Ellen S Vitetta

University of Texas Southwestern Medical Center | UT Southwestern · Department of Immunology

Single-walled carbon nanotubes (CNTs) emit heat when they absorb energy from near-infrared (NIR) light. Tissue is relatively transparent to NIR, which suggests that targeting CNTs to tumor cells, followed by noninvasive exposure to NIR light, will ablate tumors within the range of NIR. In this study, we demonstrate the specific binding of antibody-...

Inhalation of the biothreat agent, ricin toxin (RT), provokes a localized inflammatory response associated with pulmonary congestion, edema, neutrophil infiltration, and severe acute respiratory distress. The extreme toxicity of RT is the result of the toxin’s B chain (RTB) promoting rapid uptake into alveolar macrophages and lung epithelial cells,...

Fungi of the order Mucorales cause mucormycosis, a lethal infection with an incompletely understood pathogenesis. We demonstrate that Mucorales fungi produce a toxin, which plays a central role in virulence. Polyclonal antibodies against this toxin inhibit its ability to damage human cells in vitro and prevent hypovolemic shock, organ necrosis and...

Fungi of the order Mucorales cause mucormycosis, a lethal infection with an incompletely understood pathogenesis. We now demonstrate that Mucorales fungi produce a toxin that plays a central role in virulence. Polyclonal antibodies against this toxin inhibit its ability to damage human cells in vitro, and prevent hypovolemic shock, organ necrosis,...

The successful licensure of vaccines for biodefense is contingent upon the availability of well-established correlates of protection (CoP) in at least two animal species that can be applied to humans, without the need to assess efficacy in the clinic. In this report we describe a multivariate model that combines pre-challenge serum antibody endpoin...

The successful licensure of vaccines for biodefense is contingent upon the availability of well-established correlates of protection (CoP) in at least two animal species that can then be applied to humans, without the need to assess efficacy in the clinic. In this report we describe a multivariate model that combines pre-challenge serum antibody en...

Inhalation of ricin toxin (RT), a Category B biothreat agent, provokes an acute respiratory distress syndrome marked by pro-inflammatory cytokine and chemokine production, neutrophilic exudate, and pulmonary edema. The severity of RT exposure is attributed to the tropism of the toxin’s B subunit (RTB) for alveolar macrophages and airway epithelial...

Ricin toxin (RT) ranks at the top of the list of bioweapons of concern to civilian and military personnel alike, due to its high potential for morbidity and mortality after inhalation. In nonhuman primates, aerosolized ricin triggers severe acute respiratory distress characterized by perivascular and alveolar edema, neutrophilic infiltration, and s...

Ricin toxin ranks at the top of the list of potential bioweapons of concern to civilian and military personnel alike due to the high potential for morbidity and mortality after inhalation. In non-human primates, aerosolized ricin triggers a severe acute respiratory distress characterized by perivascular and alveolar edema, neutrophilic infiltration...

Cancer dormancy is a clinical state in which residual tumor cells persist for long periods of time but do not cause detectable disease. In the mouse B cell lymphoma model (BCL1), dormancy can be induced and maintained by immunizing mice with a soluble form of the IgM expressed on the surface of the tumor cells. Immunization induces an anti-idiotype...

Importance: There is increased interest in using antibodies to treat and cure HIV infection. Antibodies can neutralize free virus and kill cells already carrying the virus. The virus envelope (Env) is the only HIV protein expressed on the surfaces of virions and infected cells. In this study we examined a panel of human anti-Env antibodies for the...

Importance: It is not yet possible to cure HIV infection. Even after years of fully effective antiviral therapy, a persistent reservoir of virus-infected cells remains. Here we propose that a targeted conjugate, consisting of an anti-HIV antibody bound to a toxic moiety, could function to kill the HIV-infected cells that constitute this reservoir....

Significance The role of tumor-associated neutrophils (TANs) in cancer progression versus regression remains controversial. TANs are known to have dichotomous antitumor (N1) and protumor (N2) phenotypes depending on the tumor microenvironment. Past studies have demonstrated that TANs are polarized from an N2 to an N1 phenotype in the absence of TGF...

Abstract We demonstrate that a peptoid composed of five monomers and attached via a maleimide linker to a carrier protein elicits anti-peptoid, anti-linker and anti-carrier antibodies in rabbits. Specific anti-peptoid antibodies were affinity purified and used to reproducibly retrieve three specific peptoid-coupled beads from 20,000 irrelevant pept...

Several promising subunit vaccines against ricin toxin (RT) have been developed during the last decade and are now being tested for safety and immunogenicity in humans and for efficacy in nonhuman primates. The incentive to develop a preventive vaccine as a countermeasure against RT use as a bioweapon is based on the high toxicity of RT after aeros...

Significance Ricin toxin (RT) is a CDC-designated select agent that can be dispersed as an aerosol. In mammals, aerosolized RT causes rapid and irreversible necrosis of the lung epithelium, multifocal hemorrhagic edema, and death within 24–36 h. A safe and effective recombinant subunit vaccine (RiVax) has been developed and formulated as a thermost...

CD22 is a transmembrane glycoprotein expressed by mature B cells. It inhibits signal transduction by the B-cell receptor and its coreceptor CD19. Recent reports indicate that most human lung cancer cells and cell lines express CD22, making it an important new therapeutic target for lung cancer. The objective of our studies was to independently vali...

CD22 is a transmembrane glycoprotein expressed by mature B cells. It inhibits signal transduction by the B-cell receptor and its coreceptor CD19. Recent reports indicate that most human lung cancer cells and cell lines express CD22, making it an important new therapeutic target for lung cancer. The objective of our studies was to independently vali...

IFN-γ is a major cytokine that is critical for host resistance to a broad range of intracellular pathogens. Production of IFN-γ by natural killer and T cells is initiated by the recognition of pathogens by Toll-like receptors (TLRs). In an experimental model of toxoplasmosis, we have identified the presence of a nonlymphoid source of IFN-γ that was...

The immunodeficient mice are the standard animal model in antibody research, which include the inbred NOD-SCID strain. We report here the aberrant pharmacokinetics of chimeric and human IgGs with a human IgG1 Fc domain in NOD-SCID mice. These IgGs displayed very short in vivo half-lives (25.0±0.4 hrs and 27.6±1.3 hrs, respectively) when injected at...

Phosphatidylserine (PS) is normally intracellular but becomes exposed on the luminal surface of vascular endothelium in tumors and can also be expressed on tumor cells themselves. Studies have shown that targeting PS with an antibody enhances the antitumor effect of chemotherapy or radiation on several tumors, and induces antitumor immunity in mice...

Peptoids are synthetic molecules that share structure with peptides, but bear side groups on the backbone nitrogen. They are protease resistant and relatively cheap to synthesize. Since many amines can form peptoid side groups, peptoids are more diverse than peptides and can take on various shapes, making them good B cell epitopes or haptens. We ai...

The aim of this research is to generate vaccine candidates for any virus for which a neutralizing monoclonal antibody exists without prior knowledge of the protective epitope. We have developed a platform to generate such vaccine candidates and are working on a device to automate their identification. The platform consists of libraries of B cell ep...

There is clinical interest in the modulation of regulatory T cells for cancer therapy. The safety of these therapies in combination with conventional anti-cancer therapies, including radiation therapy, can be studied in animal models. The effects of partial depletion of regulatory T (Treg) cells with an anti-CD25 antibody in conjunction with ionizi...

Percentage of body weight change after irradiation and/or Treg cell depletion. (DOC)

Contributed by Ellen S. Vitetta, May 14, 2013 (sent for review January 10, 2013) IFN-γ is a major cytokine that is critical for host resistance to a broad range of intracellular pathogens. Production of IFN-γ by natural killer and T cells is initiated by the recognition of pathogens by Toll-like receptors (TLRs). In an experimental model of toxopla...

There is clinical interest in the modulation of regulatory T cells for cancer therapy. The safety of these therapies in combination with conventional anti-cancer therapies, including radiation therapy, can be studied in animal models. The effects of partial depletion of regulatory T (Treg) cells with an anti-CD25 antibody in conjunction with ionizi...

There is no FDA-approved vaccine for the potent plant toxin ricin. We have developed a recombinant ricin vaccine, RiVax. Without adjuvant it is safe and immunogenic in mice, rabbits, and humans. Based on our studies in mice, we now report the results of a small clinical trial with Alhydrogel-adsorbed RiVax.

With the continued failures of both early diagnosis and treatment options for pancreatic cancer, it is now time to comprehensively evaluate the role of the immune system on the development and progression of pancreatic cancer. It is important to develop strategies that harness the molecules and cells of the immune system to treat this disease. This...

An immunotoxin (IT) constructed with RFB4, a murine anti-CD22 monoclonal antibody, and the "deglycosylated" A chain of ricin has shown activity at safe doses in patients with non-Hodgkin lymphoma and in children with acute lymphoblastic leukemia. The dose limiting toxicity is vascular leak syndrome (VLS), which appears to be due to a unique amino a...

1526 BACKGROUND The immunotoxin combotox (1: 1 mixture of deglycosylated ricin-A chain (dgRTA)-containing anti-human CD19 and anti-CD22 monoclonal antibodies (MAbs) (Combotox) has demonstrated single agent activity in children (Herrera et al, 2009) and adults (Schindler et al, 2011) with relapsed/refractory B-lineage acute lymphoblastic leukemia (...

RiVax is a recombinant protein that is currently under clinical development as part of a human vaccine to protect against ricin poisoning. RiVax includes ricin A-chain (RTA) residues 1-267 with two intentional amino-acid substitutions, V76M and Y80A, aimed at reducing toxicity. Here, the crystal structure of RiVax was solved to 2.1 Å resolution and...

Ricin toxin (RT) is derived from castor beans, produced by the plant Ricinus communis. RT and its toxic A chain (RTA) have been used therapeutically to arm ligands that target disease-causing cells. In most cases these ligands are cell-binding monoclonal antibodies (MAbs). These ligand-toxin conjugates or immunotoxins (ITs) have shown success in cl...

Novel agents are needed for patients with refractory and relapsed acute lymphoblastic leukaemia (ALL). Combotox is a 1:1 mixture of two immunotoxins (ITs), prepared by coupling deglycosylated ricin A chain (dgRTA) to monoclonal antibodies directed against CD22 (RFB4-dgRTA) and CD19 (HD37-dgRTA). Pre-clinical data demonstrated that Combotox was effe...

In this chapter we discuss vaccines to protect against the highly toxic plant-derived toxin, ricin. Due to its prevalence, ease of use, and stability it has been used in sporadic incidents of espionage. There is also concern that it will be used as an agent of bioterrorism. As a result there has been a great deal of interest in developing a safe va...

CD19 is an attractive therapeutic target for treating human B-cell tumors. In our study, chimeric (c) divalent (cHD37) and tetravalent (cHD37-DcVV) anti-CD19 monoclonal antibodies (MAbs) were constructed, expressed and evaluated for their binding to human 19-positive (CD19(+)) tumor cell lines. They were also tested for proapoptotic activity and th...

Precursor B cell acute lymphoblastic leukemia (pre-B ALL) affects five to six thousand adults and almost three thousand children every year. Approximately 25% of the children and 60% of the adults die from their disease, highlighting the need for new therapies that complement rather than overlap chemotherapy and bone marrow transplantation. Immunot...

Single-walled carbon nanotubes (CNTs) convert absorbed near infrared (NIR) light into heat. The use of CNTs in the NIR-mediated photothermal ablation of tumor cells is attractive because the penetration of NIR light through normal tissues is optimal and the side effects are minimal. Targeted thermal ablation with minimal collateral damage can be ac...

Ricin toxin is a CDC level B biothreat. We have developed a ricin vaccine, RiVax, which is a recombinant mutant of ricin A chain. RiVax is safe, immunogenic and protective in mice when administered intramuscularly (IM). We have now attempted to increase the utility and immunogenicity of RiVax by administering it intradermally (ID) with or without a...

Ricin is a CDC level B biothreat. Our recombinant ricin A chain vaccine (RiVax) contains two mutations, rendering it non-toxic at high doses. Frozen or alum formulations of RiVax protected mice against ricin administered by injection, gavage or aerosol. Without alum, RiVax was safe and immunogenic in rabbits and human volunteers. For military use,...

CD22 is broadly expressed on human B cell lymphomas. Monoclonal anti-CD22 antibodies alone, or coupled to toxins, have been used to selectively target these tumors both in SCID mice with xenografted human lymphoma cell lines and in patients with B cell lymphomas. Single-walled carbon nanotubes (CNTs) attached to antibodies or peptides represent ano...

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Combotox is a 1:1 mixture of RFB4-dgA and HD37-dgA which are immunotoxins that target the CD22 and CD19 antigens, respectively. Combotox has different toxicities and targets than chemotherapy and is, thus, a new candidate for the treatment of patients with relapsed ALL. Precl...

Previous studies have shown that rapamycin can inhibit the growth of several different types of human tumor cells in vitro. In certain cases, it can reverse the phenotype of multidrug resistant (MDR) cells. However, there is limited information concerning its effect on P-glycoprotein (P-gp), a pump that is responsible for chemoresistance in many MD...

We have previously described the development and testing of a monoclonal anti-human CD54 antibody (UV3) in SCID mice xenografted with human multiple myeloma, lymphoma, and melanoma cell lines. In all 3 cases, UV3 was highly effective at slowing the growth of tumors and/or prolonging survival. Since CD54 (ICAM-1) is up-regulated on many different ty...

During last two decades, the chimerization and humanization of monoclonal antibodies (mAbs) have led to the approval of several for the treatment of cancer, autoimmune diseases, and transplant rejection. Additional approaches have been used to further improve their in vivo activity. These include combining them with other modalities such as chemoth...

The objective of this study was to generate new P-glycoprotein (P-gp)-expressing multidrug resistant (MDR) cell lines by drug selection. Since our previous studies have been carried out with cells infected with a P-gp-containing vector, it was important to confirm our findings in cells generated by drug selection. In this report, we describe three...

The regulation of tolerance to self-proteins and the suppression of T-cell responses have in part been attributed to the activity of CD25+CD4+ T regulatory (Treg) cells. Further, Treg cells can inhibit the antitumor effectiveness of adoptive immunotherapy and active immunization approaches in preclinical models. In an effort to selectively eliminat...

A major challenge in the field of hematopoietic stem cell transplantation (HSCT) is to prevent the alloreactivity of donor T-cells which leads to acute graft-versus-host disease (GVHD) while preserving a graft-versus-tumor (GVT) effect. Selective depletion using anti-CD25 immunotoxin (IT) can eliminate harmful alloreactive T-cells while preserving...

Ricin is a plant toxin that is a CDC level B biothreat. Our recombinant ricin A chain vaccine (RiVax), which contains mutations in both known toxic sites, has no residual toxicity at doses at least 800 times the immunogenic dose. RiVax without adjuvant given intramuscularly (i.m.) protected mice against intraperitoneally administered ricin. Further...

Selective depletion (SD) of host-reactive donor T cells from allogeneic stem-cell transplants (SCTs) using an anti-CD25 immunotoxin (IT) is a strategy to prevent acute graft-versus-host disease (aGvHD). There is concern that concurrent removal of regulatory T cells (T(regs)) with incomplete removal of alloactivated CD25(+) T cells could increase th...

Cancer dormancy delineates a situation in which residual tumor cells persist in a patient with no apparent clinical symptoms. Although the precise mechanisms underlying cancer dormancy have not been explained, experimental models have provided some insights into the factors that might be involved in the induction and maintenance of a tumor dormant...

The anti-CD19 immunotoxin (IT) (HD37-dgRTA) is effective in killing B-lineage leukemia cells and in curing severe combined immunodeficient mice with acute lymphoblastic leukemia. The present study aimed to identify effective combinations of HD37-dgRTA and chemotherapeutic agents. The in-vitro cytotoxicity assays demonstrate that the combination of...

We previously showed that removal of host-reactive donor T cells from allografts by anti-CD25 immunotoxin (IT) is clinically feasible and reduces the frequency of severe graft-versus-host-disease (GVHD) in a high-risk group of elderly patients undergoing matched-sibling transplantation (Blood, 2005,106:1123). However, it is possible that the concur...

Poor T lymphocyte reconstitution limits the use of haploidentical stem cell transplantation (SCT) because it results in a high mortality from viral infections. One approach to overcome this problem is to infuse donor T cells from which alloreactive lymphocytes have been selectively depleted, but the immunologic benefit of this approach is unknown....

UV3 is a monoclonal antibody that recognizes human CD54 (intercellular adhesion molecule-1), and it was generated for the therapy of human multiple myeloma. In a severe combined immunodeficient (SCID) xenograft model of human multiple myeloma, UV3 significantly prolonged the survival of mice with either early or advanced stages of disease. However,...

The objective of this study was to investigate the ability of the anti-CD20 antibody, Rituximab (RTX), to inhibit the activity of P-glycoprotein (P-gp), and reverse multidrug resistance (MDR) in 2 P-gp/CD20 lymphoma cell lines. We determined whether RTX would chemosensitize the 2 P-gp cell lines in vitro, and inhibit the ability of the cells to eff...

Unexpected dangerous side effects of antibody-based therapies may be prevented with improved design of monoclonal antibodies and of clinical testing protocols.

The purpose of this study was to prepare a tetravalent anti-human CD22 recombinant antibody with improved antitumor activity and a half life longer than that of its divalent counterpart. We compared the ability of tetravalent vs. divalent antibody to associate/dissociate to/from CD22-positive Daudi cells, to interact with murine and human Fcgamma r...

Ex vivo depletion of alloreactive CD25(+) T cells from a stem cell transplant (SCT) can reduce the incidence of graft-versus-host disease (GVHD) while preserving antimicrobial and perhaps antileukemia activity. However, the most effective methods for allodepleting T cells prior to transplant have not been determined. In this study, we have compared...

We have shown that administration of a novel anti-CD54 monoclonal antibody (UV3) results in long-term survival of SCID mice bearing human myeloma xenografts. Previous studies have demonstrated a link between the expression of CD54 and the progression of uveal melanoma. Our study assessed the expression of CD54 on 7 human uveal melanoma cell lines a...

Ricin, a highly potent toxin produced by castor beans, is classified by the Centers for Disease Control and Prevention as a level B biothreat because it is easily produced, readily available, and highly stable. There have been >750 cases of documented ricin intoxication in humans. There is no approved vaccine for ricin. Ricin contains a lectin-bind...

A study was undertaken to investigate the efficacy of a high affinity, rapidly internalizing anti-CD22 monoclonal antibody for selectively delivering high-energy (90)Y radioactivity to B lymphoma cells in vivo. The antibody, RFB4, was readily labeled with (90)Y using the highly stable chelate, 1B4M-diethylenetriaminepentaacetic acid. Labeled RFB4 s...

Ex-vivo selective depletion (SD) of alloreactive donor lymphocytes by anti-CD25 immunotoxin is a novel method to reduce the severity of graft-versus-host-disease (GVHD) in elderly patients undergoing matched-sibling transplantation (Blood 2005, 106 (3), 1123–9). Nevertheless, there is concern that the concurrent removal of CD4+CD25+ regulatory T ce...

Immunization of mice with the idiotype (Id) immunoglobulin from the murine B cell lymphoma, BCL1, before inoculating tumor cells can induce tumor dormancy. In this model, the tumor cells grow for a short period of time and then regress. The mice live for months or years with approximately 1 million tumor cells in their spleens. Some mice relapse du...

Ricin toxin is a plant-derived ribosome inactivating protein (RIP) of extraordinary toxicity. Vaccination using ricin toxoid or its A chain (RTA) is protective in animals but both vaccines have two potential toxicities, RIP and vascular leak syndrome (VLS). Previously we described three recombinant RTA constructs from which both toxicities were eli...

DNA vaccination can elicit the production of anti-tumor antibodies, thus obviating the need to continuously administer passive antibody. This vaccination strategy is particularly important where antibodies have proven to be effective anti-tumor agents. To amplify antibody responses against weak tumor antigens, we previously designed DNA-fusion vacc...

We have selectively depleted host-reactive donor T cells from peripheral blood stem cell (PBSC) transplant allografts ex vivo using an anti-CD25 immunotoxin. We report a clinical trial to decrease graft-versus-host disease (GVHD) in elderly patients receiving selectively depleted PBSC transplants from HLA-identical sibling donors. Sixteen patients...

Multi-targeting strategies improve the efficacy of antibody and immunotoxin therapies but have not yet been thoroughly explored for HER2-based cancer treatments. We investigated multi-epitope HER2 targeting to boost photosensitizer immunoconjugate uptake as a way of enhancing photoimmunotherapy. Photoimmunotherapy may allow targeted photodynamic de...

Murine and chimeric RFB4 (anti-human CD22) monoclonal antibodies (MAbs) with mutations in their Fc portions were conjugated to recombinant ricin toxin A chain to generate immunotoxins. The resulting immunotoxins (ITs) constructed with chimeric RFB4 MAbs were designed to have longer or shorter half-lives but similar binding and cytotoxic properties....

Poor immune reconstitution after haplo-identical stem cell transplantation results in high mortality from viral infections and relapse. One approach to overcome this problem is to deplete alloreactive cells selectively by deleting T cells activated by recipient stimulators, using an immunotoxin directed against the activation marker CD25. However,...

Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic stem cell transplant (SCT), especially in older patients. We previously showed that host-reactive donor T cells are selectively depleted (SD) from an allograft ex vivo, following a short co-culture of donor cells with irradiated T cell stimulators fro...