scholarly journals A Small Molecule–Drug Conjugate (SMDC) Consisting of a Modified Camptothecin Payload Linked to an αVß3 Binder for the Treatment of Multiple Cancer Types

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 391
Author(s):  
Hans-Georg Lerchen ◽  
Beatrix Stelte-Ludwig ◽  
Charlotte Kopitz ◽  
Melanie Heroult ◽  
Dmitry Zubov ◽  
...  
Keyword(s):  
Small Molecule ◽  
Tumor Targeting ◽  
Near Infrared ◽  
Cytotoxic Agents ◽  
Αvβ3 Integrin ◽  
Good Tolerability ◽  
In Vivo Models ◽  
Drug Conjugate ◽  
Small Molecule Drug

To improve tumor selectivity of cytotoxic agents, we designed VIP236, a small molecule–drug conjugate consisting of an αVβ3 integrin binder linked to a modified camptothecin payload (VIP126), which is released by the enzyme neutrophil elastase (NE) in the tumor microenvironment (TME). The tumor targeting and pharmacokinetics of VIP236 were studied in tumor-bearing mice by in vivo near-infrared imaging and by analyzing tumor and plasma samples. The efficacy of VIP236 was investigated in a panel of cancer cell lines in vitro, and in MX-1, NCI-H69, and SW480 murine xenograft models. Imaging studies with the αVβ3 binder demonstrated efficient tumor targeting. Administration of VIP126 via VIP236 resulted in a 10-fold improvement in the tumor/plasma ratio of VIP126 compared with VIP126 administered alone. Unlike SN38, VIP126 is not a substrate of P-gp and BCRP drug transporters. VIP236 presented strong cytotoxic activity in the presence of NE. VIP236 treatment resulted in tumor regressions and very good tolerability in all in vivo models tested. VIP236 represents a novel approach for delivering a potent cytotoxic agent by utilizing αVβ3 as a targeting moiety and NE in the TME to release the VIP126 payload—designed for high permeability and low efflux—directly into the tumor stroma.

STEM-12. THE SMALL MOLECULE DRUG CBL0137 INCREASES THE LEVEL OF DNA DAMAGE AND THE EFFICACY OF RADIOTHERAPY FOR GLIOBLASTOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi23-vi23
Author(s):  
Miranda Tallman ◽  
Abby Zalenski ◽  
Amanda Deighen ◽  
Treg Grubb ◽  
Morgan Schrock ◽  
...  
Keyword(s):  
Dna Damage ◽  
Small Molecule ◽  
Small Population ◽  
Orthotopic Model ◽  
Average Life Expectancy ◽  
Small Molecule Drug ◽  
Specific Cytotoxicity ◽  
Treatment Paradigm ◽  
New Treatment

Abstract Glioblastoma (GBM) is a fatal and incurable brain tumor, with an average life expectancy after diagnosis of only 12-15 months. A main reason for the lethality of GBM is inevitable recurrence, caused by a small population of the tumor cells, called cancer stem cells (CSCs). These cells are aggressive, infiltrative, and resistant to current GBM treatments of chemotherapy and radiotherapy. We use a small molecule drug, CBL0137, which inhibits the FACT (facilitates chromatin transcription) complex leading to cancer cell specific cytotoxicity. Here, we show that CBL0137 sensitized GBM CSCs to radiotherapy and hence lead to increased CSC death and prolonged survival in preclinical models. Clonogenic assays were used to show that CSCs were radiosensitized after CBL0137 treatment. We saw increased DNA damage when GBM CSCs were treated with CBL0137, as well as a decrease in foci resolution over time, when CBL0137 was combined with irradiation. In order to elucidate if the increase in DNA damage was directly due to the inhibition of the FACT complex, we depleted the level of FACT in our GBM CSCs. FACT depletion also led to increased DNA damage, and even more so when combined with irradiation. To validate whether combination therapy sensitized CSCs to radiotherapy in vivo, we used a subcutaneous mouse model and showed combination treatment decreased CSCs frequency in these tumors as well as decreased tumor volume. With an orthotopic model of GBM, we showed that CBL0137 treatment followed by radiotherapy significantly increased survival of mice bearing tumors over either treatment alone. Together, this work establishes a new treatment paradigm for GBM, which sensitizes radio-resistant GBM CSCs to irradiation, a critical component of patient care. Radio-sensitizing agents, including CBL0137, pose an exciting new therapeutic capable of increasing the efficacy of irradiation, by inclusively targeting CSCs.

Hybrid Antibodies in Cancer Diagnosis and Therapy

1989 ◽  
Vol 4 (3) ◽  
pp. 131-134 ◽  
Author(s):  
S. Ménard ◽  
S. Canevari ◽  
M.I. Colnaghi
Keyword(s):  
Tumor Cell ◽  
Cancer Diagnosis ◽  
Cytotoxic T Cells ◽  
Lymphocyte Activation ◽  
Cytotoxic Agents ◽  
Toxic Agent ◽  
In Vivo Models ◽  
Promising Tool

Monoclonal Antibodies (Mabs) represent a promising tool for cancer diagnosis and theraphy. Administration of MAbs alone or conjugated to cytotoxic agents has been attempted but has significant limitations. Another potentially effective approach is the use of bispecific or bifunctional antibodies where the capacity to recognize the tumor cell and the toxic agent or lymphocyte activation molecule are united in one MAb. The hybrid molecule can be produced by chemical linkage between the two parentalantibodies, or alternatively by a biological approach that consists in the fusion of the two selected hybridomas. In the resulting quadroma cell the hybridoma immunoglobulin chains recombine randomly to form the bifunctional MAb. In different in vitro and in vivo models, bifunctional MAbs against tumor and CDS at nanomolar concentration has been shown to promote tumor cell killing by cytotoxic T cells. Specific localization of chemotherapeutic drugs in xenografted tumors has been demonstrated in mice pretreated with hybrid MAbs. The advantages of the hybrid MAb approach are that it should reduce the MAb biodistribution problem and that it involves no chemical manipulation between the functional agent and the MAb molecules.

Subtle changes in network composition impact the biodistribution and tumor accumulation of nanogels

2018 ◽  
Vol 54 (83) ◽  
pp. 11777-11780 ◽  
Author(s):  
Ilona Zilkowski ◽  
Ioanna Theodorou ◽  
Krystyna Albrecht ◽  
Frederic Ducongé ◽  
Jürgen Groll
Keyword(s):  
Breast Tumor ◽  
Tumor Targeting ◽  
Near Infrared ◽  
Side Chain ◽  
Human Breast ◽  
Human Breast Tumor ◽  
Tumor Xenografts ◽  
Network Composition ◽  
Tumor Accumulation

We studied the effect of subtle changes in side-chain chemistry and labelling with near infrared fluorophores of nanogels (NGs) prepared from thiolated poly(glycidol) on in vivo biodistribution in mice bearing human breast tumor xenografts. Side chain chemistry as well as labelling clearly influenced tumor targeting and overall biodistribution.

In vivo tumor targeting imaging of cyclic RGD-modified heparin derivative to αvβ3-integrin expressing tumor

2012 ◽  
Vol 42 (1) ◽  
pp. 9-14 ◽  
Author(s):  
Sung Eun Kim ◽  
Jungwook Chin ◽  
Hanna Lee ◽  
Youngro Byun ◽  
Kyeongsoon Park
Keyword(s):  
Tumor Targeting ◽  
Αvβ3 Integrin ◽  
Heparin Derivative

scholarly journals Targeting CD205 with the antibody drug conjugate MEN1309/OBT076 is an active new therapeutic strategy in lymphoma models

Haematologica ◽  
2020 ◽  
Vol 105 (11) ◽  
pp. 2584-2591 ◽  
Author(s):  
Eugenio Gaudio ◽  
Chiara Tarantelli ◽  
Filippo Spriano ◽  
Francesca Guidetti ◽  
Giulio Sartori ◽  
...  
Keyword(s):  
Cell Lines ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Antibody Drug Conjugate ◽  
In Vivo Models ◽  
Drug Conjugate ◽  
Anti Tumor Activity ◽  
Class Antibody ◽  
Antibody Drug

Antibody drug conjugates represent an important class of anti-cancer drugs in both solid tumors and hematological cancers. Here, we report preclinical data on the anti-tumor activity of the first-in-class antibody drug conjugate MEN1309/OBT076 targeting CD205. The study included preclinical in vitro activity screening on a large panel of cell lines, both as single agent and in combination and validation experiments on in vivo models. CD205 was first shown frequently expressed in lymphomas, leukemias and multiple myeloma by immunohistochemistry on tissue microarrays. Anti-tumor activity of MEN1309/OBT076 as single agent was then shown across 42 B-cell lymphoma cell lines with a median IC50 of 200 pM and induction of apoptosis in 25/42 (59.5%) of the cases. The activity appeared highly correlated with its target expression. After in vivo validation as the single agent, the antibody drug conjugate synergized with the BCL2 inhibitor venetoclax, and the anti-CD20 monoclonal antibody rituximab. The first-in-class antibody drug targeting CD205, MEN1309/OBT076, demonstrated strong pre-clinical anti-tumor activity in lymphoma, warranting further investigations as a single agent and in combination.

scholarly journals Targeted pancreatic cancer therapy with the small molecule drug conjugate SW IV-134

2014 ◽  
Vol 8 (5) ◽  
pp. 956-967 ◽  
Author(s):  
Yassar M. Hashim ◽  
Dirk Spitzer ◽  
Suwanna Vangveravong ◽  
Mary C. Hornick ◽  
Gunjal Garg ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Therapy ◽  
Small Molecule ◽  
Drug Conjugate ◽  
Small Molecule Drug ◽  
Pancreatic Cancer Therapy

Preclinical investigation of a small molecule inhibitor of p300/CBP reveals efficacy in patient-derived prostate tumor explants.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e16534-e16534 ◽  
Author(s):  
Lisa Butler ◽  
Swati Irani ◽  
Margaret Centenera ◽  
Natalie Ryan ◽  
Neil Pegg ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Small Molecule ◽  
Single Agent ◽  
Specific Antigen ◽  
Resistance Mechanisms ◽  
Prostate Cancer Cells ◽  
In Vivo Models

e16534 Background: Growth and survival of prostate cancer cells are initially dependent upon androgens, and androgen deprivation therapy (ADT) is used to control tumor growth. Unfortunately, resistance to ADT inevitably occurs, and patients relapse with lethal castrate-resistant prostate cancer (CRPC). Increased expression of the androgen receptor (AR) and constitutively active AR variants are hallmarks of CRPC, and treatments targeting aberrant AR signaling are urgently required. CCS1477 is an inhibitor of p300/CBP currently in a Phase I/IIa study for CRPC. CCS1477 enhances degradation of numerous cellular proteins including the AR and AR variants in prostate cancer cells. Our preclinical studies with this compound demonstrated potent single-agent efficacy of CCS1477 using in vitro and in vivo models of prostate cancer and, when used in combination, CCS1477 enhances the efficacy of enzalutamide, a clinical AR antagonist. Understanding the response of clinical tumors to CCS1477, and their potential adaptive evolution, is essential to personalize treatment and predict potential resistance mechanisms. Methods: To assess CCS1477 in human disease, we used a unique model in which clinical prostate tumors from radical prostatectomy are cultured as explants with maintenance of tissue integrity, cell proliferation and androgen signaling. Tumors from 13 patients were cultured in the absence or presence of CCS1477 (10µM) or enzalutamide (10µM) for 48 or 72 hours; micromolar doses were selected to account for altered small molecule uptake and penetration into tissues compared to cell lines, as previously reported. Proliferation, apoptosis and androgen signaling were all analyzed post-culture. Results: Whereas the tumor explants exhibited highly heterogenous proliferative responses to enzalutamide, tumors from all patients exhibited a marked antiproliferative response to CCS1477 (mean reduction in Ki67 immunoreactivity of > 90% compared to vehicle control; p < 0.0005). Culture with CCS1477 was associated with repression of androgen signaling in the prostate tissues, measured by expression and secretion of the clinical biomarker prostate specific antigen (PSA). Conclusions: The consistent and pronounced efficacy of CCS1477 in this patient-derived model would support further investigation of this class of epigenetic agents in the castrate-sensitive prostate cancer setting.

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