A phase II study of G17DT in gastric carcinoma

Gilliam, A. D.; Watson, Susan A.; Henwood, Mark; McKenzie, Andrew J.; Humphreys, Jane; Elder, J. B.; Iftikhar, S. Y.; Welch, Neil T.; Fielding, J. W. L.; Broome, P.; Michaeli, D

doi:10.1016/j.ejso.2004.03.009

Cited by 46 publications

(25 citation statements)

References 23 publications

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“…Gastrin is expressed early in the development of gastrointestinal carcinomas (6,7), and it is being tested as a therapeutic target in pancreatic, gastric, and colorectal cancer (6,8,9). An anti-gastrin vaccine is currently in phase III clinical trials (9) for pancreatic cancer. The use of this vaccine has resulted in a significant increase in the survival time of patients.…”

mentioning

confidence: 99%

Affinity maturation of antibodies assisted by in silico modeling

Barderas

Desmet²,

Timmerman³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

124

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Rational engineering methods can be applied with reasonable success to optimize physicochemical characteristics of proteins, in particular, antibodies. Here, we describe a combined CDR3 walking randomization and rational design-based approach to enhance the affinity of the human anti-gastrin TA4 scFv. The application of this methodology to TA4 scFv, displaying only a weak overall affinity for gastrin17 (K D ‫؍‬ 6 M), resulted in a set of nine affinity-matured scFv variants with near-nanomolar affinity (KD ‫؍‬ 13.2 nM for scFv TA4.112). First, CDR-H3 and CDR-L3 randomization resulted in three scFvs with an overall affinity improvement of 15-to 35-fold over the parental. Then, the modeling of two scFv constructs selected from the previous step (TA4.11 and TA4.13) was followed by a combination of manual and molecular dynamics-based docking of gastrin17 into the respective binding sites, analysis of apparent packing defects, and selection of residues for mutagenesis through phage display. Nine scFv mutants were obtained from the second maturation step. A final 454-fold improvement in affinity compared with TA4 was obtained. These scFvs showed an enhanced potency to inhibit gastrin-induced proliferation in Colo 320 WT and BxPc3 tumoral cells. In conclusion, we propose a structure-based rational method to accelerate the development of affinity-matured antibody constructs with enhanced potential for therapeutic use.antibody engineering ͉ gastrin ͉ in vitro affinity maturation ͉ pancreatic cancer

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mentioning

confidence: 99%

Affinity maturation of antibodies assisted by in silico modeling

Barderas

Desmet²,

Timmerman³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

124

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“…In 2004, results from a Phase II trial in patients with gastric carcinoma were reported [69]. Three dose cohorts were studied and antibody response rates correlated with increased doses in stages I-III patients, but not in stage IV patients.…”

Section: Cancer Vaccine Targeting the Hormone Gastrinmentioning

confidence: 99%

Cancer Vaccines for Hormone/Growth Factor Immune Deprivation:A Feasible Approach for Cancer Treatment

Gonzalez

Lage

2007

CCDT

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One of the older and most validated cancer treatments is endocrine therapy. Some tumors are dependent on hormone stimulation for growth, and therefore therapeutic interventions aiming to deprive the cells of the hormone are feasible and have been successful. Tumor growth also depends in some cases on growth factors, so that the concept of hormone-dependence can be extended to growth factors deprivation. Hormone deprivation has been therapeutically achieved up to now by surgical, radiation and chemical means. However, the immune system usually can be manipulated to recognize hormones and growth factors, and in fact some autoimmune diseases exists involving autoantibodies against hormones. The idea of inducing a deprivation of hormones and growth factors by active immunizations is appealing, and initial evidence about the feasibility of this approach is starting to appear in the literature. Clinical trials have been initiated using immunization with human chorionic gonadotrophin (hCG), gastrin, luteinizing hormone releasing hormone (LHRH) / gonadotropin releasing hormone (GnRH) and epidermal growth factor (EGF). Preliminary data already show that antibody titers can be elicited, which results in a decrease in the concentration of a given hormone or growth factor. Both the antibody titers and the decrease in the hormone level are related to survival. This immunological approach for hormone and growth factor deprivation creates the possibility of chronic management of advanced cancer patients.

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“…The fi rst is a phase II clinical trial testing a gastrin-17-diphtheria toxoid (G17DT), which was shown to induce antibodies that block gastrin-stimulated tumor growth [ 93 ]. This study included 52 gastric cancer patients (stage I-III, n = 36; stage IV, n = 16).…”

Section: Protein or Peptide Vaccination For Esophageal And Gastric Camentioning

confidence: 99%