IntroductionA novel amyloid β (Aβ) synthetic peptide vaccine (UB-311) has been evaluated in a first-in-human trial with patients of mild-to-moderate Alzheimer's disease. We describe translational research covering vaccine design, preclinical characterization, and phase-I clinical trial with supportive outcome that advances UB-311 into an ongoing phase-II trial.MethodsUB-311 is constructed with two synthetic Aβ1–14–targeting peptides (B-cell epitope), each linked to different helper T-cell peptide epitopes (UBITh®) and formulated in a Th2-biased delivery system. The hAPP751 transgenic mouse model was used to perform the proof-of-concept study. Baboons and macaques were used for preclinical safety, tolerability, and immunogenicity evaluation. Patients with mild-to-moderate Alzheimer's disease (AD) were immunized by intramuscular route with 3 doses of UB-311 at weeks 0, 4, and 12, and monitored until week 48. Safety and immunogenicity were assessed per protocol, and preliminary efficacy was analyzed by Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAS-Cog), Mini–Mental State Examination (MMSE), and Alzheimer's Disease Cooperative Study–Clinician's Global Impression of Change (ADCS-CGIC).ResultsUB-311 covers a diverse genetic background and facilitates strong immune response with high responder rate. UB-311 reduced the levels of Aβ1–42 oligomers, protofibrils, and plaque load in hAPP751 transgenic mice. Safe and well-tolerated UB-311 generated considerable site-specific (Aβ1–10) antibodies across all animal species examined. In AD patients, UB-311 induced a 100% responder rate; injection site swelling and agitation were the most common adverse events (4/19 each). A slower rate of increase in ADAS-Cog from baseline to week 48 was observed in the subgroup of mild AD patients (MMSE ≥ 20) compared with the moderate AD subgroup, suggesting that UB-311 may have a potential of cognition improvement in patients with early stage of Alzheimer's dementia.DiscussionThe UBITh® platform can generate a high-precision molecular vaccine with high responder rate, strong on-target immunogenicity, and a potential of cognition improvement, which support UB-311 for active immunotherapy in early-to-mild AD patients currently enrolled in a phase-II trial (NCT02551809).
A peptide of 21 amino acids with the sequence Arg-Ile-Leu-Ala-Val-Glu-Arg-Tyr-Leu-Lys-Asp-Gln-GlnLeu-Leu-Gly-Ile-Trp-Gly-Cys-Ser encoded by a segment in the env gene of human T-lymphotropic virus type m (HTLV-Il), corresponding to amino acids 586-606 of the precursor envelope glycoprotein, has been synthesized by the Merrifield solid-phase method. Combined serological and chemical analyses of this peptide and related peptides have revealed the importance of certain amino acid residues in the antigenic determinant of the relevant peptide. Enzyme immunoassay (EIA) employing this peptide as an antigen adsorbent was shown to reproducibly detect antibodies in sera of patients with HTLV-II infection. This assay provided positive results with all sera that were reactive with gp4l envelope protein of HTLV-Ill in electrophoretic immunoblot analysis. Thus far, no false-positive sera have been encountered in control populations. Our EIA with this peptide as the coating antigen is shown to have advantages over that with the whole HTLV-llI virus as an immunoadsorbent.Since the identification of a human retrovirus, named human T-lymphotropic virus type III (HTLV-III), acquired immune deficiency syndrome (AIDS)-related virus (ARV), or lymphoadenopathy-associated virus (LAV) as the infectious agent for AIDS (1-4),t substantial progress has been made in the studies of the virus and in the development of diagnostic methods for the detection of HTLV-III infection. With the establishment of permissive T-cell lines for mass production of HTLV-III virus (1), it has been possible to elucidate the structure and gene organization of HTLV-III, to determine the complete nucleotide sequence of the HTLV-III genome (5-8), and to use heat-inactivated HTLV-III as the immunoadsorbent for detection of antibodies against HTLV-III in sera of patients with HTLV-III infection (9)(10)(11)(12)(13)(14)(15)(16)(17)(18).Efforts employing recombinant DNA technology to identify HTLV-III antigenic peptides reactive with sera from AIDS and AIDS-related complex (ARC) patients and asymptomatic HTLV-III-infected individuals have also been undertaken by many investigators (19)(20)(21)(22)(23). Success has been obtained by this approach. However, it has not been able to localize and identify the peptide sequences representing the antigenic epitope(s).Synthetic peptides are used increasingly to map antigenic or immunogenic sites on the surface of proteins and, in turn, as possible vaccines (reviewed in ref. 24). We have synthesized numerous peptides corresponding to various regions of envelope protein of HTLV-III and analyzed their reactivity with sera from AIDS patients. Our initial emphasis was on the gp4l glycoprotein, the transmembrane portion of envelope protein gp160, which has previously been identified as the antigen most consistently recognized by antibodies in patients with AIDS and ARC (25,26).In this paper, we report (i) the identification of a peptide 21 residues in length with the sequence Arg-Ile-Leu-Ala-ValGlu-Arg-Tyr-Leu-Lys-Asp-Gln-Gln-Le...
The induction of mRNA synthesis and accumulation of TNF/cachectin and lymphotoxin (LT) mRNAs in T leukemic cell lines and freshly isolated T cells were studied by Northern blot analyses. Without stimulation, TNF mRNA was barely detected in four T cell lines (CEM, KE4, MT-1, and SKW-3) and not detectable in Molt-4 and Jurkat cells, while a considerable amount of TNF mRNA was observed in HSB-2 cells. When stimulated by PMA, these T cell lines accumulated varying levels of TNF mRNA. All seven T cell lines expressed LT mRNA when unstimulated and responded well to PMA by increased accumulation of LT mRNA. The calcium ionophore A23187 by itself had no effect on TNF and LT mRNA accumulations in these cell lines. The CD3+ T cell lines did not respond to anti-CD3 mAb T3-II alone. However, A23187 and mAb T3-II further elevated TNF and LT mRNA accumulations in PMA-treated T cell lines. Synergism between PMA and mAb T3-II was modest in the CD3+ cell lines. A slight difference in kinetics of TNF and LT mRNA accumulations was noted. In addition, heterogeneities in TNF and LT expressions by these cell lines in responses to PMA and other stimuli were observed. In monocyte-depleted peripheral blood T cell populations. PMA was able to induce both TNF and LT mRNA syntheses. This effect was potentiated markedly by the addition of anti-CD3 mAb T3-II. This synergistic response to anti-CD3 mAb and PMA provided further evidence that T cells were the source of TNF synthesis in these cultures. There was a difference in the kinetics of TNF mRNA accumulation and that of LT mRNA. Maximal accumulation of TNF mRNA occurred at 4 h while 8-18 h was required for maximal LT mRNA accumulation. IL-2 mRNA accumulated at an intermediate peak time of 4-8 h. Western blot analyses and cytotoxicity assays with L cells as targets indicated that these T cell lines and peripheral blood T cells secreted TNF. These results provide further evidence that human T cells are capable of making TNF as well as LT under appropriate stimulations. Their productions are an integral part of T cell response to activation signals. In addition, it appears that the production of these two closely related molecules is independently regulated.
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