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Enrique Álvarez

PharmaMar (Spain)

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Alberto Múñoz

Universidad Autónoma de Madrid

Anna Bunin

Biohaven Pharmaceuticals (United States)

Laura González-Santiago

Instituto de Investigaciones Biomédicas Sols-Morreale

Luca Rastelli

Hexcel (United States)

Matthew Welsch

Columbia University

Ann Marie Rossi

Biohaven Pharmaceuticals (United States)

Krishna Menon

King's College Hospital

Katy McGrath

Lawrence G. Iben

Bristol-Myers Squibb (United States)

David Trinh

Mirati Therapeutics (United States)

Cooperative Institutions

PharmaMar (Spain)

Instituto de Investigaciones Biomédicas Sols-Morreale

Amsterdam UMC Location VUmc

Universidad Autónoma de Madrid

Harvard University

Vrije Universiteit Amsterdam

Brigham and Women's Hospital

Dana-Farber Cancer Institute

University of Amsterdam

Vrije Universiteit Brussel

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The Role of Deoxycytidine Kinase in Gemcitabine Cytotoxicity

Advances in experimental medicine and biology (2002)

C.L. van der Wilt Judith R. Kroep Andries M. Bergman Willem J.P Loves Enrique Álvarez

Deoxycytidine kinase

10.1007/0-306-46843-3_56

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Citations (27)

Abstract A28: A murine model for cancer treatment-related fatigue

Molecular Cancer Therapeutics (2009)

Kimberly Pouliot Enrique Álvarez Brynmor A. Watkins Edward G. Fey Stephen T. Sonis

Abstract Objectives: Among patients being treated for cancer, cancer treatment-related fatigue (CTRF) remains a poorly understood condition with a profound effect on quality of life. Our objective was to develop a murine model of CTRF, independent of anemia, in order to further understand its pathogenesis and provide a conduit for the development of mechanistically-based therapeutic approaches. Methods: To determine the optimal dose of ionizing radiation to produce fatigue, female BALB/c mice were irradiated with 10 doses of fractionated total body irradiation (fTBI, 8, 9, and 10 Gy, cumulative dose) or 15 doses (fTBI, 10.5 and 13.5 Gy, cumulative dose). In a separate experiment, mice received 70, 60 or 50 mg/kg of etoposide sulfate to determine the optimal dose of chemotherapy to induce CTRF. Cage-top activity sensors (Phillips Respironics) were used to evaluate daily activity patterns in animals up to 4 weeks following the completion of radiation or 12 weeks following etoposide sulfate administration. CTRF was induced by 15 doses of fractionated total body irradiation (fTBI, 10.5 Gy, cumulative dose) in female BALB/c mice or 60mg/kg etoposide sulfate administered as a single dose. Total daily animal activity and changes in wake/sleep cycles were compared to baseline levels. Systemic levels of IL-6 and TNF-α were measured and anemia and leukopenia were assessed using specimens obtained in the weeks following the last dose of radiation or etoposide sulfate administration. Results: fTBI resulted in animals with a significantly lower cumulative daily activity, disrupted sleep/wake cycles that continued up to forty days following the last dose of radiation. Administration of etoposide sulfate resulted in a significantly lower cumulative daily activity three weeks following chemotherapy administration and continued for the duration of the study. Reduced activity levels were not associated with laboratory parameters suggestive of anemia. Changes in the measured hematological parameters demonstrated a temporal, dose-dependent and reversible pattern; consistent with those previously reported in human patients. Conclusions: Despite its frequency and impact, CTRF has been accepted as a cost of successful cancer treatment. This conclusion was largely based on the supposition that, aside for symptom control, there was no opportunity to develop an effective intervention. We report the development a novel mouse model of CTRF in which administration of fractionated TBI or etoposide sulfate was able to induce behaviors consistent with fatigue reported in humans. Our data supports the hypothesis that TBI and chemotherapy induce systemic effects that result in changes in daily activity patterns and sleep/wake cycles in the absence of anemia. Consistent with reports in humans with fatigue syndromes, radiation-induced CTRF correlated with increased levels of TNF and IL-6. Additional work is ongoing to further characterize the model. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A28.

Leukopenia

Cumulative dose

Total body irradiation

Acute Radiation Syndrome

10.1158/1535-7163.targ-09-a28

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Citations (1)

Enzymatic rationale and preclinical support for a potent protein kinase Cβ inhibitor in cancer therapy

Advances in Enzyme Regulation (1999)

Beverly A. Teicher Enrique Álvarez Laurane G. Mendelsohn Gulshan Ara Krishna Menon

Carmustine

Lewis lung carcinoma

Carboplatin

10.1016/s0065-2571(98)00026-0

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Citations (27)

Pretreatment deoxycytidine kinase levels predict in vivo gemcitabine sensitivity.

PubMed (2002)

Judith R. Kroep Willem J.P Loves C.L. van der Wilt Enrique Álvarez Iannis Talianidis

Deoxycytidine kinase (dCK) is essential for the phosphorylation of gemcitabine (2',2'-difluorodeoxycytidine), a deoxycytidine analogue active against various solid tumors. Cytidine deaminase (CDA) catalyzes the degradation of gemcitabine. We determined whether dCK and/or CDA levels would predict response to gemcitabine. Activities of dCK and CDA were measured in a panel of eight gemcitabine-sensitive and -resistant tumors of a different origin (pancreas, lung, colon, ovary, and head and neck) grown as s.c. tumors in mice. Sensitivity to gemcitabine was expressed as treated versus control (tumor volume treated mice/control mice). Gemcitabine was given on days 0, 3, 6, and 9 (q3dx4) at its maximum tolerated dose. In addition, we measured the mRNA expression and protein levels of dCK in seven human tumor xenografts. dCK activity (mean +/- SE) ranged from 3.3+/-0.3 to 18.4+/-1.2 nmol/h/mg protein. Sensitivity to gemcitabine, expressed as treated versus control, ranged from 0.98 to 0.02, and the activity of CDA varied from 2+/-2 to 411+/-4 nmol/h/mg protein. In contrast to CDA, dCK activity was clearly related to gemcitabine sensitivity (p = -0.93; P < 0.001). This indicates that dCK might be an important prognostic marker for gemcitabine sensitivity. Protein levels were significantly related to both dCK activity (r = 0.96; P < 0.001) and gemcitabine sensitivity (rho = -0.96; P < 0.001). dCK expression as determined by competitive template reverse transcriptase PCR was significantly related with the dCK activity (r = 0.88; P = 0.025) and protein levels (p = 0.80; P = 0.052) but not with gemcitabine sensitivity, suggesting a post-translational regulation of dCK. In conclusion, the clear correlation between dCK levels and gemcitabine sensitivity in various murine tumors and human tumor xenografts may be a prognostic parameter when considering gemcitabine therapy.

Deoxycytidine kinase

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635 A novel site-directed chemical conjugation technology confers antitumor activity via native Fc receptor to plasma immunoglobulin by attaching tumor binders

Regular and Young Investigator Award Abstracts (2020)

Christian M. Vidal Michael Cukan Rajat Varma Lawrence G. Iben Tanya Berbasova

Background

We describe KPMW101, which was created by chemical conjugation of a CD38-specific binder to clinical grade intravenous immunoglobulin (IvIg) pooled from healthy donors. Kleo's MATE^TM technology enables efficient site-directed chemical conjugation to 'off-the-shelf' IvIg and allows the development of antitumor agents with rapidly introduced target specificity. Our platform allows for chemical engineering of existing IvIg in a cost-efficient manner. This technology relies on synthetic compounds that consists of antibody binder with react-and-release mechanism.

Methods

Design of synthetic chemical reagents included antibody binding group capable of covalent bond formation with specific lysine, CD38 binding moiety proven to work in our clinical candidate KP1237, and tunable non-cleavable linker. Conjugation efficiency to polyclonal IvIg was evaluated using LC-MS analysis of IdeZ-digests. The binding of CD38, CD16a, and FcRn were determined by ELISA and BLI.For in vitro ADCC assays, PBMCs provided NK effector function. Daudi (CD38⁺) B lymphoblast cells were treated with KPMW101 or IvIg, PBMCs were introduced and incubated for 18h, and target cellular death was measured. For an in vivo IP macrophage lavage model of ADCP, SCID mice were implanted IP with CFSE-labeled Daudi cells. Mice were injected with IvIg or KPMW101 (0.21, 0.625, 1.875 mg/kg) SQ, and tumor cell counts were measured by flow cytometry. The pharmacokinetic profile of in vivo KPMW101 was determined from blood and analyzed utilizing a human Ig isotyping array.

Results

Synthetic chemical reagents with multiple linker types have been conjugated to IvIg and evaluated in biochemical assays. KPMW101 showed the highest conjugation efficiency. Binding affinity of KPMW101 to CD38 was 27nM. ELISA results show KPMW101 binds to CD16a and FcRn, indicating that conjugation does not interfere with FcR binding.In vitro ADCC results demonstrate that KPMW101 elicited CD38⁺ target cell killing with an EC₅₀ of 0.91–2.09nM.In vivo studies showed that KPMW101 resulted in a 49.9–63.5% reduction of tumor cells. Pharmacokinetic profile showed stability of KPMW101 throughout the 144-hour study, whereby IgG1, IgG2, IgG3, and IgG4 isotypes were detectable.

Conclusions

KPMW101 is created by chemical conjugation of CD38-specific binder to IvIg using our proprietary MATE^TM technology, maintaining native binding to FcRs via the Fc domain. This ensures the stability of the molecule and retains immune-mediated mechanisms of action. KPMW101 induces IvIg to adopt Fc effector mechanisms like ADCC and ADCP. Our in vitro data and in vivo studies confirm KPMW101 ability to kill tumor cells, making IvIg into an active antitumor therapeutic agent.

Polyclonal antibodies

Linker

Ex vivo

10.1136/jitc-2020-sitc2020.0635

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Citations (0)

Proteomic Analysis of the Resistance to Aplidin in Human Cancer Cells

Journal of Proteome Research (2007)

Laura González-Santiago Patricia Alfonso Yajaira Suárez Antonio Núñez Luis García‐Fernández

Aplidin (plitidepsin) is an antitumoral agent that induces apoptosis via Rac1-JNK activation. A proteomic approach using 2D-DIGE technology found 52 cytosolic and 39 membrane proteins differentially expressed in wild-type and Aplidin-resistant HeLa cells, of which 39 and 27 were identified by MALDI-TOF mass spectrometry and database interrogation. A number of proteins involved in apoptosis pathways were found to be deregulated. Alterations in Rab geranylgeranyltransferase, protein disulfide isomerase (PDI), cystathionine gamma-lyase, ezrin, and cyclophilin A (CypA) were confirmed by immunoblotting. Moreover, the role of PDI and CypA in Aplidin resistance was functionally confirmed by using the inhibitor bacitracin and overexpression, respectively. These deregulated proteins are candidates to mediate, at least partially, Aplidin action and might provide a route to the cells to escape the induction of apoptosis by this drug.

Cypa

HeLa

10.1021/pr060430+

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Citations (36)

KPMW135, a Biosuperior CD3 Bispecific Version of Rituximab Created By a Novel Chemical Conjugation Technology Demonstrates Increased Anti-Tumor Activity By Adding T Cell-Mediated Cytotoxicity Activity to the Existing Mechanisms of Rituximab

Blood (2020)

Christian M. Vidal Michael Cukan Ada Vaill Anna Bunin Ann Marie Rossi

Conjugate

10.1182/blood-2020-142113

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Citations (0)

Plitidepsin has a dual effect inhibiting cell cycle and inducing apoptosis via Rac1/JNK activation in human melanoma cells

María José Muñoz-Alonso Laura González-Santiago Natasha Zarich Enrique Álvarez José M. Rojas

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JNK activation as an in vivo marker of Aplidin® activity.

Cancer Research (2007)

María José Muñoz Enrique Álvarez Teresa Martı́nez Laura González-Santiago Halina Sasak

5580 Aplidin® (Plitidepsin) is an anti-tumoral agent from marine origin currently under Phase II clinical trials against multiple neoplasias. In cultured cells, Aplidin® has been reported to induce an acute apoptotic process in which the rapid activation of Rac1 GTPase linked to the strong and sustained activation of Jun N-terminal kinase (JNK) plays a crucial role. Other kinases such as epidermal growth factor receptor, Src, p38 mitogen-activated protein kinase (p38MAPK), ERK or protein kinase C-δ are also activated by Aplidin® in a cell-dependent context. The objective of this study was to evaluate the possibility of using JNK activation as an in vivo marker of Aplidin® activity. To this end, the level of JNK phosphorylation was examined by Western blotting in tumors grown in athymic mice that were xenografted with human leukemia K-562 cells at different times following Aplidin® treatment. The study showed a clear tendency for increased phospho-JNK levels in tumor samples obtained 4 to 12 h after treatment with Aplidin®. This effect was transient, as phospho-JNK levels were lower at later times (24-48 h). In contrast, no changes were found in the level of phospho-p38MAPK in tumors. Our results show for the first time that JNK activation in tumors is associated with Aplidin® treatment in vivo, suggesting that JNK phosphorylation it is a potential biomarker of Aplidin® activity.

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Citations (3)

Antitumor activity of cryptophycins: effect of infusion time and combination studies

Cancer Chemotherapy and Pharmacology (2000)

Krishna Menon Enrique Álvarez P Forler Val G. Phares T Amsrud

Lewis lung carcinoma

10.1007/s002800000135

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Citations (30)