Cancer Immune Therapy Edited by G. Stuhler and P. Walden ...

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17.5 Preclinical Development of Recombinant Immunotoxins Tab. 17.2 Functional properties in vitro and in vivo of PE-based recombinant Fv±immunotoxins Immunotoxin Specificity Activity in vitro Binding Antitumor activity (IC 50, ng/ml) affinity in vivo (Kd, nM) (xenograft model) Anti-Tac(Fv)±PE38 (LMB-2) CD25 0.15 1.4 complete regressions/ cures (ATAC4) B3(Fv)±PE38 (LMB-7) LeY 1.5 1300 complete regressions/ cures (A431) B3(dsFv)±PE38 (LMB-9) LeY 1.5 24000 complete regressions/ cures (A431) e23(Fv)±PE38 (erb-38) erbB2/HER2 0.3 40 partial regressions (A431) RFB4(dsFv)±PE38 (BL22) CD22 10 10 partial and some complete regressions (CA46) SS1(Fv)±PE38 mesothelin 0.5 11 complete regressions/ cures (A431-K5) MR1(Fv)±PE38 mutant EGF 3.0 11 partial regressions receptor (glioblastoma) 55.1(Fv)±PE38 mucin 0.3 80 complete regressions carbohydrate (Colo205) sure either inhibition of protein synthesis, proliferation, colony counts or cell viability. Cytotoxicity assays on malignant, single-cell suspensions directly obtained from patients are a very useful test, if available, since such cells contain the physiological numbers of receptor or target density which in many cases is lower than established cell lines [94±96]. The stability of recombinant immunotoxins in vitro in various physiological buffers or human serum is also an important test to predict their stability in vivo [74]. In vivo efficacy of recombinant immunotoxins is usually demonstrated in immunodeficient mice bearing xenografts of human tumor cells. The tumor xenografts can be established as subcutaneous solid tumors, orthotopic implants or disseminated leukemia [97±99]. Initial toxicity and pharmacokinetics studies have also been performed in mice; however, many target antigens are present at some level on some normal tissues, and thus toxicology and pharmacokinetics studies should be tested in an animal that has normal cells capable of binding the target antigen. For most immunotoxins, this requires studies in monkeys to test for targeted damage to normal tissues to predict whether such damage will occur in humans [100, 101]. 359
360 17 Immunotoxins and Recombinant Immunotoxins in Cancer Therapy 17.6 Application of Recombinant Immunotoxins 17.6.1 Recombinant Immunotoxins against Solid Tumors The treatment of solid tumors with immunotoxins is challenging due to their physiological nature of tight junctions between tumor cells, high interstitial pressure within tumors and heterogeneous blood supply, and also antigen expression [102]. The greatest need for new therapies is in the treatment of metastatic epithelial cancers, and immunotoxins can be a useful addition to the standard procedures of surgery, radiation and chemotherapy. As already described, the use of recombinant fragments of antibodies for making recombinant immunotoxins is especially useful for the treatment of solid tumors because their small size improves tumor penetration. Over recent years, several recombinant immunotoxins that target solid tumors have been developed (Tab. 17.2); targets include breast, lung, gastric, bladder and central nervous system cancers. They are at different stages of clinical development and some are already employed in clinical trials [1±4]. mAb B3 is an antibody that reacts with the LeYantigen present on cancers of the colon, breast, stomach, lung and bladder [15]. Early trials with a first-generation immunotoxin (LMB-1) in which an antibody to LeY (mAb B3) was used to make a chemical conjugate with PE38 showed significant clinical activity, with responses in colon and breast cancer [103, 104]. The one complete response and one partial response observed in this trial were the first major responses to immunotoxins documented for metastatic breast and colon cancer, respectively. The B3 antibody was then used to make a single-chain immunotoxin termed B3(Fv)±PE38 or LMB-7 [81]. LMB-7 has shown good activity against human cancer xenografts growing in mice [105]and it is also able to cure carcinomatous meningitis in rats when given by the intrathecal route [106]. A phase I clinical trial with LMB-7 began in 1995 and is nearing completion. During the trial, it became evident that LMB-7 lost activity when incubated at 37 8C because of aggregation [86, 107], which greatly limited its ability to penetrate solid tumors. B3(dsFv)±PE38 (LMB-9) is the dsFv version of LMB-7 [107]with stability improved over that of LMB-7. This improved stability also allowed it to be used in a continuous-infusion mode in mice bearing human tumor xenografts; this route of administration showed an improved therapeutic window over a bolus injection [108]. Clinical trials with LMB-9 started in the middle of 1998. A different recombinant single-chain immunotoxin, BR96(scFv)±PE40 was derived from the anti-LeY mAb BR96 and is also currently undergoing clinical testing [109]. Monoclonal antibody e23 is directed at erbB2 (Her2/neu), which is highly expressed in many breast, lung, ovarian and stomach cancers. e23(dsFv)±PE38 is a dsFv±immunotoxin composed of the Fv portion of the e23 antibody and PE38 [68]. This dsFv±immunotoxin has a significantly improved binding affinity and stability compared with its scFv analogue, e23(Fv)±PE38 [75]. FRP5scFv±ETA is also a recombi-
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Cancer Immune Therapie: Current and
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Editors: Dr. Gernot Stuhler Univers
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VI Preface Recent years have seen a
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VIII Contents 2.5.3 Antigens Encode
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X Contents 6.4.2 Natural Killer (NK
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XII Contents 9.6 Loading DC with An
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XIV Contents 14.2.2.1 Cancer-specif
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List of Contributors Richard Bucala
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Color Plates Fig. 5.2 The MHC class
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Fig. 5.5 Different immune effector
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Fig. 5.17 Possible pathway for the
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Fig. 6.2 T lymphocytes in the tumor
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Index a acidic and basic fibroblast
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±, see also tumors cationic lipids
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e EBV see Epstein-Barr virus EDR se
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immature Mo-DCs 184 immune cells ±
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MHC class I antigen-processing mach
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±, onco- 209 ±, over-expressed ce
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TICD see tumor-induced cell death T
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Part 1 Tumor Antigenicity Cancer Im
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4 1 Search for Universal Tumor-Asso
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10 1 Search for Universal Tumor-Ass
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18 2 Serological Determinants On Tu
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30 Cancer Immune Therapie: Current
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32 3 Processing and Presentation of
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42 4 T Cells In Tumor Immunity cult
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44 4 T Cells In Tumor Immunity cell
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46 4 T Cells In Tumor Immunity to T
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48 4 T Cells In Tumor Immunity Alth
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50 4 T Cells In Tumor Immunity Tab.
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52 4 T Cells In Tumor Immunity rest
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54 4 T Cells In Tumor Immunity 53 T
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Part 2 Immune Evasion and Suppressi
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60 5 Major Histocompatibility Compl
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68 Tab. 5.1 HLA class I loss attrib
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96 6 Immune Cells in the Tumor Micr
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98 6 Immune Cells in the Tumor Micr
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100 6 Immune Cells in the Tumor Mic
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Tab. 7.1 Effects of tumor-derived m
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122 7 Immunosuppresive Factors in C
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156 8 Interleukin-10 in Cancer Immu
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Part 3 Strategies for Cancer Immuno
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180 9 Dendritic Cells and Cancer: P
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206 10 The Immune System in Cancer:
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232 11 Hybrid Cell Vaccination for
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254 12 Principles and Strategies Em
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270 13 Applications of CpG Motifs f
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288 14 The T-Body Approach: Towards
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300 15 Bone Marrow Transplantation
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Page 345 and 346: 312 16 Immunocytokines: Versatile M
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Page 415 and 416: 382 Glossary tion to the variable d
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