Special Issue "Immunotoxins: Future Advances and Directions"
A special issue of Biomedicines (ISSN 2227-9059).
Deadline for manuscript submissions: 15 October 2018
Dr. David J. Flavell
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  and then developed further by Thorpe and his co-workers . Since then a succession of next generation ITs have been under constant investigation as promising therapeutic entities particularly for haeamatological malignancies . 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.
- 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.
- 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.
- Wayne, A.S.; Fitzgerald, D.J.; Kreitman, R.J.; Pastan, I. Immunotoxins for leukemia. Blood 2014, 123, 2470-2477.
Dr. David J Flavell
Manuscript Submission Information
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- therapeutic index
- target antigens
- clinical trials
- clinical grade drug manufacture.
The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.
Title: Hosts for hostile protein production: the challenge of recombinant immunotoxin expression
Authors: Riccardo Vago and Maria Serena Fabbrini
Affiliation: Urological Research InstituteDivision of Experimental OncologyIRCCS Ospedale San RaffaeleVia Olgettina 6020132 Milano, Italy
Abstract: For expression of toxin-based drugs, a crucial step lies in the choice of the production host(s). This issue is particularly important since such products may be toxic for the expressing host itself. To avoid or limit the intoxication of productive cells, while obtaining a consistent yield, several different cellular systems ranging from bacterial to mammalian cells have been investigated. In this review, we will discuss the development of recombinant immunotoxin expression systems, placing special emphasis on the advantages and drawbacks, as one single perfect host for every protein toxin or recombinant immunotoxin does not exist.
Title: The TLR3 Agonist Poly Inosinic:Cytidylic Acid Significantly Augments the Therapeutic Activity of An Anti-CD7 Immunotoxin for Human T-cell Leukaemia
Authors: David J Flavell, Suzanne E. Holmes & Sopsamorn U Flavell
Affiliation: The Simon Flavell Leukaemia Research Unit, Southampton General Hospital, Southampton, Hampshire SO16 6YD, United Kingdom
Abstract: We have previously shown that ADCC cooperates with immunotoxin (IT)-mediated killing of human leukaemia cells in a SCID mouse model of human T-ALL (SCID-HSB-2 mice) but fails to do so in an equivalent NOD/SCID mouse model. We reasoned that diminished ADCC due to the functional deficit in NK cell activity in NOD/SCID mice resulted in a failure of effective perforin/granzyme-mediated cytotoxicity necessary for delivery of the augmentative effect to IT cytotoxicity. Poly-inosinic-cytidylic acid [poly (I:C)] is a synthetic dsRNA TLR3 agonist that activates NK cells in vivo. We show here that i.v. injection of SCID mice with [poly (I:C)] results in characteristic time-related changes in serum IL-2, IL-12 and INFg 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 (FcgRII/RIII), CD161 (NK1.1) and F4/80 in the bulk splenocyte population. These observed changes correlate with an increase in the lytic capabilities of putative NK cells from within the bulk splenocyte population of [poly (I:C)] treated SCID mice. We were able to demonstrate that the in vivo activation of SCID mouse NK cells by [poly (I:C)] resulted in a significant improvement in therapeutic activity of the anti-CD7 MoAb, HB2, HB2-SAPORIN immunotoxin constructed with the same intact antibody (HB2-SAPORIN) but not with an IT constructed with a F(ab)2 derivative (HB2-F(ab)2-SAPORIN) in SCID-HSB-2 mice. This study further demonstrates the reinforcing role of ADCC in augmenting IT cytotoxicity and the potential it offers for improving the therapeutic performance of this class of therapeutic molecule. Our study provides the rationale to justify exploring the clinical utility of IT plus TLR3 agonists for the treatment of haematological and possibly other malignancies.