Review
`
`Oncologic, Endocrine & Metabolic
`
`Immunotherapeutic and
`antitumour potential of
`thalidomide analogues
`J Blake Marriott, George Muller, David Stirling & Angus G Dalgleish
`Division of Oncology, Department of Cellular & Molecular Sciences, St George’s Hospital Medical
`School, Cranmer Terrace, London, UK and Celgene Corporation, Warren, NJ, USA
`
`The immunomodulatory drug thalidomide has been shown to be clinically
`useful in a number of conditions including various immunological disorders
`and cancers. Clinical activity in vivo is attributed to the wide ranging immu-
`nological and non-immunological properties possessed by this drug; these
`include anti-TNF-α, T-cell co-stimulatory, anti-angiogenic activities and also
`direct antitumour activity. Recently, the design of compounds based on the
`thalidomide structure has led to the synthesis of analogues with greatly
`enhanced immunological activity and with similarly decreased toxicity. These
`derivatives fall into at least two categories; selective cytokine inhibitory drugs
`(SelCID), which are phosphodiesterase Type 4 (PDE4) inhibitors and immu-
`nomodulatory drugs (IMiD), similar to thalidomide which act via unknown
`mechanism(s). These compounds are in the process of being characterised in
`laboratory studies and are also now being assessed in Phase I and Phase I/II
`clinical studies. In this review we will highlight the properties of these two
`novel classes of compound in terms of their effects on both immunological
`and non-immunological systems in vitro. We will also describe how these
`studies are enabling the characterisation and development of these com-
`pounds into clinically relevant drugs in widely varying diseases. To this end
`we will describe the various clinical studies of lead compounds that are in
`progress and speculate as to the potential and future development of these
`exciting compounds.
`
`Keywords: anti-TNF-α, antitumour, immunotherapy, PDE4, T-cell co-stimulation, thalidomide
`analogues
`
`Expert Opin. Biol. Ther. (2001) 1(4):675-682
`
`1. History of thalidomide use
`Thalidomide (α-N-phthalimidoglutarimide) is a synthetic derivative of glutamic
`acid designed and synthesised by the German company Chemie Gruenthal GmvH
`in the mid-1950s. Thalidomide was marketed as a non-toxic replacement for barbit-
`urates in Europe, New Zealand, Australia and Canada. Its apparent lack of toxicity
`led to the drug’s popularity as a sleeping aid. However, thalidomide did not receive
`FDA approval in the United States at this time due to concerns of neuropathy asso-
`ciated with the drug’s use. However, early in 1960 alarming reports suggested that
`thalidomide was associated with neuropathies [1] and birth defects [2]. By the time it
`was taken off the market thalidomide had been taken by thousands of pregnant
`women to counter the effects of morning sickness resulting in more than 10,000
`children being born with thalidomide type birth defects.
`Forty years later, thalidomide is now established as an effective immunomodula-
`tory and anti-inflammatory drug [3-5]. In fact, for many years thalidomide has been
`the World Health Organization (WHO) drug of choice for the treatment of ery-
`
`675
`
`1. History of thalidomide use
`
`2. Mechanisms of thalidomide
`activity
`
`3. Development of thalidomide
`analogues
`
`4. Characterisation of thalidomide
`analogues
`
`5. Differential effects of
`thalidomide analogues on
`cytokine production
`
`6. Other in vitro characterisation
`
`7. Clinical development of SelCID
`analogues
`
`8. Clinical development of IMiD
`analogues
`
`9. Expert opinion
`
`Ashley Publications
`www.ashley-pub.com
`
`
`
`DR. REDDY’S LABS., INC. EX. 1017 PAGE 1
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`Immunotherapeutic and antitumour potential of thalidomide analogues
`
`thema nodosum leprosum (ENL), a potentially life-threaten-
`ing
`inflammatory complication of
`lepromatous
`leprosy
`characterised by inflammatory nodules, night sweats and
`fever. The process of rehabilitation can be traced back to the
`serendipitous discovery of thalidomide’s immunomodulatory
`properties which was reported in 1965 by Israeli dermatolo-
`gist, Jacob Sheskin. He reported that his use of thalidomide as
`a sedative in ENL patients was remarkably effective in treating
`this disfiguring condition [6]. Clinical efficacy was confirmed
`in later studies, including a WHO co-ordinated double-blind
`clinical study in male patients [7,8]. Thalidomide has also been
`used for many years as an immunosuppressant in the treat-
`ment of patients with complications arising from receiving
`bone marrow allografts and its clinical efficacy in chronic graft
`versus host disease (GvHD) has been well established [9,10].
`The majority of the available clinical information on tha-
`lidomide has arisen as a result of small open label studies and
`unpublished anecdotal reporting. These have shown that
`thalidomide appears to be a useful drug in a number of clin-
`ical conditions for which there is little other treatment
`option. In particular, thalidomide has shown potential for
`the treatment of a range of conditions, including rheuma-
`toid arthritis (RA) [10], the inflammatory and wasting effects
`of chronic tuberculosis [11], Behcet’s disease [12] and Crohn’s
`disease [13-15]. Thalidomide is also effective in the treatment
`of aphthous ulcers [16-18] and cachexia (wasting) associated
`with HIV infection [19,20] and AIDS related Kaposi’s sar-
`coma [21]. In 1998, it was reported by researchers at the Uni-
`versity of Arkansas that thalidomide was an effective
`treatment for refractory multiple myeloma with positive
`effects being observed in approximately 30% of the patients
`[22]. There is an increasing body of evidence from larger scale
`studies showing the effectiveness of thalidomide in the treat-
`ment of patients with multiple myeloma [22-25] and also in
`the treatment of patients with a number of other tumours
`[26-29].
`The obvious clinical benefits associated with thalidomide
`treatment in acute ENL led to thalidomide (THALOMID®)
`being given FDA approval for treatment of this condition in
`1998. However, this was necessarily subject to very strict con-
`trols. These include a distribution program, developed and
`patented by Celgene Corporation, called STEPS. (System for
`Thalidomide Education and Prescribing Safety) which
`involves comprehensive patient counselling, a cautionary mes-
`sage from thalidomide victims, a detailed consent form and a
`mandatory thalidomide survey form [30]. In Britain, the drug
`remains unlicensed and is only available on a named patient
`basis although there have been a number of clinical studies in
`HIV infected patients and end stage cancer patients.
`
`2. Mechanisms of thalidomide activity
`
`It is only in the last ten years that information concerning
`
`possible mechanisms behind thalidomide’s clinical activity has
`become known. In 1992, a breakthrough in thalidomide’s
`immunomodulatory properties was reported. Thalidomide
`was shown to have the ability to inhibit synthesis of the pro-
`inflammatory cytokine TNF-α by activated human mono-
`cytes [31]. TNF-α is a key regulator of other pro-inflammatory
`cytokines and leukocyte adhesion molecules and therefore
`represents a therapeutic target in a number of conditions
`where the overproduction of TNF-α is associated with a path-
`ological inflammatory cascade [32,33]. In the last few years two
`anti-TNF-α biological agents have received FDA approval.
`Enbrel, a TNF-α receptor received approval for the treatment
`of RA and Infliximab, a TNF-α antibody received approval
`for Crohn’s disease. The success of both of these drugs vali-
`dated TNF-α blockage as therapeutic treatment.
`In 1994 it was also shown that thalidomide is anti-ang-
`iogenic [34]. The ability of a tumour to induce new blood ves-
`sel formation is crucial for the growth of solid tumours and
`for metastasis. The similarities between this process in the
`promotion of tumour growth and in chronic inflammation
`may support a possible role for thalidomide in the treatment
`of cancers. Indeed, it has been proposed that most solid
`tumours arise in sites of chronic inflammation [35]. In this
`respect it is also worth noting that TNF-α is involved in the
`upregulation of endothelial integrin expression, a process that
`is crucial for new vessel formation [36].
`More recently, thalidomide has been associated with immu-
`nomodulatory activity; on the one hand upregulating Th2-
`type immunity [37] and inhibiting the production of IL-12 by
`mononuclear cells [38] and on the other hand providing activa-
`tion signals to T-cells stimulated in the absence of co-stimula-
`tory signals [39]. These activities may help to explain
`thalidomide’s diverse effects; for example, beneficial activity in
`some autoimmune conditions associated with elevated Th1-
`type cellular immunity as well as possible adjuvant activity in
`the promotion of T-cell responses in a clinical setting. The
`mechanisms for these activities remains unknown although
`they may also explain the bidirectional effect of thalidomide
`on TNF-α production in vitro which is cell and stimulus
`dependent.
`The side effect profile (that includes teratogenicity and
`neuropathy), the low aqueous solubility and the poor aqueous
`stability of thalidomide may impose limits on the dose that
`can be tolerated. Thalidomide contains one chiral centre but
`has always been used clinically as a racemic mixture. Previous
`reports in the literature have suggested that the teratogenic
`effects may only be associated with the S-isomer. Therefore, to
`get around this problem it has been suggested that the admin-
`istration of a single thalidomide enantiomer rather than the
`racemic mixture present in normal preparations would
`improve the side effect profile. However, it has recently been
`reported that thalidomide rapidly undergoes racemisation
`under both in vitro and in vivo conditions making administra-
`
`676
`
`Expert Opin. Biol. Ther. (2001) 1(4)
`
`
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`

`Marriott, Muller, Stirling & Dalgleish
`
`mide is outlined in Table 1. Compounds in this series have
`been reported with sub-µM TNF-α IC50 values in LPS stim-
`ulated human PBMC [44]. These analogues have also been
`shown to modestly stimulate the anti-inflammatory cytokine
`IL-10 in this assay [43]. All of these compounds are potent
`PDE4 inhibitors and this activity appears to correlate well
`with TNF-α inhibition (unpublished observations). Several
`of these analogues have been reported to show good activity in
`the inhibition of serum TNF-α levels in LPS treated mice.
`One of these compounds demonstrated good activity in the
`rat model of adjuvant arthritis [47].
`
`4.2 IMiD analogues
`There are several published papers on the activities of the
`IMiD class of thalidomide analogues. However, only three
`IMiD structures have been published to date and these are
`shown in Table 2. The least active IMiD reported is approxi-
`mately 2000-fold more potent than thalidomide in terms of
`inhibiting TNF-α in LPS stimulated human PBMC. In fact,
`the S-enantiomer of one IMiD was reported to be 50,000-
`fold more potent against TNF-α production than thalido-
`mide [48]. Thalidomide was originally reported to be a selective
`TNF-α inhibitor, although more recently inhibition of IL-12
`has also been reported [38]. Interestingly, this class of thalido-
`mide analogue with only minimal structural differences from
`the parent compound are also potent inhibitors of IL-1β in
`LPS stimulated hPBMC [46,49].
`
`5. Differential effects of thalidomide ana-
`logues on cytokine production
`
`The SelCID and IMiD analogues differ with respect to their
`effects on cytokine production after activation of either
`monocytes or T-cells. During LPS stimulation of PBMC it
`was shown that in addition to inhibiting TNF-α production
`IMiDs potently inhibit IL-1β, IL-12 and to a lesser extent
`IL-6 production and upregulate IL-10 production [46]. In
`contrast, SelCIDs weakly inhibit IL-1β and IL-12, have a
`more modest effect on IL-10 stimulation and have no effect
`on IL-6. During T-cell co-stimulation of αCD3 activated
`PBMC by IMiDs there is strong induction of IL-2 and IFN-
`γ associated with increased T-cell proliferation. Further-
`more, during T-cell co-stimulation by IMiDs production of
`TNF-α and soluble IL-2 receptor by PBMC is increased in
`an IL-2 dependent manner. This is strongly associated with
`decreased T-cell surface expression of TNF-R2 (unpublished
`observations). These effects are not seen during LPS stimu-
`lation of PBMC cultures. The importance of co-stimulus is
`similarly highlighted by the bidirectional effect of IMiDs on
`IL-12 production; decreased production during LPS stimu-
`lation while increased production during α-CD3 mediated
`T-cell activation.
`
`O
`
`NH
`
`O
`
`O
`
`N
`
`O
`
`Figure 1. Structure of thalidomide.
`
`tion of a single isomer non-viable [40,41].
`
`3. Development of thalidomide analogues
`
`Thalidomide is a clinically effective compound that has
`shown activity in a wide variety of inflammatory and autoim-
`mune diseases and in cancer. However, thalidomide was ini-
`tially developed as a sedative and its anti-inflammatory and
`anticancer activities were discovered later. Thus, it would
`seem likely that novel compounds designed using thalido-
`mides structure as a lead would allow optimisation of its
`immunological and anticancer properties while decreasing its
`side effects (Figure 1).
`Celgene Corporation initiated a medicinal chemistry pro-
`gram to design and prepare thalidomide analogues. Initial
`focus of this program was on improving thalidomide’s anti-
`TNF-α properties [42,43]. Primary screening is based on the
`ability of these compounds to inhibit the TNF-α production
`by activated human PBMC. Subsequent in vitro assays
`include testing for TNF-α inhibition in activated human and
`rat whole blood. A primary in vivo assay for potent TNF-α
`inhibitors is to test the analogues for their ability to decrease
`TNF-α levels in LPS treated mice. More recently the empha-
`sis has changed to focus not only on anti-inflammatory prop-
`erties but also anticancer properties.
`
`4. Characterisation of thalidomide analogues
`
`Thalidomide analogues are presently being assessed in labora-
`tory studies and several reports into their activity have been
`published. During the characterisation of these compounds it
`has become apparent that there are at least two distinct classes
`of thalidomide analogues. These have been termed SelCIDs
`consisting of PDE4 inhibitors and IMiDs which do not
`inhibit PDE4 and act via an unknown mechanism(s) [42-46].
`Both groups of compounds are potent TNF-α inhibitors,
`although T-cell co-stimulatory activity is limited to the latter
`group [39,46].
`
`4.1 SelCID analogues
`Information on the characterisation of SelCID analogues, a
`number of which contain the phthalimide moiety of thalido-
`
`Expert Opin. Biol. Ther. (2001) 1(4)
`
`677
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`

`Immunotherapeutic and antitumour potential of thalidomide analogues
`
`Table 1. Structures of SelCID analogues consisting of PDE4 inhibitors.
`Compound
`
`TNF IC50 (µµµµM)
`13.0
`
`PDE4 IC50 (µµµµM)
`9.4
`
`1.1
`
`3.0
`
`0.70
`
`0.23
`
`0.12
`
`0.13
`
`0.115
`
`0.051
`
`4.3
`
`3.8
`
`O
`
`O
`
`O
`
`NH2
`
`O
`
`O
`
`OO
`
`O
`
`O
`
`OO
`
`O
`
`O
`
`N
`
`O
`
`OH
`
`O
`
`O
`
`O
`
`NH
`
`O
`
`O
`
`NH2
`
`NO
`
`NO
`
`O
`
`NO
`
`O
`
`NO
`
`O
`
`NO
`
`O
`
`NO
`
`678
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`Expert Opin. Biol. Ther. (2001) 1(4)
`
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`

`Marriott, Muller, Stirling & Dalgleish
`
`7. Clinical development of SelCID analogues
`
`The development of these compounds is being expanded
`quickly and should soon lead to full-scale clinical trials. For
`example, the National Cancer Institute is supporting both the
`research & clinical development of SelCID and IMiD ana-
`logues.
`Clinical development of the SelCID compounds have been
`underway for the past five years although no clinical data has
`yet been published. The first SelCID to enter into clinical
`development was CDC-801. This compound is approxi-
`mately 10-fold more potent a TNF-α inhibitor than thalido-
`mide and was found to be non-teratogenic in a New Zealand
`rabbit developing embryo study. This is an animal model of
`choice for observing thalidomide’s teratogenicity as thalido-
`mide is not teratogenic in rodent models. CDC-801 has suc-
`cessfully completed two Phase I clinical trials in the UK. The
`first trial was an escalating single oral dose trial of 50 mg to 1
`g [53]. The second trial was a multiple dose trial to determine
`safety and pharmacokinetics [54]. No serious adverse advents
`were observed in this trial. CDC-801 is presently being evalu-
`ated in a Phase II double-blinded placebo-controlled clinical
`trial for the treatment of moderate-to-severe Crohn’s disease at
`a number of sites. A drop of 70 points in the Crohn’s disease
`activity index (CDAI) will be considered a response. This trial
`was expanded in late 2000 to include increased dosage groups
`and treatment period and should be completed in 2001.
`Celgene has also begun clinical development of a second
`SelCID, CDC-998. CDC-998 is approximately 1000-fold
`more potent than thalidomide in inhibiting TNF-α in LPS
`stimulated human PBMC. CDC-998 is a selective PDE4
`inhibitor with a PDE4 IC50 of approximately 80 nM. It
`shows minimal inhibition of PDE1, 2, 3, 5, or 6 at 10 µM.
`One of the major side effects observed for PDE4 inhibitors
`evaluated in the clinic has been emesis. This effect can be eval-
`uated in dogs and studies to assess CDC-998 in this model
`have shown no emetic effects (unpublished observations).
`CDC-998 has completed initial preclinical safety studies and
`has now moved forward into a Phase I trial programme that
`was initiated in the UK at the end of 2000.
`
`8. Clinical development of IMiD analogues
`
`The clinical development of the IMiD class of compounds was
`initiated in 2000. The IMiDs are a class of thalidomide analogues
`that potently inhibit TNF-α and IL-1β and stimulate IL-10 for-
`mation in LPS stimulated human PBMC [46,50]. The IMiDs also
`stimulate T-cell proliferation in anti-CD3 mAb activated T-cells
`to a greater extent than thalidomide [50]. The lead IMiD (CDC-
`501) completed a Phase I clinical trials programme in the UK in
`2000. It was found to be safe and well-tolerated at the dosages
`tested and CDC-501 was therefore advanced into a two-centre
`Phase I/II clinical trial in relapsed and refractory multiple mye-
`loma at the Dana-Farber Cancer Institute and the University of
`Arkansas Medical Centre. These studies are ongoing.
`
`Table 2. Structures of IMiD analogues.
`TNF-αααα IC50 (µµµµM)
`Compound
`0.10
`
`NH
`
`O
`
`NO
`
`O
`
`O
`
`O
`
`0.013
`
`0.044
`
`NH2
`
`NH
`
`O
`
`NO
`
`NH2
`
`O
`
`NH
`
`O
`
`NO
`
`NH2
`
`O
`
`6.Other in vitro characterisation
`
`A number of laboratories have recently published other in
`vitro data that highlights the potential of these compounds for
`future clinical use. For example, one group has shown that
`thalidomide analogues are more effective than thalidomide in
`the inhibition of HIV replication in human macrophages [50].
`Furthermore, this activity appears to be due to inhibition of
`transcription factor NF-κB-binding activity. Another group
`has shown that the previously characterised [51] SelCID ana-
`logue, CC-3052, was able to inhibit HIV replication in
`chronically and acutely infected monocytes and T-cells [52].
`This activity was attributed to its inhibitory effect on TNF-α
`production by both cell types since NF-κB is unaffected by
`this analogue [51].
`Thalidomide analogues also clearly possess enhanced activ-
`ity over the parent compound in their relative effects on the
`growth inhibition of chemoresistant human myeloma cells
`[25]. IMiD analogues were far more effective than both thalid-
`omide and SelCID analogues with IC50 values of 0.1 - 1.0
`µM. Furthermore, their effect appeared to be IL-6 dependent.
`Subsequently at least one subgroup of SelCID analogues pos-
`sess potent antimyeloma activity and this appears to be IL-6
`independent (unpublished results). This activity is also
`observed in a range of solid tumour types and is currently
`under investigation. Furthermore, unpublished preliminary
`studies suggest that both SelCID and IMiD analogues dem-
`onstrate improved anti-angiogenic activity in both rat and
`human in vitro systems and this is clearly an area of considera-
`ble interest.
`
`Expert Opin. Biol. Ther. (2001) 1(4)
`
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`
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`

`Immunotherapeutic and antitumour potential of thalidomide analogues
`
`9. Expert opinion
`
`This review has outlined the history of probably the most
`infamous drug in recent pharmaceutical history. However,
`thalidomide is making a surprising comeback as an anticancer
`and anti-inflammatory drug after receiving its first United
`States FDA approval in 1998. Some of the results of Celgene’s
`drug discovery program using thalidomide as a lead structure
`have also been reviewed here. To date these efforts have led to
`three compounds in clinical development, two of which are
`now being tested in the treatment of cancer or inflammatory
`disease. Several other research groups also have published
`drug discovery efforts using thalidomide as a lead structure.
`None of these groups have yet reported on advancement into
`clinical studies.
`In the next few years the success or failure of these com-
`pounds as pharmaceuticals will become apparent. Certainly,
`
`laboratory studies and initial clinical studies are encouraging.
`In particular, the potential of these compounds span such
`diverse activities as anti-TNF-α action, T-cell costimulation
`(suggesting possible use in the augmentation of vaccination
`regimens), anti-angiogenesis and direct antitumour effects.
`However, it must be noted that no data concerning clinical
`efficacy has yet been published. Furthermore, far more data
`are required concerning the mechanisms of action of these
`compounds and the cellular targets that characterise their
`activities. Similarly, safety concerns associated with thalido-
`mide will have to be closely monitored during use of the ana-
`logues. Bearing in mind the potential clinical efficacy of
`thalidomide in a range of conditions with very little therapeu-
`tic option it is an exciting prospect that these novel com-
`pounds may provide us with a new generation of clinically
`effective drugs. If so this may provide at least partial atone-
`ment for one of the worst episodes in medical history.
`
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