated antigens were unaffected. These results suggest that tDC therapy against multiple antigens might be useful in a subset of T1D patients. 相似文献
949.
950.
Silvia Lee Henny Saraswati Evy Yunihastuti Rino Gani Patricia Price 《Clinical immunology (Orlando, Fla.)》2014,155(2):149-159
When severely immunodeficient HIV/HCV co-infected patients are treated with antiretroviral therapy, it is important to know whether HCV-specific antibody responses recover and whether antibody profiles predict the occurrence of HCV-associated immune restoration disease (IRD). In 50 HIV/HCV co-infected patients, we found that antibody reactivity and titres of neutralising antibodies (nAb) to JFH-1 (HCV genotype 2a virus) increased over 48 weeks of therapy. Development of HCV IRD was associated with elevated reactivity to JFH-1 before and during the first 12 weeks of therapy. Individual analyses of HCV IRD and non-HCV IRD patients revealed a lack of an association between nAb responses and HCV viral loads. These results showed that increased HCV-specific antibody levels during therapy were associated with CD4+ T-cell recovery. Whilst genotype cross-reactive antibody responses may identify co-infected patients at risk of developing HCV IRD, neutralising antibodies to JFH-1 were not involved in suppression of HCV replication during therapy. 相似文献