Special Issue "Immunotoxins: Future Advances and Directions"

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Tumor Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (30 November 2018)

Special Issue Editor

Guest Editor
Dr. David J. Flavell

The Simon Flavell Leukaemia Research Laboratory, Southampton General Hospital, Southampton SO16 6YD, United Kingdom
Website | E-Mail
Interests: leukaemia; lymphoma; monoclonal antibodies; immunotherapy; immunotoxins; strategies to improve immunotoxin therapeutic index; cell death mechanisms

Special Issue Information

Dear Colleagues,

Immunotoxins (ITs) are hybrid protein molecules comprised of an antibody component coupled either chemically or fused genetically to a large proteinaceous bacterial or plant-derived toxin molecule such as diphtheria toxin, pseudomonas exotoxin or saporin. Their selective cytotoxicity for target antigen bearing cells is exerted once the toxin component gains access to the target cell cytosol where it irreversibly inhibits protein synthesis, thus bringing about apoptotic cell death. ITs can rightly be considered as the predecessors of today’s antibody drug conjugates (ADC) that are now in rapid clinical development. It is now 48 years since the first IT was described by Moolten and coworkers in 1970 [1] and then developed further by Thorpe and his co-workers [2]. Since then a succession of next generation ITs have been under constant investigation as promising therapeutic entities particularly for haeamatological malignancies [3]. During this time they have been repeatedly shown to possess significant selective cytotoxicity for target cells bearing the target antigen and furthermore have, in some cases, exhibited significant activity against a range of cancers in clinical trials. The question therefore is why have IT’s largely failed to capture the attention of the pharmaceutical industry whereas ADC’s have succeeded in doing so?

The series of papers presented in this special edition of Biomedicines on immunotoxins will critically examine the major issues that have ostensibly prevented the widespread commercial clinical development of ITs. Each paper will examine a particular practical problem and offer a solution to this with a view to improving the therapeutic efficacy and safety of IT therapy. Amongst the subject areas covered will be the importance of single versus multiple antigen targeting, target antigen internalization and trafficking, the problem of immunogenicity, off-target toxicities, and a variety of other strategies that could be brought to bear to improve the overall therapeutic index of ITs. The matter of manufacturing methods for recombinant ITs will also be covered with an eye on the practicalities for the large scale manufacture of clinical grade IT.  All these aspects of pre- clinical IT development will be presented in the context of past clinical studies that have brought to our attention the problems that have limited the full clinical development of ITs. It is to be hoped that the solutions on offer through these series of papers will reinvigorate the field once it is clear that previously encountered problems are indeed surmountable. This we hope will provide a sound rationale that will argues for the continued clinical development of ITs for a variety of human malignancies.

We cordially invite authors working in this field to submit original research or review articles that are relevant to the stated objectives of this special edition of Biomedicines on immunotoxins.

The guest editors would like to dedicate this special edition of Biomedicines on Immunotoxins to the memory of Dr Philip E. Thorpe (1951 – 2013) for his seminal contributions over many years to the immunotoxin field.

  1. Moolten, F.L.; Cooperband, S.R. Selective destruction of target cells by diphtheria toxin conjugated to antibody directed against antigens on the cells. Science 1970, 169, 68-70.
  2. Thorpe, P.E.; Ross, W.C.; Cumber, A.J.; Hinson, C.A.; Edwards, D.C.; Davies, A.J. Toxicity of diphtheria toxin for lymphoblastoid cells is increased by conjugation to antilymphocytic globulin. Nature 1978, 271, 752-755.
  3. Wayne, A.S.; Fitzgerald, D.J.; Kreitman, R.J.; Pastan, I. Immunotoxins for leukemia. Blood 2014, 123, 2470-2477.

Dr. David J Flavell
Guest Editor

Manuscript Submission Information

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Keywords

  • Immunotoxins
  • therapy
  • cancer
  • augmentation
  • therapeutic index
  • immunogenicity
  • target antigens
  • clinical trials
  • clinical grade drug manufacture.

Published Papers (4 papers)

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Research

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Open AccessArticle
The TLR3 Agonist Poly Inosinic:Cytidylic Acid Significantly Augments the Therapeutic Activity of an Anti-CD7 Immunotoxin for Human T-Cell Leukaemia
Biomedicines 2019, 7(1), 13; https://doi.org/10.3390/biomedicines7010013
Received: 15 January 2019 / Revised: 7 February 2019 / Accepted: 12 February 2019 / Published: 16 February 2019
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Abstract
We have previously shown that antibody-dependent cellular cytotoxicity (ADCC) cooperates with immunotoxin (IT)-mediated killing of human leukaemia cells in an severe combined immunodeficient (SCID) mouse model of human T-cell acute lymphoblastic leukaemia (SCID-HSB-2 mice), but not in an equivalent non-obese diabetic (NOD)/SCID mouse [...] Read more.
We have previously shown that antibody-dependent cellular cytotoxicity (ADCC) cooperates with immunotoxin (IT)-mediated killing of human leukaemia cells in an severe combined immunodeficient (SCID) mouse model of human T-cell acute lymphoblastic leukaemia (SCID-HSB-2 mice), but not in an equivalent non-obese diabetic (NOD)/SCID mouse model. In these earlier studies, we reasoned that diminished ADCC due to the functional deficit in natural killer (NK) cell activity in NOD/SCID mice resulted in a failure of effective perforin/granzyme-mediated cytotoxicity necessary for the delivery of the augmentative effect. Poly-inosinic-cytidylic acid [poly (I:C)] is a synthetic dsRNA toll-like receptor 3 (TLR3) agonist that possesses a number of biological properties that includes the in vivo activation of NK cells. We show here that intravenous (i.v.) injection of SCID mice with [poly (I:C)] results in characteristic time-related changes in serum interleukin 2 (IL-2), IL-12, and interferon γ (INFγ) cytokine levels that are consistent with TLR3 driven activation of SCID mouse NK cells. Concomitantly, there are changes in the expression levels of CD2, CD16/32 (FcγRII/RIII), CD161 (NK1.1), and F4/80 in the bulk splenocyte population. These observed changes correlate with an increase in the in vitro lytic capabilities of putative NK cells from within the splenocyte population of [poly (I:C)] treated SCID mice. We demonstrate that the in vivo activation of NK cells with [poly (I:C)] in SCID mice bearing disseminated human T-cell leukaemia xenografts resulted in a significant improvement in the therapeutic activity exerted by an intact murine monoclonal antibody against human CD7. This was also seen for a saporin-based immunotoxin constructed with the same intact antibody (HB2-SAPORIN), but not with an F(ab’)2 derivative of the same antibody or of an IT constructed with the same F(ab’)2 HB2 antibody derivative. This study further demonstrates the previously reported reinforcing role of ADCC for the therapeutic activity of IT in an SCID mouse model of human T-ALL and the potential to significantly boost this further with [poly (I:C)]. Our study provides the rationale to justify the exploration of the clinical utility of IT based therapeutics in combination with TLR3 agonists, such as [poly (I:C)], for the treatment of haematological, and possibly other, malignancies. Full article
(This article belongs to the Special Issue Immunotoxins: Future Advances and Directions)
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Review

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Open AccessReview
Hosts for Hostile Protein Production: The Challenge of Recombinant Immunotoxin Expression
Biomedicines 2019, 7(2), 38; https://doi.org/10.3390/biomedicines7020038
Received: 31 March 2019 / Revised: 7 May 2019 / Accepted: 13 May 2019 / Published: 17 May 2019
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Abstract
For the recombinant expression of toxin-based drugs, a crucial step lies not only in the choice of the production host(s) but also in the accurate design of the protein chimera. These issues are particularly important since such products may be toxic to the [...] Read more.
For the recombinant expression of toxin-based drugs, a crucial step lies not only in the choice of the production host(s) but also in the accurate design of the protein chimera. These issues are particularly important since such products may be toxic to the expressing host itself. To avoid or limit the toxicity to productive cells while obtaining a consistent yield in chimeric protein, several systems from bacterial to mammalian host cells have been employed. In this review, we will discuss the development of immunotoxin (IT) expression, placing special emphasis on advantages and on potential drawbacks, as one single perfect host for every chimeric protein toxin or ligand does not exist. Full article
(This article belongs to the Special Issue Immunotoxins: Future Advances and Directions)
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Open AccessReview
Clinical Activity and Tolerability of SL-401 (Tagraxofusp): Recombinant Diphtheria Toxin and Interleukin-3 in Hematologic Malignancies
Received: 20 November 2018 / Revised: 26 December 2018 / Accepted: 3 January 2019 / Published: 5 January 2019
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Abstract
Overcoming the leukemia stem cell resistance to intensive chemotherapy has been an area of extensive research over the last two decades. Advances and greater understanding of the molecular biology of leukemia stem cells are in rapid progress. Targeted therapies are currently being used [...] Read more.
Overcoming the leukemia stem cell resistance to intensive chemotherapy has been an area of extensive research over the last two decades. Advances and greater understanding of the molecular biology of leukemia stem cells are in rapid progress. Targeted therapies are currently being used in clinical practice with reasonable response rates, but a cure is being achieved in only a small percentage of patients, most likely due to tumor mutational heterogeneity. A genetically engineered diphtheria toxin fused with interleukin-3 (SL-401 or tagraxofusp) has shown robust activity in blastic plasmacytoid dendritic cell neoplasm and promising response rates in different myeloid malignancies, including eradication of minimal residual disease. Multiple clinical trials are being conducted using this drug and the preliminary results are encouraging. This article reviews the clinical trials for SL-401, its mechanism of action, clinical activity, and the adverse event profile. Full article
(This article belongs to the Special Issue Immunotoxins: Future Advances and Directions)
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Open AccessReview
Immunotoxins Targeting B cell Malignancy—Progress and Problems With Immunogenicity
Received: 28 November 2018 / Revised: 17 December 2018 / Accepted: 19 December 2018 / Published: 21 December 2018
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Abstract
Few immunotoxins or targeted toxins have become mainline cancer therapies. Still immunotoxins continue to be of major interest and subject of research and development as alternative therapies for drug resistant cancer. A major matter of concern continues to be immunogenicity exemplified by the [...] Read more.
Few immunotoxins or targeted toxins have become mainline cancer therapies. Still immunotoxins continue to be of major interest and subject of research and development as alternative therapies for drug resistant cancer. A major matter of concern continues to be immunogenicity exemplified by the anti-toxin response of the treated patient. Since some of our most effective toxins are bacterial in nature and bacterial proteins are highly immunogenic, this review describes some efforts to address this pressing issue. Full article
(This article belongs to the Special Issue Immunotoxins: Future Advances and Directions)
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