A Proof-of-Concept Phase II Trial to Evaluate the EMT Inhibitor Sotevtamab Combined With FOLFOX Administered as Neoadjuvant Treatment Prior to Resection of Colorectal Cancer Liver Metastasis

This Phase II study will recruit 17 colorectal cancer patients with liver-dominant metastases. All recruited patients will receive Sotevtamab at a dose of 800 mg once weekly for 6 cycles combined with FOLFOX once every 2 weeks for the first 4 cycles followed by liver metastases resection surgery with or without primary cancer resection. One cycle of treatment will consist of 14 days (2 weeks).

Start Date15 Feb 2024

Sponsor / Collaborator

Alethia Biotherapeutics, Inc.

NCT04364620 / CompletedPhase 2

A Phase II Study of AB-16B5 Combined With Docetaxel in Previously Treated Subjects With Metastatic Non-Small Cell Lung Cancer (EGIA-002)

This Phase II study will recruit 40 metastatic non-small cell lung cancer patients who failed treatment with a platinum-containing doublet treatment and an anti-PD1 or PD-L1 immune checkpoint antibody, administered simultaneously or sequentially. All recruited patients will receive AB-16B5 at a dose of 12 mg/kg once weekly combined with docetaxel at a dose of 75 mg/m2 once every 3 weeks.

Start Date23 Feb 2021

Sponsor / Collaborator

Alethia Biotherapeutics, Inc.

NCT02412462 / CompletedPhase 1

A Phase I Dose-Escalation Study to Evaluate the Safety, Tolerability and Pharmacokinetics of AB-16B5 in Subjects With an Advanced Solid Malignancy

This is a Phase 1 clinical study to investigate the safety, pharmacokinetics and pharmacodynamics of AB-16B5 in patients with an advanced solid malignancy. AB-16B5 is a humanized monoclonal antibody that inhibits the activity of the secreted form of clusterin (sCLU), a potent inducer of the epithelial-to-mesenchymal transition (EMT). Eligible subjects will have a disease that has been refractory to prior therapy and is unlikely to benefit from known therapies.

Start Date01 Apr 2015

Sponsor / Collaborator

Alethia Biotherapeutics, Inc.

100 Clinical Results associated with Alethia Biotherapeutics, Inc.

0 Patents (Medical) associated with Alethia Biotherapeutics, Inc.

Literatures (Medical) associated with Alethia Biotherapeutics, Inc.

15 Jul 2016·Cancer Research

Abstract LB-091: Inhibition of Siglec-15 prevents bone loss in a mouse model of multiple myeloma

Author: Filion, Mario ; Tremblay, Gilles B. ; Vanderkerken, Karin ; Moraitis, Anna

AbstractMultiple myeloma (MM) is a B-cell malignancy associated with infiltration and growth of plasma cells in the bone marrow resulting in end-organ damage including devastating osteolytic bone disease. We examined the ability of 25B2, an antibody targeting Siglec-15, to prevent bone loss in the 5T2MM syngeneic model of MM. C57BlKaLwRij male mice (n = 10/group) were injected with 5T2MM cells and 24h later treated for 12 weeks with the PBS, 25B2 (10 mg/kg, q3d), bortezomib (0.7 mg/kg, q3d) or a combination of 25B2 and bortezomib. 25B2 treatment caused a 3.7-, 5.4- and 1.2-fold increase in bone volume (%BV/TV) compared to PBS-treated mice in the tibia, femur and lumbar vertebra (LV), respectively. Increases in bone volume were also seen with bortezomib with 3.1-, 4.1- and 1.4-fold increases in the tibia, femur and LV, respectively. Combination of the two agents further increased%BV/TV by 6.9-, 10.5- and 1.5-fold in the tibia, femur and LV, respectively, when compared to the PBS treated mice. All of the changes were statistically significant with the exception of those in the LV. Unlike bortezomib treatment, which inhibits the growth of 5T2MM cells in this model, there was no direct effect of 25B2 on tumor burden in 5T2MM mice when the percentage of plasmacytosis and the serum paraprotein levels were measured. However, 25B2 caused a significant decrease in the number of bone lesions by 49.5%. The number of lesions in the bortezomib group decreased by 71.7%, but there was no significant difference between the 25B2 and bortezomib groups. The number of lesions decreased by 89.4% in the combination group. Consistent with the mechanism of action of Siglec-15 antibodies, osteoclasts were rendered inactive, however cross-talk with bone-forming osteoblasts was likely maintained. This unique mechanism of action would be particularly appropriate for MM, where osteolytic disease is not only the result of increased osteoclast activity but also decreased osteoblast-mediated bone formation. The 5T2MM model is one of the most representative of the human pathology and therefore, the effect observed in response to the Siglec-15 antibody holds the promise that such a treatment in MM patients could provide benefit and further delay skeletal related events.Citation Format: Gilles B. Tremblay, Anna Moraitis, Karin Vanderkerken, Mario Filion. Inhibition of Siglec-15 prevents bone loss in a mouse model of multiple myeloma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-091.

01 Oct 2014·Cancer Research

Abstract 666: AB-3A4: A novel KAAG1-targeting antibody-drug conjugate is active in models of ovarian carcinoma, triple-negative breast cancer and castration-resistant prostate cancer

Author: Pagé, Martine ; Tremblay, Gilles B. ; Mes-Masson, Anne-Marie ; Bédard, Dominique ; Filion, Mario ; Orimoto, Adriana ; Moraitis, Anna

AbstractStarting from total RNA prepared from late-stage serous ovarian tumors and low-malignancy potential tumors, a sensitive subtractive cloning technology called STAR was used to identify differentially expressed sequences that were up-regulated in the malignant tumors. This analysis led to the identification of KAAG1, an antigen that is specifically expressed in the vast majority of the ovarian tumors. Monoclonal antibodies (mAbs) that bind to human KAAG1 were generated and one of these, AB-3A4, interacted with KAAG1 expressed on the surface of several ovarian cancer, triple-negative breast cancer (TNBC) and prostate cancer cell lines. Further studies indicated that the AB-3A4/KAAG1 complex was rapidly internalized and co-localized with LAMP1, a marker of lysosomes, indicating that AB-3A4 has potential as an antibody-drug conjugate (ADC). Here we describe preclinical results of AB-3A4 conjugated to the cytotoxic agent monomethyl auristatin E (AB-3A4-vcMMAE). Binding studies with KAAG1-positive cell lines, such as the SKOV-3 (ovarian), MDA-MB-231 (TNBC) and PC-3 (prostate) showed that AB-3A4-vcMMAE interacted with its antigen in a similar manner to the unconjugated AB-3A4. In cytotoxicity assays, AB-3A4-vcMMAE killed cancer cell lines expressing KAAG1 with an IC50 value of 1 - 2 nM, whereas it displayed no specific potency in KAAG1-low or -negative cells. SKOV-3 cells were subcutaneously implanted in SCID mice and allowed to grow to a volume of 150 - 200 mm3 after which four injections of AB-3A4-vcMMAE at 5 mg/kg were administered over two weeks. Rapid and sustained tumor regression was observed for several weeks post-injection. In PC-3 xenografts, a single injection of AB-3A4-vcMMAE at 3 mg/kg was sufficient to cause significant tumor regression and this efficacy was found to be dose-dependent between doses of 1 and 10 mg/kg. In parallel treatment groups, no significant tumor shrinkage was observed with either a control IgG-vcMMAE or a mixture of unconjugated AB-3A4 and free MMAE at a drug-antibody ratio corresponding to that of AB-3A4-vcMMAE. Furthermore, xenografts of TNBC MDA-MB-231 cells were significantly regressed following a single injection of AB-3A4-vcMMAE with no recurrence after several weeks post-treatment. Finally, using an intraperitoneal orthotopic model of ovarian cancer, treatment with AB-3A4-vcMMAE significantly increased the overall survival of mice compared to mice treated with the control ADC. Collectively, our results demonstrate the potent efficacy of AB-3A4-vcMMAE in several disease models and underscore the potential of this novel agent in ovarian cancer, TNBC and castration-resistant prostate cancer, three areas for which very few targeted therapies exist.Citation Format: Gilles B. Tremblay, Anna Moraitis, Dominique Bédard, Adriana Orimoto, Martine Pagé, Anne-Marie Mes-Masson, Mario Filion. AB-3A4: A novel KAAG1-targeting antibody-drug conjugate is active in models of ovarian carcinoma, triple-negative breast cancer and castration-resistant prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 666. doi:10.1158/1538-7445.AM2014-666

15 Apr 2012·Cancer Research

Abstract LB-297: The EMT inhibitor AB-16B5 interacts with specific isoforms of secreted clusterin

Author: Viau, Elisabeth ; Filion, Mario ; Tremblay, Gilles B.

AbstractSecreted clusterin (sCLU) exhibits elevated expression in several cancer indications. sCLU plays a pro-survival role in tumors and, more recently, it was found to be a potent stimulator of the epithelial-to-mesenchymal transition (EMT). These findings led to the development of a monoclonal antibody, AB-16B5, that interacts with a specific EMT-inducing domain in sCLU resulting in abrogation of migration and invasion of many types of cancer cells. We previously showed that blocking tumor-associated sCLU with AB-16B5 reduced the expression of mesenchymal markers and restored the expression of epithelial markers in human tumor xenografts, observations that were in line with inhibition of EMT in vivo. Consequently, this resulted in reduced metastatic invasion and increased response to cytotoxic agents in animal models of human cancer. We now report new results that shed light on the biochemical differences between sCLU that is secreted by tumor cells or normal cells. Using two-dimensional gel electrophoresis, we found that there was a difference in the number and composition of sCLU isoforms present in the plasma of cancer patients compared with those expressed in healthy individuals. In particular, the post-translational modifications were more complex on sCLU secreted from tumor cells compared with those present in sCLU from healthy individuals. Moreover, AB-16B5 was found to specifically interact with several of the isoforms expressed from tumor cells but exhibited a reduced ability to interact with sCLU from plasma from healthy individuals. We also examined the interaction between AB-16B5 and tumor-associated sCLU in vivo. In these studies, injection of AB-16B5 conjugated to a fluorophore in mice harboring sub-cutaneously implanted human pancreatic tumor xenografts resulted in a rapid enrichment of fluorescence signal in the tumors. Interestingly, administration of high concentrations of human recombinant sCLU immediately prior to injection of the AB-16B5 fluorophore-conjugate still resulted in enrichment of fluorescence signal in the tumors, albeit at slightly lower intensity than was observed in the absence of recombinant sCLU. Our findings indicate that AB-16B5 can efficiently interact with tumor-associated sCLU despite the presence of excess concentrations of sCLU in the circulation. Taken together, our results suggest that AB-16B5 has increased affinity for sCLU isoforms that are specifically expressed from tumor cells that have undergone an EMT.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-297. doi:1538-7445.AM2012-LB-297

100 Deals associated with Alethia Biotherapeutics, Inc.

100 Translational Medicine associated with Alethia Biotherapeutics, Inc.

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The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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Current Projects

Drug(Targets)	Indications	Global Highest Phase

Sotevtamab ( CLU )	colon cancer liver metastasis More	Phase 2
AB-0531	Neoplasms More	Preclinical
AB-3A4 ( KAAG1 )	Neoplasms More	Discovery
AB-25B8 ( RANKL )	Osteoporosis More	Pending
AB-25E9 ( CTSK x Siglec-15 )	Bone Diseases More	Pending

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