Michael Super - Academia.edu (original) (raw)

Papers by Michael Super

Open Forum Infectious Diseases, Nov 26, 2023

Journal of Immunology, May 1, 2017

There is an urgent need to develop vaccines against bacteria due to the rise of Multi-drug resist... more There is an urgent need to develop vaccines against bacteria due to the rise of Multi-drug resistant (MDR & XDR) organisms. To date, it has been difficult to produce protective vaccines against bacterial pathogens; there is a danger of outgrowth of fast growing attenuated bacterial strains while polysaccharide cell walls are poorly immunogenic and subunit vaccines are ineffective, generating TI (T-independent) immune responses, characterized by low affinity, short lived, non-class switched IgM antibodies. We are developing technologies for generating vaccines in mice against multiple pathogen species, including bacterial; MDR E. coli, MRSA, MTb LAM, Viral; HIV gp120, parasitic; P. falciparum and fungal; C. albicans. We capture pathogens using FcMBL Opsonin technology (which binds more than 90 different pathogen species), and present the killed pathogens in an immune modulating biomaterial system. This lyophilized product provides long-lasting protection with a single dose through a novel self-boosting mechanism of action. Our vaccines can protect mice against MDR strains of E. coli which are lethal within 12 hours. We have raised antibodies with titers which are sustained beyond 90 days (to date) with a single vaccination (the biomaterial system has demonstrated titers beyond 1 year in other indications). Using this opsonin and immune modulating technology, E. coli can be captured from the blood and tissues of one animal and used to vaccinate other animals.

PubMed, Aug 1, 1992

The human mannose-binding protein (MBP) appears to function as an "ante-antibody" as its physiolo... more The human mannose-binding protein (MBP) appears to function as an "ante-antibody" as its physiological role is in first line host defense. Low baseline serum levels are rapidly increased as part of the acute phase reactant and circulating MBP can act as a direct opsonin or activate the classical alternative complement pathway. MBP appears to selectively recognize an array of apparently disparate oligosaccharides that decorate gram-negative and gram-positive bacteria as well as certain parasites, yeasts, and fungi. MBP may be considered a "pattern" recognition molecule that has homologs in primitive life forms. Its ability to distinguish self from nonself indicates that it may play an important role in innate immunity.

PubMed, May 1, 1999

Fusion proteins between whole antibodies (Abs) and cytokines (immunocytokines) such as interleuki... more Fusion proteins between whole antibodies (Abs) and cytokines (immunocytokines) such as interleukin 2 have shown efficacy in several mouse tumor models despite a circulating half-life that is significantly shorter than that of the original Ab. We have examined the potential mechanisms responsible for clearance and shown that an important factor is enhanced binding to Fc receptor (FcR). Improvements in the half-lives of two different immunocytokines were made by changing the isotype of the human heavy chain C region from IgG1 or IgG3 to those with reduced binding to FcR, e.g., IgG4. The same effect could also be achieved through site-directed mutagenesis of the FcR binding site in the IgG1 H chain. In vitro studies using mouse J774 FcR-expressing cells showed increased binding of interleukin 2-based immunocytokines, relative to their corresponding Abs, and that this was reversed in those fusion proteins made with IgG4 or mutated IgG1 H chains. All of the fusion proteins showing reduced FcR binding also had reduced Ab-dependent cellular cytotoxicity activity, as measured in 4-h chromium release assays. A complete loss of complement-dependent cytotoxicity activity was seen with an IgG4-based immunocytokine derived from an IgG1 Ab with potent activity. Despite these reduced effector functions, the IgG4-based immunocytokines with extended circulating half-lives showed equivalent (in the case of severe combined immunodeficiency mouse xenograft models) or better (in the case of syngeneic models) efficacy in mouse tumor models than the original IgG1-based molecules. These novel immunocytokines may show improved efficacy in therapeutic situations where T cell- rather than natural killer- or complement-mediated antitumor mechanisms are involved.

PubMed, Nov 1, 1997

A recombinant humanized antibody-interleukin 2 fusion protein (huKS1/4-IL-2) was used to direct I... more A recombinant humanized antibody-interleukin 2 fusion protein (huKS1/4-IL-2) was used to direct IL-2 to the tumor microenvironment and elicit a T cell-mediated eradication of established pulmonary and hepatic CT26-KSA colon carcinoma metastases in syngeneic BALB/c mice. This antitumor effect was specific because a fusion protein, which was nonreactive with these tumor cells, failed to exert any such effect. The efficacy of the huKS1/4-IL-2 fusion protein in eliminating metastases was documented because mixtures of monoclonal antibody huKS1/4 with recombinant human IL-2 were ineffective and, at best, only partially reduced tumor load. Two lines of evidence indicated the eradication of metastases and the absence of minimal residual disease in animals treated with the fusion protein: first, the lack of detection of CT26-KSA cells by reverse transcription-PCR, which can detect one tumor cell in 10(6) liver cells; and second, the tripling of life span. The effector mechanism involved in this tumor eradication is dependent on T cells because the IL-2-directed therapy is ineffective in T cell-deficient SCID mice. The essential effector cells were further characterized as CD8+ T cells by in vivo depletion studies. Such T cells, isolated from tumor-bearing mice after fusion protein therapy, elicited MHC class I-restricted cytotoxicity in vitro against colon carcinoma target cells. Taken together, these data indicate that fusion protein-directed IL-2 therapy induces a T cell-dependent host immune response capable of eradicating established colon cancer metastases in an animal tumor model.

Journal of Immunology, Jun 15, 1998

A Novel Recombinant Fusion Protein Encoding a 20-Amino Acid Residue of the Third Extracellular (E... more A Novel Recombinant Fusion Protein Encoding a 20-Amino Acid Residue of the Third Extracellular (E3) Domain of CCR2 Neutralizes the Biological Activity of CCL2

Expert Opinion on Drug Discovery, Jan 25, 2008

Many diseases and disorders are best treated by a combination of drugs. Unlike small molecules, e... more Many diseases and disorders are best treated by a combination of drugs. Unlike small molecules, engineered proteins can be designed to incorporate multiple independent drug activities. Compared with a combination of two or more proteins, the potential benefits of a single biologic that inhibits multiple targets may include lower cost, simplified clinical testing and greater patient convenience. The evolution of HIV combination therapy is a useful point of comparison, as it occurred in an unusual regulatory environment that allowed the testing of combinations when the clinical benefit of component drugs was unproven. The epidermal growth factor receptor family of cancer targets illustrates how a particular single-molecule combination therapy might be used for cancer therapy, so some attempts to construct single-protein agents with multiple activities that include anti-EGFR moieties are reviewed. Protein engineers have created an armory of multiply-targeted antibody derivatives, but such engineered molecules often have a shorter serum half-life than IgG antibodies. New protein engineering approaches may be needed to address this problem. Nonetheless, multiply-targeted single-protein agents may be an economical solution to the problem of antibody combination therapy for cancer.

Clinical and Experimental Immunology, Feb 1, 1990

When sera diluted to 5 % in a buffer containing calcium and magnesium were incubated with mannanc... more When sera diluted to 5 % in a buffer containing calcium and magnesium were incubated with mannancoated ELISA plates, C4 fragments, properdin and factor B were bound to the plates as well as the expected opsonic C3 fragments, C3b and C3bi. The calcium-dependent lectin mannan-binding protein, which is structurally similar to C lq, was also shown to bind in this assay and analysis of sera from 179 healthy blood donors revealed that the binding levels of all these proteins were highly significantly correlated. Results obtained with a previously described C3b opsonic assay using zymosan also correlated with the mannan-binding levels. When the sera were diluted to 5% in the presence of Mg-EGTA there was no detectable binding of complement proteins to the mannan surface, confirming that no alternative pathway activation occurred at this serum concentration. When sera were diluted to 5% in a buffer containing EDTA in order to study immunoglobulin binding in the absence ofcomplement activation, the levels of bound IgG 1, IgG2, IgG3, IgA and IgM antibodies were found to be completely unrelated to the C3bi binding levels previously observed. The results suggest that in this experimental system using low concentrations of serum, mannan-binding protein initiates an antibody-independent mechanism of cleavage of the classical pathway component C4, which subsequently regulates the degree of cleavage of C3 and recruitment of alternative pathway proteins.

The Lancet, Jul 1, 1988

74 patients receiving cadaver kidney grafts were investigated prospectively for cytomegalovirus (... more 74 patients receiving cadaver kidney grafts were investigated prospectively for cytomegalovirus (CMV) infection. Among seropositive recipients CMV infection, especially symptomatic and disseminated infection, occurred significantly more frequently when kidneys came from seropositive than from seronegative donors. Since seropositive recipients can become infected with donor virus, the excess is probably accounted for by reinfection. This conclusion was supported by restriction enzyme typing of virus isolates from recipient pairs receiving kidneys from the same donor; proven reinfection with donor strain virus was significantly commoner than proven reactivation of recipient virus. Furthermore, symptoms occurred only in the proven reinfection group. Although the proportion of reinfections that caused symptoms was less than that seen in primary infections, prior natural infection with CMV clearly does not prevent symptomatic reinfection in seropositive recipients, a point which has profound implications for future vaccination strategies in renal allograft recipients and choice of donors.

The Lancet, Jun 1, 1991

A r i n g ; , Forsgren M. Rapid diagnosis of herpes simplex encephalitis by nested polymerase cha... more A r i n g ; , Forsgren M. Rapid diagnosis of herpes simplex encephalitis by nested polymerase chain reaction assay of cerebrospinal fluid. Lancet 1991; 337: 189-92. 6. Kristiansen BE, Rådstrøm P, Jenkins A, et al. Cloning and characterization of a DNA fragment that confers sulfonamide resistance in a serogroup B, serotype 15 strain of Neisseria meningitidis.

Clinical & Experimental Allergy, May 1, 1991

The opsonisation defect Opsonisation is the process of coating microorganisms with various molecu... more The opsonisation defect Opsonisation is the process of coating microorganisms with various molecules which interact specifically with receptors on neutrophils and mononuclear phagocytes. It is a major defence mechanism and plays a central role in much anti-microbial immunity.

Cancer Immunology, Immunotherapy, Jul 6, 1999

The fusion protein formed from ch14.18 and interleukin-2 (ch14.18±IL-2), shown to exhibit antitum... more The fusion protein formed from ch14.18 and interleukin-2 (ch14.18±IL-2), shown to exhibit antitumor ecacy in mouse models, consists of IL-2 genetically linked to each heavy chain of the ch14.18 chimeric anti-GD2 monoclonal antibody. The purpose of this study was to determine the pharmacokinetics of ch14.18±IL-2 in mice and assess its stability in murine serum. Following i.v. injection, the fusion protein was found to have a terminal half-life of 4.1 h. Detection of IL-2 following injection of the ch14.18±IL-2 fusion protein showed a similar half-life, indicating that the fusion protein prolongs the circulatory half-life of IL-2. Detection of human IgG1 following injection of ch14.18±IL-2 showed a terminal half-life of 26.9 h. These data suggested that the native fusion protein is being altered in vivo, resulting in a somewhat rapid loss of detectable IL-2, despite prolonged circulation of its immunoglobulin components. In vitro incubation of the ch14.18±IL-2 fusion protein in pooled mouse serum at 37°C for 48 h resulted in a loss of its IL-2 component, as detected in enzyme-linked immunosorbent assay systems and in proliferation assays. Polyacrylamide gel electrophoresis and Western blot analysis of the fusion protein incubated in mouse serum at 37°C indicated that the ch14.18±IL-2 is cleaved, resulting in a loss of the 67-kDa band (representing the IL-2 linked to the IgG1 heavy chain) and the detection of a band of more than 50 kDa, slightly heavier than the IgG1 heavy chain itself. This suggests that the fusion protein is being cleaved in vitro within the IL-2 portion of the molecule. These studies show that (1) ch14.18±IL-2 prolongs the circulatory half-life of IL-2 (compared to that of soluble IL-2) and (2) the in vivo clearance of the fusion protein occurs more rapidly than the clearance of the ch14.18 antibody itself, possibly re¯ecting in vivo cleavage within the IL-2 portion of the molecule, resulting in loss of IL-2 activity.

Journal of Hepatology, 1991

Open Forum Infectious Diseases, Oct 1, 2019

and will conclude in June 2019. BCID2 Panel performance is compared with reference methods of mic... more and will conclude in June 2019. BCID2 Panel performance is compared with reference methods of microbial culture as well as PCR/sequencing for AMR genes. In addition, BCID2 Panel MRSA results are compared with the FDA-cleared Xpert MRSA/SA BC system (Cepheid, Inc). Relevant bacterial isolates recovered from PBCs are also evaluated by various phenotypic antimicrobial susceptibility testing (AST) methods. The prospective evaluation is supplemented with a second study that involves testing of ~300 pre-selected, archived PBCs containing rare organisms. The third study includes over 500 seeded blood cultures containing very rare organisms with an evaluation of co-spiked samples. Results. With over 1,200 samples tested to date (out of an anticipated 1,800 total), the BCID2 Panel has demonstrated an overall sensitivity of >98% and specificity of >99% for identification of microorganisms compared with culture. Concordance between the BCID2 Panel and the Xpert MRSA/SA BC test is >99% for identification of MRSA. Evaluation of BCID2 Panel AMR gene detection relative to AST and PCR is ongoing. Conclusion. The FilmArray® BCID2 Panel appears to be a sensitive, specific, and robust test for rapid detection of microorganisms and MRSA in PBCs. With the use of this comprehensive test, improved antimicrobial stewardship is anticipated. Disclosures. All authors: No reported disclosures 652.

Procedia Engineering, 2011

In this work, we demonstrate an impedance approach to detect pathogens bound to magnetic beads. T... more In this work, we demonstrate an impedance approach to detect pathogens bound to magnetic beads. The approach was demonstrated with C-Albicans. We show that when an appropriate frequency is applied to two electrodes present in a microfluidic channel the impedance change in the detection volume can be used to distinguish between unbound beads and beads bound to pathogens. Furthermore, we present a model to relate measured impedance changes to an effective particle diameter.

Applied Physics Letters, May 23, 2016

Asaio Journal, Jun 1, 2023

Advanced Science, Sep 1, 2022

Advanced Science, Jun 15, 2022

Current therapeutic strategies against bacterial infections focus on reduction of pathogen load u... more Current therapeutic strategies against bacterial infections focus on reduction of pathogen load using antibiotics; however, stimulation of host tolerance to infection in the presence of pathogens might offer an alternative approach. Computational transcriptomics and Xenopus laevis embryos are used to discover infection response pathways, identify potential tolerance inducer drugs, and validate their ability to induce broad tolerance. Xenopus exhibits natural tolerance to Acinetobacter baumanii, Klebsiella pneumoniae, Staphylococcus aureus, and Streptococcus pneumoniae bacteria, whereas Aeromonas hydrophila and Pseudomonas aeruginosa produce lethal infections. Transcriptional profiling leads to definition of a 20‐gene signature that discriminates between tolerant and susceptible states, as well as identification of a more active tolerance response to gram negative compared to gram positive bacteria. Gene pathways associated with active tolerance in Xenopus, including some involved in metal ion binding and hypoxia, are found to be conserved across species, including mammals, and administration of a metal chelator (deferoxamine) or a HIF‐1α agonist (1,4‐DPCA) in embryos infected with lethal A. hydrophila increased survival despite high pathogen load. These data demonstrate the value of combining the Xenopus embryo infection model with computational multiomics analyses for mechanistic discovery and drug repurposing to induce host tolerance to bacterial infections.

Lab on a Chip, 2014

Sepsis diagnosis requires development of methods to identify rare pathogen cells in small samples... more Sepsis diagnosis requires development of methods to identify rare pathogen cells in small samples of human blood. Magnetic beads functionalized with pathogen-binding ligands have been used to rapidly isolate microbes from blood; however, it is commonly difficult to optically detect the captured species because the excess numbers of beads required for pathogen binding physically interfere with light transmission after they have been concentrated. Here we describe a microdevice that uses microfluidics combined with optimized magnetic field concentrators and magnetic beads coated with a generic blood opsonin to efficiently capture unknown blood pathogens and spread them into a thin layer suitable for automated optical detection. Using this device, we have been able to detect fungal pathogens in less than three hours after sample collection compared to days with current technology, and with an extremely high sensitivity (<1 cell mL −1 of human blood).