Bstrongximab-MMAE, a novel antibody-drug-conjugate for metastatic gastric and pancreatic cancers.

e15620 Background: As of today, there are no current beneficial clinical therapeutic cancer treatments for advance metastatic gastric or pancreatic cancers. A new approach to finding effective and meaningful drugs to treat these cancers is based an emerging hypothesis that cancer is a reprogramming disease and its origin and development is due to retrograde-like malignant cells with primitive and embryonic characteristics which are responsible for the dissemination of the disease and the almost universal clinical response of tumor resistance when treated with standard current therapies. Methods: A pluripotent human germ cell tumor cell line, TERA-1, was used to isolate and purify embryonic antigens which where used to immunized mice and, with standard B-cell hybridoma technology, to generate monoclonal antibodies. Antibodies were screened by ELISA and SDS-PAGE Western blotting to identify antibodies specific to gastric and pancreatic cancers but not to normal tissues. A second assay was used to screen the potential of the antibodies to function as antibody-drug-conjugate therapeutics against cancer. Results: A lead therapeutic antibody, Bstrongomab, was identified in the antibody screens: it is positive for gastric and pancreatic cancers but does not react with normal tissues. Bstrongomab is an IgG1 monoclonal antibody which has high affinity and specificity to the embryonic target TRA-1-60. TRA-1-60 is a carbohydrate molecule which is highly expressed in normal embryonic stem cells and not expressed in normal tissues but is re-expressed in gastric and pancreatic cancers. Immunohistochemical tissue staining studies show TRA-1-60 is expressed in gastric and pancreatic cancers. Recent published scientific reports confirm this finding. A human/mouse therapeutic version of Bstrongomab was developed - Bstrongximab - and used to generate a novel therapeutic antibody-drug-conjugate with Bstongximab and the toxic payload MMAE (Monomethyl auristatin E). Pre-clinical i n-vitro and in-vivo studies show Bstrongximab-MMAE is a potent drug for gastric and pancreatic cancers. Conclusions: Bstrongximab is a novel IgG1 human/mouse chimeric therapeutic antibody that targets TRA-1-60, a novel and yet to be tried cancer target that is highly expressed in gastric and pancreatic cancers but not in normal tissues. Bstrongximab-MMAE has the potential to be a first-in-class cancer therapeutic that provides real and meaningful benefits to patients with metastatic gastric and pancreatic cancers.

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SYD985, a novel duocarmycin-based HER2-targeting antibody-drug conjugate, shows promising antitumor activity in epithelial ovarian carcinoma with HER2/neu expression.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e14009 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e14009-e14009

Author(s):

Gulden Menderes ◽

Elena Bonazzoli ◽

Stefania Bellone ◽

Jonathan Black ◽

Gary Altwerger ◽

...

Keyword(s):

Ovarian Cancer ◽

Cell Lines ◽

Gynecological Cancer ◽

In Vivo Studies ◽

Her2 Overexpression ◽

Antibody Drug Conjugate ◽

Drug Conjugate ◽

Bystander Killing ◽

Antibody Drug

e14009 Background: Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer. HER2 overexpression/amplification in EOC show considerable variation ranging from 8% to 66%. SYD985 (Synthon Biopharmaceuticals BV, Nijmegen, the Netherlands) is a novel HER2-targeting antibody-drug conjugate (ADC) composed of the monoclonal antibody (mAb) trastuzumab linked to a highly potent DNA-alkylating agent (i.e., duocarmycin). The objective of this study was to compare the anti-tumor activity of SYD985 to trastuzumab emtansine (T-DM1) in EOC. Methods: The cytotoxicity of SYD985 and T-DM1 was evaluated using ten primary EOC cell lines with 0/1+, 2+, and 3+ HER2/neu expression in antibody-dependent cellular cytotoxicity (ADCC), proliferation, viability and bystander killing experiments. Finally, the in vivo activity of SYD985 and T-DM1 was also studied in ovarian cancer xenografts. Results: SYD985 and T-DM1 induced similar ADCC in the presence of effector cells [i.e., peripheral blood lymphocytes (PBL)] against EOC cell lines with high, moderate and low HER2/neu expression. In contrast, SYD985 was 3 to 42 fold more cytotoxic in the absence of PBL when compared to T-DM1. Specifically, in HER2/neu 1+ cell lines the mean IC50’s were 0.072 µg/mL and 3.035 µg/mL for SYD985 vs T-DM1 (p < 0.0001), in HER2/neu 2+ cell lines 0.054 µg/mL and 1.168 µg/mL, (p < 0.0001) and in HER2/neu 3+ cell lines 0.024 µg/mL and 0.088 µg/mL, respectively, (p < 0.0001). Unlike T-DM1, SYD985 induced efficient bystander killing of HER2/neu 0/1+ EOC cells admixed with HER2/neu 3+ cells. In vivo studies confirmed that SYD985 is more active than T-DM1 in EOC and effective against HER2/neu 3+ xenografts. Additional (HER2/neu 2+ & 1+) EOC xenograft studies are ongoing. Conclusions: SYD985 is a novel ADC with remarkable in vitro activity against EOC with strong (3+) as well as low to moderate (i.e., 1+/2+) HER2/neu expression. SYD985 is more potent than T-DM1 in comparative experiments and unlike T-DM1, it may be active against EOC demonstrating moderate/low or heterogeneous HER2/neu expression. Clinical studies with SYD985 in EOC patients harboring chemo-resistant disease are needed.

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Discovery and Development of MEDI7247, a Novel Pyrrolobenzodiazepine (PBD)-Based Antibody Drug Conjugate Targeting ASCT2, for Treating Hematological Cancers

Blood ◽

10.1182/blood-2018-99-119836 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4071-4071 ◽

Cited By ~ 2

Author(s):

Nabendu Pore ◽

Kevin P Schifferli ◽

Noel R Monks ◽

Ravinder Tammali ◽

Martin Borrok ◽

...

Keyword(s):

Stem Cells ◽

Flow Cytometry ◽

Standard Of Care ◽

High Expression ◽

Antibody Drug Conjugate ◽

Drug Conjugate ◽

Normal Tissues ◽

Significant Survival ◽

Hematological Cancers ◽

Antibody Drug

Abstract The neutral amino acid transporter, ASCT2, is frequently overexpressed in several cancers to sustain "glutamine addiction" of cancer cells. High expression of ASCT2 is often associated with poor disease prognosis. Immuno-histochemistry (IHC) on formalin-fixed paraffin embedded (FFPE) tissue samples revealed high prevalence of membranous ASCT2 expression in several hematological cancers, including MM, AML, and DLBCL summarized in Table1. ASCT2 expression was predominantly on the plasma membrane of the carcinoma cells. ASCT2 staining was observed in almost all the samples with high positivity (>2+ and in >50% of tumor cells) in 98, 74 and 55% of MM, AML and DLBCL samples respectively. Additionally, flow cytometry analyses suggest significantly high expression of ASCT2 in bone marrow (BM) samples from AML and MM patients in comparison to BM from healthy donors. Also, our data suggest relatively less expression of ASCT2 in LT-HSC (long term hematopoietic stem cells) in comparison to prominent myeloid-associated marker CD33. In contrast, we found similar expression profile of ASCT2 and CD33 in downstream lineage-committed progenitor cells, such as MPP (multi potent progenitors) and CP (common progenitors). Furthermore, IHC evaluated across normal tissues suggest restricted ASCT2 expression in the normal tissues of vital organs. Broad expression across various unmet cancers and restricted expression in normal tissues warrant ASCT2 as an attractive candidate for an antibody drug conjugate. MEDI7247 is a novel investigational antibody-drug conjugate (ADC) comprising an anti-ASCT2 human monoclonal antibody site-specifically conjugated to pyrrolobenzodiazepine (PBD) dimer via a protease-cleavable linker, with a drug to antibody ratio (DAR) of 2. MEDI7247 specifically binds to the cell surface ASCT2 while exhibiting no affinity to the other members of the family, including ASCT1. Following binding to the extracellular region of ASCT2 antigen, MEDI7247 is internalized and trafficked to the lysosomes to subsequently release the PBD warhead. The release of PBD induces DNA damage and results in tumor cell death. MEDI7247 shows potent in vitro cytotoxic killing in several heme cancer cell lines (IC50 range of 0.05 ng/ml to ~65 ng/ml) with variable levels of ASCT2 expression (e.g. H929 (high) ~ 1.1 X106 copies/cell; Nomo (low) ~ 1.3 X105 copies/cell). In vivo anti-tumor activity of MEDI7247 was evaluated in a panel of hematological tumor models (CDx) representing AML, MM, DLBCL, cALL, and Burkitt's lymphoma. Briefly, MEDI7247 (dosed: single dose or Q1Wx4) demonstrated a significant survival advantage in disseminated or subcutaneous tumor models, when compared to the untreated control or standard of care (SOC) at the various dose levels examined: 0.05, 0.1 and 0.4 mg/kg, respectively. Likewise, MEDI7247 was also tested in disseminated AML PDX (ASCT2-low) models. Significant improvement in survival was observed at both 0.1 and 0.4 mg/kg with the higher dose level extending survival by >80 days and PDX models showed robust antitumor effect and significant survival benefit compared to standard of care (SOC). We used flow cytometry sorting of CD34+ and CD38+ populations from AML BM and ran colony forming assays in methocult culture conditions to confirm that CD34+CD38+ cells are leukemic stem cells (LSC) of AML BM samples. Furthermore, we confirmed high expression of ASCT2 in LSC and in the bulk population of AML BM. Similar analyses suggest relatively high expression of ASCT2 in MM plasma cells (CD138+CD19-) and modest to low expression in MM stem cells (CD19+ CD138-). This may yield opportunity for more durable clinical response in AML, genetically heterogeneous diseases. Furthermore, MEDI7247 demonstrated acceptable safety profile in toxicity studies with non-human primates to support first in human trials. In conclusion, based on its combined efficacy and safety, MEDI7247, a first-in class ADC is currently being evaluated in clinic for the treatment of ASCT2 positive hematological malignancies (NCT03106428). Disclosures Pore: Medimmune: Employment. Schifferli:Medimmune: Employment. Monks:Medimmune: Employment. Tammali:Medimmune: Employment. Borrok:Medimmune: Employment. Hurt:Medimmune: Employment. Flynn:Medimmune: Employment. Rebelatto:Medimmune: Employment. Townsley:Medimmue: Employment. Hinrichs:Medimmune: Employment. Dixit:Medimmune: Employment. Coats:Medimmune: Employment. Herbst:Medimmune: Employment. Tice:Medimmune: Employment.

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Bstronximab, a novel therapeutic antibody to treat metastatic testis cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e15621 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e15621-e15621

Author(s):

William Michael Schopperle

Keyword(s):

Monoclonal Antibody ◽

Metastatic Cancer ◽

Therapeutic Antibody ◽

Therapeutic Drug ◽

Testis Cancer ◽

Antibody Drug Conjugate ◽

Drug Conjugate ◽

Current Therapies ◽

Antibody Drug ◽

Novel Therapeutic

e15621 Background: The treatment of metastatic testis cancer is by far the gold standard for treating metastatic solid cancers: over 90% of men diagnosis with metastatic testis cancer are completely cured with current therapies. What seems to be lost and somewhat surprising within this truly remarkable therapeutic cancer success in treating a metastatic cancer is the fact that in United States alone there are still over 400 young men who died from this disease because they do not respond to current therapies. Thus, despite the tremendous clinical success with treating this disease, there is still a strong unmet need to develop new treatments for men with metastatic testis cancer who fall outside the celebration of this disease as being completely cured. Methods: The human germ cell tumor embryonal carcinoma line, TERA-1. was used to generate purified testis cancer-specific cell membrane antigens to immunize mice and generated antibodies, by standard conventional mouse B cell hybridoma protocols. Isolated monoclonal antibodies where tested by ELISA and SDS-PAGE Western blotting to identify testis cancer specific antibodies. Testis cancer positive antibodies were further screen in an antibody-drug-conjugate screen to determine if the monoclonal antibody could function as a antibody-drug-conjugate therapeutic drug for metastatic testis cancer. Results: Dozens of monoclonal antibodies were generated with our antibody screen. Based on the screen results, a lead monoclonal antibody, named Bstrongomab, was selected for further development as a testis cancer therapeutic antibody. Bstrongomab is an IgG1 monoclonal antibody specific to the human embryonic cell marker, and testis cancer marker, TRA-1-60, a carbohydrate molecule which has been identified over 4 decades ago as a true human testis cancer marker. A human/mouse chimeric version of Bstrongomab was created - Bstrongximab - as a human therapeutic antibody. An antibody-drug-conjugate using Bstrongximab and the toxic payload MMAE (Monomethyl auristatin E) was developed and tested in pre-clinical human cancer testis in-vitro and in-vivo models and showed to be a powerful testis cancer therapeutic drug targeting TRA-1-60. Conclusions: Bstrongximab-MMAE is a novel therapeutic antibody-drug-conjugate which targets the testis cancer antigen TRA-1-60. TRA-1-60 is not expressed in normal tissues. Bstrongximab-MMAE is a new cancer drug ready to move into clinical trials for men with metastatic cancer that do not respond with current therapy protocols.

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