Resimmune

Resimmune or A-dmDT390-bisFv(UCHT1) is an experimental drug — an anti-T cell immunotoxin — that is being investigated for 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.

Resimmune
Clinical data
Trade namesResimmune
Pregnancy
category
  • (no adequate human studies)
Routes of
administration		Intravenous
ATC code
  • none
Legal status
Legal status
  • Experimental
Pharmacokinetic data
Elimination half-life42–66 min
Identifiers
ChemSpider
  • none

Clinical trials

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] 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).[5]

A second clinical trial is open to test if Resimmune can act as an immunomodulator of late stage metastatic melanoma.[6]

Description of molecule

Resimmune is a bivalent anti-T cell immunotoxin, A-dmDT390-bisFv(UCHT1).[7] 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;[8] Thompson et al., 2001;[9] Woo et al., 2002[10]). The bivalent immunotoxin, A-dmDT390-bisFv(UCHT1)[11] 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 (Ratts et al., 2003). 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.

Mechanism of action

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
  1. Frankel AE, Zuckero SL, Mankin AA, Grable M, Mitchell K, Lee YJ, Neville DM, Woo JH (2009). "Anti-CD3 recombinant diphtheria immunotoxin therapy of cutaneous T cell lymphoma". Curr Drug Targets. 10 (Feb, 10(2)): 104–9. Review. doi:10.2174/138945009787354539. PMID 19199905.
  2. Clinical trial number NCT00611208 for "A-dmDT390-bisFv(UCHT1) Immunotoxin Therapy for Patients With T-cell Diseases" at ClinicalTrials.gov
  3. 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
  4. Angimmune: Clinical Trials: Identification of a Cutaneous T-Cell Lymphoma (CTCL) Subgroup Experiencing a High Treatment Response Rate: Paragraph 1
  5. Angimmune: Clinical Trials: Trial Description: Paragraph 2
  6. 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
  7. Woo, JH; Lee YJ; Neville DM; Frankel AE. (2010). Pharmacology of anti-CD3 diphtheria immunotoxin in CD3 positive T-cell lymphoma trials. Methods Mol. Biol. 651. pp. 157–75. doi:10.1007/978-1-60761-786-0_10. ISBN 978-1-60761-785-3. PMID 20686966.
  8. Liu YY, Gordienko I, Mathias A, Ma S, Thompson J, Woo JH, Neville DM (19 Jul 2000). "Expression of an anti-CD3 single-chain immunotoxin with a truncated diphtheria toxin in a mutant CHO cell line". Protein Expr. Purif. 19 (2): 304–11. doi:10.1006/prep.2000.1255. PMID 10873546.
  9. Thompson J, Stavrou S, Weetall M, Hexham JM, Digan ME, Wang Z, Woo JH, Yu Y, Mathias A, Liu YY, Ma S, Gordienko I, Lake P, Neville DM (14 Dec 2001). "Improved binding of a bivalent single-chain immunotoxin results in increased efficacy for in vivo T-cell depletion". Protein Eng. 14 (12): 1035–41. doi:10.1093/protein/14.12.1035. PMID 11809934.
  10. Woo JH, Liu YY, Mathias A, Stavrou S, Wang Z, Thompson J, Neville DM (25 Jul 2002). "Gene optimization is necessary to express a bivalent anti-human anti-T cell immunotoxin in Pichia pastoris". Protein Expr. Purif. 25 (2): 270–82. doi:10.1016/S1046-5928(02)00009-8. PMID 12135560.
  11. National Cancer Institute (NCI) Drug Dictionary: anti-CD3 immunotoxin A-dmDT390-bisFv(UCHT1)
  12. Sustained Effect Theory
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