Jean-francois Prost - Academia.edu (original) (raw)
Papers by Jean-francois Prost
Biology, 2021
The anti-Müllerian hormone (AMH) belongs to the TGF-β family and plays a key role during fetal se... more The anti-Müllerian hormone (AMH) belongs to the TGF-β family and plays a key role during fetal sexual development. Various reports have described the expression of AMH type II receptor (AMHRII) in human gynecological cancers including ovarian tumors. According to qRT-PCR results confirmed by specific In-Situ Hybridization (ISH) experiments, AMHRII mRNA is expressed in an extremely restricted number of normal tissues. By performing ISH on tissue microarray of solid tumor samples AMHRII mRNA was unexpectedly detected in several non-gynecological primary cancers including lung, breast, head and neck, and colorectal cancers. AMHRII protein expression, evaluated by immunohistochemistry (IHC) was detected in approximately 70% of epithelial ovarian cancers. Using the same IHC protocol on more than 900 frozen samples covering 18 different cancer types we detected AMHRII expression in more than 50% of hepato-carcinomas, colorectal, lung, and renal cancer samples. AMHRII expression was not ob...
Cell Communication and Signaling, 2019
Background: HER3/ErbB3 receptor deletion or blockade leads to tumor cell apoptosis, whereas its o... more Background: HER3/ErbB3 receptor deletion or blockade leads to tumor cell apoptosis, whereas its overexpression confers anti-cancer drug resistance through upregulation of protective mechanisms against apoptosis. We produced the anti-HER3 antibody 9F7-F11 that promotes HER3 ubiquitination and degradation via JNK1/2-dependent activation of the E3 ubiquitin ligase ITCH, and that induces apoptosis of cancer cells. Cellular FLICE-like inhibitory protein (c-FLIP) is a key regulator of apoptotic pathways. Here, we wanted to determine the mechanisms underlying the pro-apoptotic effect of 9F7-F11. Methods: Anti-HER3 antibody-induced apoptosis was assessed by western blot, and by flow cytometry measurement of Annexin V/7-AAD-labelled tumor cells (BxPC3, MDA-MB-468 and DU145 cell lines). c-FLIP/ITCH interaction and subsequent degradation/ubiquitination were investigated by co-immunoprecipitation of ITCH-silenced vs scramble control cells. The relationship between ITCH-mediated c-FLIP degradation and antibody-induced apoptosis was examined by western blot and flow cytometry of tumor cells, after ITCH RNA interference or by pre-treatment with ITCH chemical inhibitor chlorimipramine (CI). Results: Following incubation with 9F7-F11, cancer cell apoptosis occurs through activation of caspase-8, − 9 and − 3 and the subsequent cleavage of poly (ADP-ribose) polymerase (PARP). Moreover we showed that ubiquitination and proteasomal degradation of the anti-apoptotic protein c-FLIP was mediated by USP8regulated ITCH recruitment. This effect was abrogated by ITCH-and USP8-specific RNA interference (siRNA), or by the ITCH chemical inhibitor CI. Specifically, ITCH silencing or CI blocked 9F7-F11-induced caspase-8mediated apoptosis of tumor cells, and restored c-FLIP expression. ITCH-silencing or CI concomitantly abrogated HER3-specific antibody-induced apoptosis of Annexin V/7-AAD-labelled BxPC3 cells. 9F7-F11 favored the extrinsic apoptosis pathway by inducing TRAIL-R2/DR5 upregulation and TRAIL expression that promoted the formation of death-inducing signaling complex (DISC), leading to caspase-8-mediated apoptosis. Incubation with 9F7-F11 also induced BID cleavage, BAX upregulation and BIM expression, which initiated the caspase-9/3-mediated mitochondrial death pathway. The anti-HER3 antibody pro-apoptotic effect occurred concomitantly with downregulation of the pro-survival proteins c-IAP2 and XIAP.
Cancers, 2021
AMHRII, the anti-Müllerian hormone receptor, is selectively expressed in normal sexual organs but... more AMHRII, the anti-Müllerian hormone receptor, is selectively expressed in normal sexual organs but is also re-expressed in gynecologic cancers. Hence, we developed murlentamab, a humanized glyco-engineered anti-AMHRII monoclonal antibody currently in clinical trial. Low-fucosylated antibodies are known to increase the antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) potency of effector cells, but some preliminary results suggest a more global murlentamab-dependent activation of the immune system. In this context, we demonstrate here that the murlentamab opsonization of AMHRII-expressing ovarian tumor cells, in the presence of unstimulated- or tumor-associated macrophage (TAM)-like macrophages, significantly promotes macrophage-mediated ADCC and shifts the whole microenvironment towards a pro-inflammatory and anti-tumoral status, thus triggering anti-tumor activity. We also report that murlentamab orients both unstimulated- and T...
The present invention relates to a monoclonal antibody directed against the CD20 antigen, includi... more The present invention relates to a monoclonal antibody directed against the CD20 antigen, including the variable domain of each light chain is encoded by the nucleic acid sequence murine SEQ ID NO: 5, the variable domain of each of the heavy chains is encoded by the nucleic acid sequence murine SEQ ID nO: 7, and the constant regions of the light chains and heavy chains are constant regions from a non-murine species, as well as the use of this antibody for activating FcgammaRIII receptors of immune effector cells, and for the manufacture of a medicament, particularly for the treatment of leukemia or lymphoma.
Journal of Clinical Oncology, 2012
5069 Background: Expressed on most OC subtypes while displaying a restricted expression profile i... more 5069 Background: Expressed on most OC subtypes while displaying a restricted expression profile in adult normal tissues, MISRII represents a potentialtarget for OC immunotherapy. We present here the preclinical assessment of a humanized anti-MISRII EMABling mAb, 3C23K. Methods: Either quantitative RT-PCR or immunohistochemistry (IHC) studies were performed to confirm MISRII expression profile in Granulosa Cell Tumor (GCT) or Epithelial OC (EOC) patient samples and to evaluate tissue cross-reactivity. For in vitro and in vivo experiments, we have generated 4 patient-derived MISRII expressing EOC cell lines. Xenograft studies were conducted in swiss nude mice on established tumors (100 mm3). Mice received 2 to 3 weekly i.p. injections (10 mg/kg/inj) for 4 to 6 wks and tumor volumes were compared with control groups. Comparison of i.p. vs i.v. injections were assessed as well as combination with carboplatin (once a week for 4 weeks, 60 mg/kg/inj). In addition, 3C23K plasma level was mo...
Blood, 2012
1654 Background: Anti-CD20 monoclonal antibody (mAb) therapy is an important therapeutic option i... more 1654 Background: Anti-CD20 monoclonal antibody (mAb) therapy is an important therapeutic option in the treatment of Waldenström's Macroglobulinemia (WM), exhibiting an ORR up to 55% when used as monotherapy. NK cells are involved in mAb therapy by an antibody-dependent cellular cytotoxicity (ADCC) mechanism through their FcγRIIIa (CD16) receptor. Ublituximab (TGTX-1101 or LFB-R603) is a novel, glycoengineered chimeric anti-CD20 mAb that has a high affinity for FcγRIIIa (CD16) receptors. In this study, we evaluate the ADCC functional capacities of NK cells in the presence of ublituximab compared to rituximab. Patients and Methods: Blood samples from 37 un-treated, or without ongoing treatment WM patients and from 30 age-matched healthy donors (Ctl) were collected to quantify CD16 expression (clone 3G8, Quantibrite) on NK cells and/or to measure their functional capacities. Patients were divided in two groups relative to the presence (WM clone+) or absence (WM clone-) of blood cl...
Journal of Hypertension, 1989
Molecular cancer therapeutics, Jan 15, 2017
Exploratory clinical trials using therapeutic anti-HER3 antibodies strongly suggest that neuregul... more Exploratory clinical trials using therapeutic anti-HER3 antibodies strongly suggest that neuregulin (NRG1; HER3 ligand) expression at tumor sites is a predictive biomarker of anti-HER3 antibody efficacy in cancer. We hypothesized that in NRG1-expressing tumors, where the ligand is present before antibody treatment, anti-HER3 antibodies that do not compete with NRG1 for receptor binding have a higher receptor-neutralizing action than antibodies competing with the ligand for binding to HER3. Using time resolved-fluorescence energy transfer (TR-FRET), we demonstrated that in the presence of recombinant NRG1, binding of 9F7-F11 (a non-ligand competing anti-HER3 antibody) to HER3 is increased, whereas that of ligand-competing anti-HER3 antibodies (H4B-121, U3-1287, Ab#6, Mab205.10.2 and MOR09825) is decreased. Moreover, 9F7-F11 showed higher efficacy than antibodies that compete with the ligand for binding to HER3. Specifically, 9F7-F11 inhibition of cell proliferation and of HER3/AKT/ER...
The invention concerns the use of minalcipran for preparing a medicine for treating certain psych... more The invention concerns the use of minalcipran for preparing a medicine for treating certain psychiatric diseases such as panic, post-traumatic, obsessional-compusive disorders, drug addiction disintoxication, sleeplessness, pre-menstrual dysphoria and eating disorders.
Ash Annual Meeting Abstracts, Nov 18, 2011
In the study reported here, we further investigated the B-cell lysis activity of LFB-R603 (ublitu... more In the study reported here, we further investigated the B-cell lysis activity of LFB-R603 (ublituximab), a novel anti-CD20 monoclonal antibody (mAb), as compared with ofatumumab and rituximab on various cell lines and on PBMCs from CLL patients. In terms of CDC-mediated lysis, we observed higher CDC activity of ofatumumab when compared with LFB-R603 on several cell lines expressing high CD20 levels (data not shown). Rituximab displayed CDC activity slightly superior to that of LFB-R603. In contrast, CDC activity against CD20-low expressing cells, the SUDHL-8 cell line, and CLL patient-derived PBMCs was very low with all three mAbs, rituximab, ofatumumab and LFB-R603. Consistent with previous results, LFB-R603 was shown to mediate high ADCC against all cell lines tested, including CD20-low expressing cells, whereas both ofatumumab and rituximab mediated ADCC at low levels. Altogether, these results support the fact that the therapeutic use of LFB-R603 may be advantageous over currently approved anti-CD20 mAbs in targeting malignant cells where surface CD20 molecules are known to be expressed at low levels such as in CLL and small lymphocytic lymphomas.
Cancer Research, 2011
Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Often diagnosed at an ad... more Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Often diagnosed at an advanced stage, ovarian cancer is responsible for the highest mortality rate among patients with gynecologic malignancies. Due to the limitations of the current therapeutic approaches, there is a strong need for novel, more efficient, therapies, among which targeted immunotherapy. The monoclonal antibody 12G4 specifically recognizes the human Mullerian Inhibiting Substance type II Receptor (MISRII). Expressed at high levels on most human Granulosa Cell Tumors (GCT) as well as on a majority of human epithelial ovarian cancer (EOC) cells, MISRII represents a good target for antibody-based tumor targeting. Characterization of murine antibody 12G4 has been previously reported, in particular epitope mapping and in vitro assays showing that 12G4 binding does not affect MIS interaction with MISRII. In the present study we further assess 12G4 activity in vitro and in vivo. 12G4 was shown to induce 37% and 30% apoptosis in vitro (FACS, DNA fragmentation) on the two MISRII expressing cell lines cov434-MISRII and OVCAR3, respectively. Internalization of the antibody-MISRII complex was also observed in vitro on cov434-MISRII. Using 12G4 antibody we confirmed by immunohistochemistry the expression of the MISRII target in all GTC samples and all but one EOC tissue sections (13/14). Furthermore, we have developed several immunodeficient Nude mouse models of ovarian tumor xenografts expressing human MISRII. In these models the efficacy of 12G4 could be clearly demonstrated with a significant effect on tumor growth. According to our data, MISRII, expressed on a majority of EOCs appears as a good target for ovarian cancer immunotherapy. Furthermore, based on the good efficacy observed in vivo for 12G4, the development of a humanized anti-MISRII antibody, derived from 12G4, has been initiated and represents a new promising targeted therapeutic approach. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4568. doi:10.1158/1538-7445.AM2011-4568
Oncotarget, Jan 21, 2017
Müllerian inhibiting substance, also called anti-Müllerian hormone (AMH), inhibits proliferation ... more Müllerian inhibiting substance, also called anti-Müllerian hormone (AMH), inhibits proliferation and induces apoptosis of AMH type II receptor-positive tumor cells, such as human ovarian cancers (OCs). On this basis, a humanized glyco-engineered monoclonal antibody (3C23K) has been developed. The aim of this study was therefore to experimentally confirm the therapeutic potential of 3C23K in human OCs. We first determined by immunofluorescence, immunohistochemistry and cytofluorometry analyses the expression of AMHRII in patient's tumors and found that a majority (60 to 80% depending on the detection technique) of OCs were positive for this marker. We then provided evidence that the tumor stroma of OC is enriched in tumor-associated macrophages and that these cells are responsible for 3C23K-induced killing of tumor cells through ADCP and ADCC mechanisms. In addition, we showed that 3C23K reduced macrophages induced-T cells immunosuppression. Finally, we evaluated the therapeutic ...
Oncotarget, 2017
Ovarian cancer is the leading cause of death in women with gynecological cancers and despite rece... more Ovarian cancer is the leading cause of death in women with gynecological cancers and despite recent advances, new and more efficient therapies are crucially needed. Müllerian Inhibiting Substance type II Receptor (MISRII, also named AMHRII) is expressed in most ovarian cancer subtypes and is a novel potential target for ovarian cancer immunotherapy. We previously developed and tested 12G4, the first murine monoclonal antibody (MAb) against human MISRII. Here, we report the humanization, affinity maturation and glyco-engineering steps of 12G4 to generate the Fc-optimized 3C23K MAb, and the evaluation of its in vivo anti-tumor activity. The epitopes of 3C23K and 12G4 were strictly identical and 3C23K affinity for MISRII was enhanced by a factor of about 14 (K D = 5.5 × 10 −11 M vs 7.9 x 10 −10 M), while the use of the EMABling ® platform allowed the production of a low-fucosylated 3C23K antibody with a 30-fold K D improvement of its affinity to FcγRIIIa. In COV434-MISRII tumor-bearing mice, 3C23K reduced tumor growth more efficiently than 12G4 and its combination with carboplatin was more efficient than each monotherapy with a mean tumor size of 500, 1100 and 100 mm 3 at the end of treatment with 3C23K (10 mg/kg, Q3-4D12), carboplatin (60 mg/kg, Q7D4) and 3C23K+carboplatin, respectively. Conversely, 3C23K-FcKO, a 3C23K form without affinity for the FcγRIIIa receptor, did not display any anti-tumor effect in vivo. These results strongly suggested that 3C23K mechanisms of action are mainly Fc-related. In vitro, antibody-dependent cytotoxicity (ADCC) and antibody-dependent cell phagocytosis (ADCP) were induced by 3C23K, as demonstrated with human effector cells. Using human NK cells, 50% of the maximal lysis was obtained with a 46-fold lower concentration of low-fucosylated 3C23K (2.9 ng/ml) than of 3C23K expressed in CHO cells (133.35 ng/ml). As 3C23K induced strong ADCC with human PBMC but almost none with murine PBMC, antibody-dependent cell
Journal of Medicinal Chemistry, 1994
Starting from 2-(2-aminoethyl)-6-methoxy-1-methylcarbazole, ethyl 9-methoxy-5-methyl-6H-pyrido[4,... more Starting from 2-(2-aminoethyl)-6-methoxy-1-methylcarbazole, ethyl 9-methoxy-5-methyl-6H-pyrido[4,3-b]carbazole-1-carboxylate was obtained through a three-step sequence. This compound and its 6-methyl derivative react with (dialkylamino)alkylamines to provide various 9-methoxy-5-methyl-6H-pyrido[4,3-b]carbazole-1-(N-substituted carboxamides) whose boron tribromide demethylation afforded corresponding 9-hydroxy-1-(N-substituted carbamoyl)-olivacines. The same pathway but starting from 2-(2-aminoethyl)-6-methoxy-1,4-dimethylcarbazole led to ethyl 9-methoxy-5,11-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxylate which did not normally react with amines. It provided either the recovered starting material at 120 degrees C or 9-methoxyellipticine resulting from an unexpected decarboethylation in a steel vessel at 180 degrees C. Biological testing of the newly obtained 1-carbamoylolivacine derivatives showed that 9-hydroxylated compounds displayed high cytotoxicity for cultured L1210 and colon 38 cells (IC50 range 5-10 nM) and good antitumor activity in vivo in the P388 leukemia and colon 38 models when administered by the iv route. The most active compound in these series is 9-hydroxy-5,6-dimethyl-1-[N-[2-(dimethylamino)ethyl]carbamoyl]-6H- pyrido[4,3-b]carbazole which was selected for further evaluation on murine solid tumors and for toxicological studies.
Journal of Medicinal Chemistry, 1992
A series of 70 triazine derivatives have been synthesized and tested for their capacity to modula... more A series of 70 triazine derivatives have been synthesized and tested for their capacity to modulate multidrug resistance (MDR) in DC-3F/AD and KB-A1 tumor cells in vitro, in comparison with verapamil (VRP), a calcium channel antagonist currently used in therapy as an antihypertensive drug, which also shows MDR modulating activity. Among the 12 selected compounds, 16 (S9788) showed high MDR reversing properties in vitro (300- and 6-fold VRP at 5 microM in DC-3F/AD and KB-A1 cells, respectively) and induced a strong accumulation of adriamycin. The relationship between the increase of ADR accumulation and the fold reversal induced by these compounds and their lack of effects on the sensitive DC-3F cells suggest that they act mainly by inhibiting the P-glycoprotein (Pgp) catalyzed efflux of cytotoxic agents, as already described for a majority of MDR modulators. In vivo, in association with the antitumor drug vincristine (0.25 mg/kg), 16 (100 mg/kg) increased the T/C by 39% in mice bearing the resistant tumor cell line P388/VCR. According to these interesting properties, 16 was selected for a clinical development because it was more bioavailable than 34, even though it was less active.
The Journal of Clinical Pharmacology, 1988
The systemic and renal hemodynamic effects of tertatolol, a new noncardioselective beta blocker w... more The systemic and renal hemodynamic effects of tertatolol, a new noncardioselective beta blocker without partial agonist activity, given alone or in combination with cyclooxygenase inhibition by acetylsalicylic acid (aspirin), were investigated in eight healthy volunteers. Tertatolol 5 mg, aspirin 1 g, tertatolol 5 mg together with aspirin 1 g and placebo were administered at 1-week intervals in a random order and in a double-blind fashion. Cardiac output was measured by Doppler echography and renal blood flow and glomerular filtration rate (GFR) by constant infusion techniques using (123I) iodohippurate and (51Cr) EDTA, respectively. Measurements were performed before and then successively 2 and 4 hours after oral intake of drugs or placebo. Tertatolol decreased cardiac output by 22% (P less than .05) and heart rate by 17% (P less than .05) without change in blood pressure, renal blood flow, and GFR. The same effects occurred when tertatolol was given together with aspirin. Either placebo or aspirin alone had no effect on systemic and renal hemodynamics. These results suggest that cardiac output is redistributed to the kidneys after tertatolol intake in normal humans. This favorable effect on renal hemodynamics is probably not mediated by a local release of vasodilating prostaglandins.
European Journal of Pharmacology, 1995
Since tachykinins released from lung sensory nerve endings are thought to play a role in inflamma... more Since tachykinins released from lung sensory nerve endings are thought to play a role in inflammatory diseases of airways via NK1 and NK2 receptors, dual tachykinin NK1 and NK2 receptor antagonists may have a great therapeutic potential. In vitro, the cyclopeptide S 16474 (cyclo-[Abo-Asp(D-Trp(Suc0Na)-Phe-N-(Me)Bzl)]) bound to both human tachykinin NK1 and NK2 receptors expressed in two lines of transfected Chinese hamster ovary cells (IC50 values 85 nM and 129 nM, respectively), while showing a poor affinity for the rat tachykinin NK1 receptor. S 16474 inhibited the contractions induced by substance P in isolated rabbit vena cava (pA2 7.0) and by neurokinin A in rabbit pulmonary artery (pA2 5.6). In vivo in anaesthetized guinea-pigs, S 16474 was found to dose dependently inhibit the bronchoconstrictions induced by intravenously administered substance P, neurokinin A and capsaicin. Plasma extravasation evoked in bronchi by endogenously released tachykinins under vagus nerve stimulation was abolished by S 16474 (10 mu mol/kg i.v.). These results demonstrate clearly that S 16474 is a tachykinin receptor antagonist exhibiting, in vitro and in vivo, a dual inhibitory effect on NK1 and NK2 receptors.
British Journal of Haematology, 2008
A human anti-RhD immunoglobulin G1 monoclonal antibody (mAb), R297, was tested in a phase I study... more A human anti-RhD immunoglobulin G1 monoclonal antibody (mAb), R297, was tested in a phase I study to assess its ability to induce the clearance of antibody-coated autologous RhD + red blood cells (RBCs) in healthy male volunteers. The clearance potency of R297 was compared with that of a marketed human polyclonal anti-D product (Rhophylac Ò ). This mAb has been selected for its ability to strongly engage Fc-gamma receptor IIIA and to mediate a potent antibody-dependent cell cytotoxicity (ADCC) against RhD + RBCs. Autologous RhD + RBCs were sensitized with either Rhophylac Ò or R297 at three different coating percentages (25, 12AE5 and 6AE25%), before re-infusion. This phase I study showed that the human R297 mAb promoted rapid and complete clearance of RBCs, and showed activity that was at least as potent as the human polyclonal anti-D antibody preparation. Clearance of RBCs could still be observed when the percentage of R297 used to coat the RBCs was reduced to 6AE25%. Finally, none of the adverse events was severe or considered to be related to R297. Thus, R297 is a promising candidate for the prevention of allo-immunization and represents a new generation of Fc-modified monoclonal antibodies with increased FccRIII binding and increased ADCC.
British Journal of Haematology, 2008
Biology, 2021
The anti-Müllerian hormone (AMH) belongs to the TGF-β family and plays a key role during fetal se... more The anti-Müllerian hormone (AMH) belongs to the TGF-β family and plays a key role during fetal sexual development. Various reports have described the expression of AMH type II receptor (AMHRII) in human gynecological cancers including ovarian tumors. According to qRT-PCR results confirmed by specific In-Situ Hybridization (ISH) experiments, AMHRII mRNA is expressed in an extremely restricted number of normal tissues. By performing ISH on tissue microarray of solid tumor samples AMHRII mRNA was unexpectedly detected in several non-gynecological primary cancers including lung, breast, head and neck, and colorectal cancers. AMHRII protein expression, evaluated by immunohistochemistry (IHC) was detected in approximately 70% of epithelial ovarian cancers. Using the same IHC protocol on more than 900 frozen samples covering 18 different cancer types we detected AMHRII expression in more than 50% of hepato-carcinomas, colorectal, lung, and renal cancer samples. AMHRII expression was not ob...
Cell Communication and Signaling, 2019
Background: HER3/ErbB3 receptor deletion or blockade leads to tumor cell apoptosis, whereas its o... more Background: HER3/ErbB3 receptor deletion or blockade leads to tumor cell apoptosis, whereas its overexpression confers anti-cancer drug resistance through upregulation of protective mechanisms against apoptosis. We produced the anti-HER3 antibody 9F7-F11 that promotes HER3 ubiquitination and degradation via JNK1/2-dependent activation of the E3 ubiquitin ligase ITCH, and that induces apoptosis of cancer cells. Cellular FLICE-like inhibitory protein (c-FLIP) is a key regulator of apoptotic pathways. Here, we wanted to determine the mechanisms underlying the pro-apoptotic effect of 9F7-F11. Methods: Anti-HER3 antibody-induced apoptosis was assessed by western blot, and by flow cytometry measurement of Annexin V/7-AAD-labelled tumor cells (BxPC3, MDA-MB-468 and DU145 cell lines). c-FLIP/ITCH interaction and subsequent degradation/ubiquitination were investigated by co-immunoprecipitation of ITCH-silenced vs scramble control cells. The relationship between ITCH-mediated c-FLIP degradation and antibody-induced apoptosis was examined by western blot and flow cytometry of tumor cells, after ITCH RNA interference or by pre-treatment with ITCH chemical inhibitor chlorimipramine (CI). Results: Following incubation with 9F7-F11, cancer cell apoptosis occurs through activation of caspase-8, − 9 and − 3 and the subsequent cleavage of poly (ADP-ribose) polymerase (PARP). Moreover we showed that ubiquitination and proteasomal degradation of the anti-apoptotic protein c-FLIP was mediated by USP8regulated ITCH recruitment. This effect was abrogated by ITCH-and USP8-specific RNA interference (siRNA), or by the ITCH chemical inhibitor CI. Specifically, ITCH silencing or CI blocked 9F7-F11-induced caspase-8mediated apoptosis of tumor cells, and restored c-FLIP expression. ITCH-silencing or CI concomitantly abrogated HER3-specific antibody-induced apoptosis of Annexin V/7-AAD-labelled BxPC3 cells. 9F7-F11 favored the extrinsic apoptosis pathway by inducing TRAIL-R2/DR5 upregulation and TRAIL expression that promoted the formation of death-inducing signaling complex (DISC), leading to caspase-8-mediated apoptosis. Incubation with 9F7-F11 also induced BID cleavage, BAX upregulation and BIM expression, which initiated the caspase-9/3-mediated mitochondrial death pathway. The anti-HER3 antibody pro-apoptotic effect occurred concomitantly with downregulation of the pro-survival proteins c-IAP2 and XIAP.
Cancers, 2021
AMHRII, the anti-Müllerian hormone receptor, is selectively expressed in normal sexual organs but... more AMHRII, the anti-Müllerian hormone receptor, is selectively expressed in normal sexual organs but is also re-expressed in gynecologic cancers. Hence, we developed murlentamab, a humanized glyco-engineered anti-AMHRII monoclonal antibody currently in clinical trial. Low-fucosylated antibodies are known to increase the antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) potency of effector cells, but some preliminary results suggest a more global murlentamab-dependent activation of the immune system. In this context, we demonstrate here that the murlentamab opsonization of AMHRII-expressing ovarian tumor cells, in the presence of unstimulated- or tumor-associated macrophage (TAM)-like macrophages, significantly promotes macrophage-mediated ADCC and shifts the whole microenvironment towards a pro-inflammatory and anti-tumoral status, thus triggering anti-tumor activity. We also report that murlentamab orients both unstimulated- and T...
The present invention relates to a monoclonal antibody directed against the CD20 antigen, includi... more The present invention relates to a monoclonal antibody directed against the CD20 antigen, including the variable domain of each light chain is encoded by the nucleic acid sequence murine SEQ ID NO: 5, the variable domain of each of the heavy chains is encoded by the nucleic acid sequence murine SEQ ID nO: 7, and the constant regions of the light chains and heavy chains are constant regions from a non-murine species, as well as the use of this antibody for activating FcgammaRIII receptors of immune effector cells, and for the manufacture of a medicament, particularly for the treatment of leukemia or lymphoma.
Journal of Clinical Oncology, 2012
5069 Background: Expressed on most OC subtypes while displaying a restricted expression profile i... more 5069 Background: Expressed on most OC subtypes while displaying a restricted expression profile in adult normal tissues, MISRII represents a potentialtarget for OC immunotherapy. We present here the preclinical assessment of a humanized anti-MISRII EMABling mAb, 3C23K. Methods: Either quantitative RT-PCR or immunohistochemistry (IHC) studies were performed to confirm MISRII expression profile in Granulosa Cell Tumor (GCT) or Epithelial OC (EOC) patient samples and to evaluate tissue cross-reactivity. For in vitro and in vivo experiments, we have generated 4 patient-derived MISRII expressing EOC cell lines. Xenograft studies were conducted in swiss nude mice on established tumors (100 mm3). Mice received 2 to 3 weekly i.p. injections (10 mg/kg/inj) for 4 to 6 wks and tumor volumes were compared with control groups. Comparison of i.p. vs i.v. injections were assessed as well as combination with carboplatin (once a week for 4 weeks, 60 mg/kg/inj). In addition, 3C23K plasma level was mo...
Blood, 2012
1654 Background: Anti-CD20 monoclonal antibody (mAb) therapy is an important therapeutic option i... more 1654 Background: Anti-CD20 monoclonal antibody (mAb) therapy is an important therapeutic option in the treatment of Waldenström's Macroglobulinemia (WM), exhibiting an ORR up to 55% when used as monotherapy. NK cells are involved in mAb therapy by an antibody-dependent cellular cytotoxicity (ADCC) mechanism through their FcγRIIIa (CD16) receptor. Ublituximab (TGTX-1101 or LFB-R603) is a novel, glycoengineered chimeric anti-CD20 mAb that has a high affinity for FcγRIIIa (CD16) receptors. In this study, we evaluate the ADCC functional capacities of NK cells in the presence of ublituximab compared to rituximab. Patients and Methods: Blood samples from 37 un-treated, or without ongoing treatment WM patients and from 30 age-matched healthy donors (Ctl) were collected to quantify CD16 expression (clone 3G8, Quantibrite) on NK cells and/or to measure their functional capacities. Patients were divided in two groups relative to the presence (WM clone+) or absence (WM clone-) of blood cl...
Journal of Hypertension, 1989
Molecular cancer therapeutics, Jan 15, 2017
Exploratory clinical trials using therapeutic anti-HER3 antibodies strongly suggest that neuregul... more Exploratory clinical trials using therapeutic anti-HER3 antibodies strongly suggest that neuregulin (NRG1; HER3 ligand) expression at tumor sites is a predictive biomarker of anti-HER3 antibody efficacy in cancer. We hypothesized that in NRG1-expressing tumors, where the ligand is present before antibody treatment, anti-HER3 antibodies that do not compete with NRG1 for receptor binding have a higher receptor-neutralizing action than antibodies competing with the ligand for binding to HER3. Using time resolved-fluorescence energy transfer (TR-FRET), we demonstrated that in the presence of recombinant NRG1, binding of 9F7-F11 (a non-ligand competing anti-HER3 antibody) to HER3 is increased, whereas that of ligand-competing anti-HER3 antibodies (H4B-121, U3-1287, Ab#6, Mab205.10.2 and MOR09825) is decreased. Moreover, 9F7-F11 showed higher efficacy than antibodies that compete with the ligand for binding to HER3. Specifically, 9F7-F11 inhibition of cell proliferation and of HER3/AKT/ER...
The invention concerns the use of minalcipran for preparing a medicine for treating certain psych... more The invention concerns the use of minalcipran for preparing a medicine for treating certain psychiatric diseases such as panic, post-traumatic, obsessional-compusive disorders, drug addiction disintoxication, sleeplessness, pre-menstrual dysphoria and eating disorders.
Ash Annual Meeting Abstracts, Nov 18, 2011
In the study reported here, we further investigated the B-cell lysis activity of LFB-R603 (ublitu... more In the study reported here, we further investigated the B-cell lysis activity of LFB-R603 (ublituximab), a novel anti-CD20 monoclonal antibody (mAb), as compared with ofatumumab and rituximab on various cell lines and on PBMCs from CLL patients. In terms of CDC-mediated lysis, we observed higher CDC activity of ofatumumab when compared with LFB-R603 on several cell lines expressing high CD20 levels (data not shown). Rituximab displayed CDC activity slightly superior to that of LFB-R603. In contrast, CDC activity against CD20-low expressing cells, the SUDHL-8 cell line, and CLL patient-derived PBMCs was very low with all three mAbs, rituximab, ofatumumab and LFB-R603. Consistent with previous results, LFB-R603 was shown to mediate high ADCC against all cell lines tested, including CD20-low expressing cells, whereas both ofatumumab and rituximab mediated ADCC at low levels. Altogether, these results support the fact that the therapeutic use of LFB-R603 may be advantageous over currently approved anti-CD20 mAbs in targeting malignant cells where surface CD20 molecules are known to be expressed at low levels such as in CLL and small lymphocytic lymphomas.
Cancer Research, 2011
Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Often diagnosed at an ad... more Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Often diagnosed at an advanced stage, ovarian cancer is responsible for the highest mortality rate among patients with gynecologic malignancies. Due to the limitations of the current therapeutic approaches, there is a strong need for novel, more efficient, therapies, among which targeted immunotherapy. The monoclonal antibody 12G4 specifically recognizes the human Mullerian Inhibiting Substance type II Receptor (MISRII). Expressed at high levels on most human Granulosa Cell Tumors (GCT) as well as on a majority of human epithelial ovarian cancer (EOC) cells, MISRII represents a good target for antibody-based tumor targeting. Characterization of murine antibody 12G4 has been previously reported, in particular epitope mapping and in vitro assays showing that 12G4 binding does not affect MIS interaction with MISRII. In the present study we further assess 12G4 activity in vitro and in vivo. 12G4 was shown to induce 37% and 30% apoptosis in vitro (FACS, DNA fragmentation) on the two MISRII expressing cell lines cov434-MISRII and OVCAR3, respectively. Internalization of the antibody-MISRII complex was also observed in vitro on cov434-MISRII. Using 12G4 antibody we confirmed by immunohistochemistry the expression of the MISRII target in all GTC samples and all but one EOC tissue sections (13/14). Furthermore, we have developed several immunodeficient Nude mouse models of ovarian tumor xenografts expressing human MISRII. In these models the efficacy of 12G4 could be clearly demonstrated with a significant effect on tumor growth. According to our data, MISRII, expressed on a majority of EOCs appears as a good target for ovarian cancer immunotherapy. Furthermore, based on the good efficacy observed in vivo for 12G4, the development of a humanized anti-MISRII antibody, derived from 12G4, has been initiated and represents a new promising targeted therapeutic approach. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4568. doi:10.1158/1538-7445.AM2011-4568
Oncotarget, Jan 21, 2017
Müllerian inhibiting substance, also called anti-Müllerian hormone (AMH), inhibits proliferation ... more Müllerian inhibiting substance, also called anti-Müllerian hormone (AMH), inhibits proliferation and induces apoptosis of AMH type II receptor-positive tumor cells, such as human ovarian cancers (OCs). On this basis, a humanized glyco-engineered monoclonal antibody (3C23K) has been developed. The aim of this study was therefore to experimentally confirm the therapeutic potential of 3C23K in human OCs. We first determined by immunofluorescence, immunohistochemistry and cytofluorometry analyses the expression of AMHRII in patient's tumors and found that a majority (60 to 80% depending on the detection technique) of OCs were positive for this marker. We then provided evidence that the tumor stroma of OC is enriched in tumor-associated macrophages and that these cells are responsible for 3C23K-induced killing of tumor cells through ADCP and ADCC mechanisms. In addition, we showed that 3C23K reduced macrophages induced-T cells immunosuppression. Finally, we evaluated the therapeutic ...
Oncotarget, 2017
Ovarian cancer is the leading cause of death in women with gynecological cancers and despite rece... more Ovarian cancer is the leading cause of death in women with gynecological cancers and despite recent advances, new and more efficient therapies are crucially needed. Müllerian Inhibiting Substance type II Receptor (MISRII, also named AMHRII) is expressed in most ovarian cancer subtypes and is a novel potential target for ovarian cancer immunotherapy. We previously developed and tested 12G4, the first murine monoclonal antibody (MAb) against human MISRII. Here, we report the humanization, affinity maturation and glyco-engineering steps of 12G4 to generate the Fc-optimized 3C23K MAb, and the evaluation of its in vivo anti-tumor activity. The epitopes of 3C23K and 12G4 were strictly identical and 3C23K affinity for MISRII was enhanced by a factor of about 14 (K D = 5.5 × 10 −11 M vs 7.9 x 10 −10 M), while the use of the EMABling ® platform allowed the production of a low-fucosylated 3C23K antibody with a 30-fold K D improvement of its affinity to FcγRIIIa. In COV434-MISRII tumor-bearing mice, 3C23K reduced tumor growth more efficiently than 12G4 and its combination with carboplatin was more efficient than each monotherapy with a mean tumor size of 500, 1100 and 100 mm 3 at the end of treatment with 3C23K (10 mg/kg, Q3-4D12), carboplatin (60 mg/kg, Q7D4) and 3C23K+carboplatin, respectively. Conversely, 3C23K-FcKO, a 3C23K form without affinity for the FcγRIIIa receptor, did not display any anti-tumor effect in vivo. These results strongly suggested that 3C23K mechanisms of action are mainly Fc-related. In vitro, antibody-dependent cytotoxicity (ADCC) and antibody-dependent cell phagocytosis (ADCP) were induced by 3C23K, as demonstrated with human effector cells. Using human NK cells, 50% of the maximal lysis was obtained with a 46-fold lower concentration of low-fucosylated 3C23K (2.9 ng/ml) than of 3C23K expressed in CHO cells (133.35 ng/ml). As 3C23K induced strong ADCC with human PBMC but almost none with murine PBMC, antibody-dependent cell
Journal of Medicinal Chemistry, 1994
Starting from 2-(2-aminoethyl)-6-methoxy-1-methylcarbazole, ethyl 9-methoxy-5-methyl-6H-pyrido[4,... more Starting from 2-(2-aminoethyl)-6-methoxy-1-methylcarbazole, ethyl 9-methoxy-5-methyl-6H-pyrido[4,3-b]carbazole-1-carboxylate was obtained through a three-step sequence. This compound and its 6-methyl derivative react with (dialkylamino)alkylamines to provide various 9-methoxy-5-methyl-6H-pyrido[4,3-b]carbazole-1-(N-substituted carboxamides) whose boron tribromide demethylation afforded corresponding 9-hydroxy-1-(N-substituted carbamoyl)-olivacines. The same pathway but starting from 2-(2-aminoethyl)-6-methoxy-1,4-dimethylcarbazole led to ethyl 9-methoxy-5,11-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxylate which did not normally react with amines. It provided either the recovered starting material at 120 degrees C or 9-methoxyellipticine resulting from an unexpected decarboethylation in a steel vessel at 180 degrees C. Biological testing of the newly obtained 1-carbamoylolivacine derivatives showed that 9-hydroxylated compounds displayed high cytotoxicity for cultured L1210 and colon 38 cells (IC50 range 5-10 nM) and good antitumor activity in vivo in the P388 leukemia and colon 38 models when administered by the iv route. The most active compound in these series is 9-hydroxy-5,6-dimethyl-1-[N-[2-(dimethylamino)ethyl]carbamoyl]-6H- pyrido[4,3-b]carbazole which was selected for further evaluation on murine solid tumors and for toxicological studies.
Journal of Medicinal Chemistry, 1992
A series of 70 triazine derivatives have been synthesized and tested for their capacity to modula... more A series of 70 triazine derivatives have been synthesized and tested for their capacity to modulate multidrug resistance (MDR) in DC-3F/AD and KB-A1 tumor cells in vitro, in comparison with verapamil (VRP), a calcium channel antagonist currently used in therapy as an antihypertensive drug, which also shows MDR modulating activity. Among the 12 selected compounds, 16 (S9788) showed high MDR reversing properties in vitro (300- and 6-fold VRP at 5 microM in DC-3F/AD and KB-A1 cells, respectively) and induced a strong accumulation of adriamycin. The relationship between the increase of ADR accumulation and the fold reversal induced by these compounds and their lack of effects on the sensitive DC-3F cells suggest that they act mainly by inhibiting the P-glycoprotein (Pgp) catalyzed efflux of cytotoxic agents, as already described for a majority of MDR modulators. In vivo, in association with the antitumor drug vincristine (0.25 mg/kg), 16 (100 mg/kg) increased the T/C by 39% in mice bearing the resistant tumor cell line P388/VCR. According to these interesting properties, 16 was selected for a clinical development because it was more bioavailable than 34, even though it was less active.
The Journal of Clinical Pharmacology, 1988
The systemic and renal hemodynamic effects of tertatolol, a new noncardioselective beta blocker w... more The systemic and renal hemodynamic effects of tertatolol, a new noncardioselective beta blocker without partial agonist activity, given alone or in combination with cyclooxygenase inhibition by acetylsalicylic acid (aspirin), were investigated in eight healthy volunteers. Tertatolol 5 mg, aspirin 1 g, tertatolol 5 mg together with aspirin 1 g and placebo were administered at 1-week intervals in a random order and in a double-blind fashion. Cardiac output was measured by Doppler echography and renal blood flow and glomerular filtration rate (GFR) by constant infusion techniques using (123I) iodohippurate and (51Cr) EDTA, respectively. Measurements were performed before and then successively 2 and 4 hours after oral intake of drugs or placebo. Tertatolol decreased cardiac output by 22% (P less than .05) and heart rate by 17% (P less than .05) without change in blood pressure, renal blood flow, and GFR. The same effects occurred when tertatolol was given together with aspirin. Either placebo or aspirin alone had no effect on systemic and renal hemodynamics. These results suggest that cardiac output is redistributed to the kidneys after tertatolol intake in normal humans. This favorable effect on renal hemodynamics is probably not mediated by a local release of vasodilating prostaglandins.
European Journal of Pharmacology, 1995
Since tachykinins released from lung sensory nerve endings are thought to play a role in inflamma... more Since tachykinins released from lung sensory nerve endings are thought to play a role in inflammatory diseases of airways via NK1 and NK2 receptors, dual tachykinin NK1 and NK2 receptor antagonists may have a great therapeutic potential. In vitro, the cyclopeptide S 16474 (cyclo-[Abo-Asp(D-Trp(Suc0Na)-Phe-N-(Me)Bzl)]) bound to both human tachykinin NK1 and NK2 receptors expressed in two lines of transfected Chinese hamster ovary cells (IC50 values 85 nM and 129 nM, respectively), while showing a poor affinity for the rat tachykinin NK1 receptor. S 16474 inhibited the contractions induced by substance P in isolated rabbit vena cava (pA2 7.0) and by neurokinin A in rabbit pulmonary artery (pA2 5.6). In vivo in anaesthetized guinea-pigs, S 16474 was found to dose dependently inhibit the bronchoconstrictions induced by intravenously administered substance P, neurokinin A and capsaicin. Plasma extravasation evoked in bronchi by endogenously released tachykinins under vagus nerve stimulation was abolished by S 16474 (10 mu mol/kg i.v.). These results demonstrate clearly that S 16474 is a tachykinin receptor antagonist exhibiting, in vitro and in vivo, a dual inhibitory effect on NK1 and NK2 receptors.
British Journal of Haematology, 2008
A human anti-RhD immunoglobulin G1 monoclonal antibody (mAb), R297, was tested in a phase I study... more A human anti-RhD immunoglobulin G1 monoclonal antibody (mAb), R297, was tested in a phase I study to assess its ability to induce the clearance of antibody-coated autologous RhD + red blood cells (RBCs) in healthy male volunteers. The clearance potency of R297 was compared with that of a marketed human polyclonal anti-D product (Rhophylac Ò ). This mAb has been selected for its ability to strongly engage Fc-gamma receptor IIIA and to mediate a potent antibody-dependent cell cytotoxicity (ADCC) against RhD + RBCs. Autologous RhD + RBCs were sensitized with either Rhophylac Ò or R297 at three different coating percentages (25, 12AE5 and 6AE25%), before re-infusion. This phase I study showed that the human R297 mAb promoted rapid and complete clearance of RBCs, and showed activity that was at least as potent as the human polyclonal anti-D antibody preparation. Clearance of RBCs could still be observed when the percentage of R297 used to coat the RBCs was reduced to 6AE25%. Finally, none of the adverse events was severe or considered to be related to R297. Thus, R297 is a promising candidate for the prevention of allo-immunization and represents a new generation of Fc-modified monoclonal antibodies with increased FccRIII binding and increased ADCC.
British Journal of Haematology, 2008