Resimmune
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| Trade names | Resimmune |
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| Routes of administration | Intravenous |
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| Elimination half-life | 42–66 min |
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Resimmune or A-dmDT390-bisFv(UCHT1) is an experimental drug — an anti-T cell immunotoxin — that is being investigated for the treatment of T cell blood cancers such as cutaneous T cell lymphoma (CTCL).[1] 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.
Clinical trials
[edit]Since 2009, Resimmune is being tested against cutaneous T cell lymphoma, and is in a Phase II trial: A-dmDT390-bisFv(UCHT1) Immunotoxin Therapy for Patients With T-cell Diseases.[2][3] 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.[4]: Paragraph 1 This subgroup was Stage IB-IIB with mSWAT scores of less than 50. The complete response rate was 50% (two of which are over 72 months duration and could represent cures). A major exclusion to entering the trial is a past history of heart disease, or prior treatment with alemtuzumab (Campath).[4]: Paragraph 12
A second clinical trial is open to test if Resimmune can act as an immunomodulator of late stage metastatic melanoma.[5]
Description of molecule
[edit]Resimmune is a bivalent anti-T cell immunotoxin, A-dmDT390-bisFv(UCHT1).[6] 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.[7][8][9]). The bivalent immunotoxin, A-dmDT390-bisFv(UCHT1)[10] contains the first 390 amino acid residues of diphtheria toxin (DT) and two tandem sFv molecules derived from UCHT1 parental antibody (an anti-CD3 antibody). The first 390 amino acid residues of DT (DT390) contain the catalytic domain or A chain of DT that inhibits protein synthesis by ADP ribosylation of elongation factor 2 (EF-2) and the translocation domain that translocates the catalytic domain to the cytosol by interaction with cytosolic Hsp90 and thioredoxin reductase.[11] This single chain recombinant immunotoxin selectively kills human malignant T cells and transiently depletes normal T cells. Malignant T cells are 30-fold more sensitive to A-dmDT390-bisFv(UCHT1) compared to normal resting T cells.[citation needed]
Mechanism of action
[edit]Resimmune works by killing malignant T cells, targeting the CD3 T cell receptor complex and transiently depleting all T cells by 2-3 log units. After the four-day treatment, normal T cells are repopulated by homeostatic proliferation. This process may have an immunomodulatory effect that leads to further elimination of residual tumor cells by activation of novel naïve T cells.[1][12]
References
[edit]- ^ a b Frankel AE, Zuckero SL, Mankin AA, Grable M, Mitchell K, Lee YJ, et al. (February 2009). "Anti-CD3 recombinant diphtheria immunotoxin therapy of cutaneous T cell lymphoma". Current Drug Targets. 10 (2): 104–109. doi:10.2174/138945009787354539. PMID 19199905.
- ^ Clinical trial number NCT00611208 for "A-dmDT390-bisFv(UCHT1) Immunotoxin Therapy for Patients With T-cell Diseases" at ClinicalTrials.gov
- ^ 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
- ^ a b "Clinical Trials: Identification of a Cutaneous T-Cell Lymphoma (CTCL) Subgroup Experiencing a High Treatment Response Rate". Angimmune.
- ^ Clinical trial number NCT01888081 for "A-dmDT390-bisFv(UCHT1) Fusion Protein in Combination With Ionizing Radiation for Treatment of Stage IV Melanoma" at ClinicalTrials.gov
- ^ Woo JH, Lee YJ, Neville DM, Frankel AE (2010). "Pharmacology of Anti-CD3 Diphtheria Immunotoxin in CD3 Positive T-Cell Lymphoma Trials". Immunotherapy of Cancer. Methods in Molecular Biology. Vol. 651. pp. 157–175. doi:10.1007/978-1-60761-786-0_10. ISBN 978-1-60761-785-3. PMID 20686966.
- ^ Liu YY, Gordienko I, Mathias A, Ma S, Thompson J, Woo JH, Neville DM (July 2000). "Expression of an anti-CD3 single-chain immunotoxin with a truncated diphtheria toxin in a mutant CHO cell line". Protein Expression and Purification. 19 (2): 304–311. doi:10.1006/prep.2000.1255. PMID 10873546.
- ^ Thompson J, Stavrou S, Weetall M, Hexham JM, Digan ME, Wang Z, et al. (December 2001). "Improved binding of a bivalent single-chain immunotoxin results in increased efficacy for in vivo T-cell depletion". Protein Engineering. 14 (12): 1035–1041. doi:10.1093/protein/14.12.1035. PMID 11809934.
- ^ Woo JH, Liu YY, Mathias A, Stavrou S, Wang Z, Thompson J, Neville DM (July 2002). "Gene optimization is necessary to express a bivalent anti-human anti-T cell immunotoxin in Pichia pastoris". Protein Expression and Purification. 25 (2): 270–282. doi:10.1016/S1046-5928(02)00009-8. PMID 12135560.
- ^ "anti-CD3 immunotoxin A-dmDT390-bisFv(UCHT1)". National Cancer Institute (NCI) Drug Dictionary.
- ^ Ratts R, Zeng H, Berg EA, Blue C, McComb ME, Costello CE, et al. (March 2003). "The cytosolic entry of diphtheria toxin catalytic domain requires a host cell cytosolic translocation factor complex". The Journal of Cell Biology. 160 (7): 1139–1150. doi:10.1083/jcb.200210028. PMC 2172777. PMID 12668662.
- ^ Sustained Effect Theory