He is currently co-chief of the LMB and is working on various Immunotoxin Therapies.
|
|
Anti-CD19 immunotoxin is a monoclonal antibody linked to a toxic substance. It is being studied in the treatment of some types of B-cell cancer. Anti-CD19 immunotoxin is made in the laboratory. It binds to CD19, a protein on the surface of normal B cells and B-cell tumors, and kills the cells.
|
|
This single chain recombinant immunotoxin selectively kills human malignant and transiently depletes normal . Malignant are 30-fold more sensitive to compared to normal resting .
|
|
Christine Campo Alewine is an American oncologist and biologist researching immunotoxin therapeutics in pancreatic cancer. She is an investigator at the National Cancer Institute.
|
|
An immunotoxin, BL22, that targets this receptor is being tested at the NIH. As a treatment for acute lymphoblastic leukemia (ALL), Inotuzumab ozogamicin is an antibody-drug conjugate that targets this molecule.
|
|
J. Clin. Oncol. 30: 1822-1828, 2012 Moxe also produced complete remissions in children with drug resistant Acute Lymphoblastic Leukemia and is being developed for the treatment of that disease. Another immunotoxin, SS1P,Chowdhury, P.S. and Pastan, I. Improving antibody affinity by mimicking somatic hypermutation in vitro.
|
|
One of these, HA22 or Moxetumomab pasudotox (Moxe), targets CD22 on B cell malignancies; it has produced many complete and durable remissions in chemotherapy resistant Hairy cell leukemia and is now in a phase 3 trial to gain FDA approval.Kreitman, R.J., Wilson, W.H., Bergeron, K., Raggio, M., Stetler-Stevenson, M., FitzGerald, D.J., and Pastan, I.: Efficacy of the anti- CD22 recombinant immunotoxin BL22 in chemotherapy-resistant Hairy-cell leukemia. N. Engl. J. Med. 345: 241-247, 2001Kreitman, R.J., Tallman, M.S., Robak, T., Coutre, S., Wilson, W.H., Stetler-Stevenson, M., FitzGerald, D.J., Lechleider, R., and Pastan, I.: Phase I trial of anti-CD22 recombinant immunotoxin Moxetumomab pasudotox (CAT-8015 or HA22) in patients with hairy cell leukemia.
|
|
Resimmune is a bivalent anti-T cell immunotoxin, . The diphtheria toxin moiety has been modified to include an NH2 terminal alanine (A) and two double mutations (dm) have been made to prevent glycosylation in the eukaryotic expression system, Pichia pastoris (Liu et al., 2000; Thompson et al., 2001; Woo et al.
|
|
An immunotoxin is an artificial protein consisting of a targeting portion linked to a toxin. When the protein binds to that cell, it is taken in through endocytosis, and the toxin kills the cell. They are used for the treatment of some kinds of cancer and a few viral infections.
|
|
An anti-CD22 immunotoxin is a monoclonal antibody (targeting CD22) linked to a cytotoxic agent. They are being studied in the treatment of some types of B-cell cancer. They bind to CD22, a receptor protein on the surface of normal B cells and B-cell tumors, and, upon internalization, kill the cells.
|
|
Immunoconjugates are antibodies conjugated (joined) to a second molecule, usually a toxin, radioisotope or label. These conjugates are used in immunotherapy and to develop monoclonal antibody therapy as a targeted form of chemotherapy when they are often known as antibody-drug conjugates. When the conjugates include a radioisotope see radioimmunotherapy. When the conjugates include a toxin see immunotoxin.
|
|
The Recombinant Immunotoxin Collaborative Group (RICG) is a group of scientists specialising in immunology, biochemistry and molecular biology from the United Kingdom and Italy. The group is working toward the development of genetically engineered immunotoxins made from monoclonal antibody fragments genetically fused to either saporin or Pseudomonas exotoxin (PE) for the treatment of human hematological malignancies such as leukaemia, lymphoma and multiple myeloma.
|
|
The best clinical success has been achieved in treating patients with refractory hairy cell leukemia. These patients were treated with the recombinant immunotoxin which targets the CD22 cell surface receptor on these leukemic cells. In two uncontrolled clinical studies, about half of participants achieved a complete response after BL22 treatment. This therapeutic has been superseded by HA22, a slightly modified version.
|
|
Abrin is significantly more toxic following intravenous administration. The LD50 values obtained vary between 0.03 and 0.06 μg/kg in rabbits and between 1.25 and 1.3 μg/kg in dogs, depending on the species. In clinical studies involving cancer patients, up to 0.3 μg/kg intravenous of abrin immunotoxin was tolerated without the development of serious symptoms of toxicity. The toxicity of abrin is also increased if it is inhaled.
|
|
Calcium imaging observation following immunotoxin use showed that some correlated firing still remained where coupled voltage clamp recording showed significant reduction in correlated firing. The remaining correlated firing could explain the formation of eye- specific retinogeniculate projections that was found. Using calcium imaging and MEA recording these cells have shown to have no correlated firing. Instead, reduced firing rates have been observed, and depolarization in one cell seemed to inhibit surrounding cells.
|
|
One of the major obstacles to the success of RIT therapy is that antibodies often form and neutralize the RIT preventing additional treatment cycles. Pastan has developed methods to make active RITs in which the major B cell and T cell epitopes have been identified and silenced.Liu, W., Onda, M., Lee, B., Kreitman, R.J., Hassan, R., Xiang, L., and Pastan, I.: Recombinant immunotoxin engineered for low immunogenicity and antigenicity by identifying and silencing human B-cell epitopes. Proc. Natl. Acad. Sci.
|
|
Resimmune or A-dmDT390-bisFv(UCHT1) is an experimental drug -- an anti-T cell immunotoxin -- that is being investigated for treatment of blood cancers such as cutaneous T cell lymphoma (CTCL). It was developed by Doctors Neville, Woo, and Liu while at the National Institutes of Health (NIH) and is under exclusive license to Angimmune, LLC. The therapy has potential applications for lymphomas and T cell driven autoimmune diseases, including multiple sclerosis, and graft-versus-host disease following stem cell or bone marrow transplant.
|
|
She joined NCI's laboratory of molecular biology as an assistant clinical investigator through the support of the clinical investigator development program in 2014 and became a tenure-track investigator through the NIH Lasker Scholar program in 2016. Alewine researches the use of immunotoxin therapeutics in pancreatic cancer. Her lab and clinic are testing and refining two recombinant immunotoxins that target a protein called mesothelin that is present on the surface of several types of cancer tumor cells, including pancreatic, ovarian, and some lung cancers.
|
|
On 1 November 2005 CAT announced it was acquiring two anti- CD22 immunotoxin products from Genencor, namely GCR-3888 and GCR-8015. Genencor is the biotechnology division of Danisco and the acquisition meant CAT would hire certain former Genencor key employees to be responsible for the development of the programmes. GCR-3888 and GCR-8015 were discovered and initially developed by the National Cancer Institute, which is part of the U.S. National Institutes of Health. Genencor licensed the candidates for hematological malignancies and entered into a Cooperative Research and Development Agreement (CRADA) with the NIH, which will now be continued by CAT.
|
|
On the other hand, Opn4-/- mice had difficulties adjusting to new phases in response to pulses of monochromatic light. The implication was that melanopsin was necessary for phase resetting but other mechanisms of light inputs might be involved in circadian entrainment as well. In 2008, the Provencio lab was able to specifically destroy melanopsin cells in the fully developed mouse retina using an immunotoxin made of an anti-melanopsin antibody conjugated to the protein saporin. This resulted in lowered responsiveness to light/dark cycles; a similar characteristic was observed in gene-knockout mutants lacking rods, cones or melanopsin.
|
|
On 1 November 2005, Cambridge Antibody Technology (CAT) announced it was acquiring two anti-CD22 immunotoxin products from Genencor, namely GCR-3888 and GCR-8015. Genencor is the biotechnology division of Danisco and the acquisition meant CAT would hire certain former Genencor key employees to be responsible for the development of the programmes. GCR-3888 and GCR-8015 were discovered and initially developed by the National Cancer Institute, which is part of the U.S. National Institutes of Health. Genencor licensed the candidates for hematological malignancies and entered into a Cooperative Research and Development Agreement (CRADA) with the NIH, which will now be continued by CAT.
|
|
Since 2009, Resimmune is being tested against cutaneous T cell lymphoma, and is in a Phase II trial: Immunotoxin Therapy for Patients With T-cell Diseases.Scott & White Healthcare Cancer Research Institute: Clinical Trial 071163 - A Phase I/II study of A-dmDT390-bisFv(UCHT1) Fusion Protein in Patients with Cutaneous T-Cell Lymphoma All patients had failed at least one conventional therapy. In the Phase I portion of the trail, a subgroup of nine patients was identified with an 89% response rate.Angimmune: Clinical Trials: Identification of a Cutaneous T-Cell Lymphoma (CTCL) Subgroup Experiencing a High Treatment Response Rate: Paragraph 1 This subgroup was Stage IB-IIB with mSWAT scores of less than 50.
|
|
The Hairy Cell Leukemia Consortium was founded in 2008 to address researchers' concerns about the long-term future of research on the disease. Partly because existing treatments are so successful, the field has attracted very few new researchers. In 2013 the Hairy Cell Leukemia Foundation was created when the Hairy Cell Leukemia Consortium and the Hairy Cell Leukemia Research Foundation joined together. The HCLF is dedicated to improving outcomes for patients by advancing research into the causes and treatment of hairy cell leukemia, as well as by providing educational resources and comfort to all those affected by hairy cell leukemia. Three immunotoxin drugs have been studied in patients at the NIH National Cancer Institute in the U.S.: BL22, HA22 and LMB-2.
|
|
These immunotoxin designs based on the use of ribotoxins have been shown to be highly effective, although in laboratory experiments, with mice and tumour cells in culture. They have not yet been tested in humans. The additional benefit of not showing any detectable undesirable side effects, most likely due to the highly specific recognition of the antigen by the antibody used, makes them attractive for the therapeutic treatment of certain solid tumors. This approach has recently been improved with the incorporation of different artificial variants of ribotoxins, such as one that cannot cross the membranes on its own, but retains the ribosome inactivating activity, or a de-immunized version of α-sarcin which, in vitro, has been proven incapable of triggering a T-lymphocyte response.
|
|
First, the long-term effects of treatment with TTX are unknown, as it is not yet possible to monitor the retinal activity for a long duration in an intact animal. The finding that long-term injection of TTX did not inhibit and instead merely delayed eye-specific layer formation could be explained then by the reduced effects of TTX on retinal activity at a longer duration. This supports the argument that blocking all retinal activity prevents eye-specific projection formation remains to be determined. Furthermore, since immunotoxin treatment to kill starburst amacrine cells shows no difference in the formation of eye-specific retinogeniculate projections while treatment with epibatidine does, it could suggest that some sort of retinal activity is essential for the eye-specific layer formation, but not retinal waves.
|
|
USA 93: 136-140, 1996 SS1P has shown anti-tumor activity in a phase I trial when combined with chemotherapy. In a recently completed clinical trial, SS1P was combined with the immunosuppressive drugs cyclophospamide and pentostatin and produced remarkable major and sustained tumor regressions lasting up to 2 years in patients with advanced chemotherapy resistant mesothelioma.Hassan, R., Miller, A.C., Sharon, E., Thomas, A., Reynolds, J.C., Ling, A., Kreitman, R.J., Miettinen, M.M., Steinberg, S.M., Fowler, D.H., and Pastan, I.: Major cancer regressions in mesothelioma after treatment with an anti-mesothelin immunotoxin and immune suppression. Sci. Transl. Med. 5: 208ra147, 2013 Tumor shrinkage of this magnitude and duration has never before been observed in mesothelioma. Pastan’s current efforts are directed at improving the activity and usefulness of immunotoxins he has developed.
|
|
Moxetumomab pasudotox, sold under the brand name Lumoxiti, is an anti-CD22 immunotoxin for the treatment of adults with relapsed or refractory hairy cell leukemia (HCL) who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog. Moxetumomab pasudotox is a CD22-directed cytotoxin and is the first of this type of treatment for adults with HCL. The drug consists of the binding fragment (Fv) of an anti- CD22 antibody fused to a toxin called PE38. This toxin is a 38 kDa fragment of Pseudomonas exotoxin A. Hairy cell leukemia (HCL) is a rare, slow-growing cancer of the blood in which the bone marrow makes too many B cells (lymphocytes), a type of white blood cell that fights infection. HCL is named after these extra B cells which look “hairy” when viewed under a microscope.
|
|
Saporin is not the only molecule that is used in this way; the enzymatic chain of ricin, the RIP gelonin, the enzymatic chain of Pseudomonas exotoxin, the enzymatic chain of diphtheria toxin have also been used, again with variations in success. Immunotoxins consisting of a monoclonal antibody linked to saporin have been developed and evaluated in formal clinical trials in patients with leukaemia and lymphoma in the UK and Germany. One disadvantage of these types of immunotoxin for clinical use is their relatively narrow therapeutic window and associated potentially life-threatening toxicities at dose levels that are therapeutic. During the past 15 years the research group of Dr David Flavell at Southampton General Hospital in the UK have been investigating various ways of improving the potency and widening the therapeutic window for saporin-based immunotoxins thereby opening up new possibilities for this class of drug.
|
|