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Transgene’s and BioInvent’s BT-001 Achieves Outstanding Tumor Cure Rates in Preclinical Models

On June 22, 2020 Transgene (Paris:TNG), a biotech company that designs and develops virus-based immunotherapies for the treatment of cancer, and BioInvent International AB ("BioInvent") (OMXS: BINV), a biotech company focused on the discovery and development of novel and first-in-class immune-modulatory antibodies for cancer immunotherapy, reported preclinical data demonstrating high cure rates in solid tumors of BT-001, an anti-CTLA4 antibody-encoding oncolytic virus (Press release, Transgene, JUN 22, 2020, View Source [SID1234561354]).

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Cure rates exceeding 70% were seen in multiple mouse models, demonstrating the powerful therapeutic effect of BT-001 when used as a single agent, providing a solid basis for BT-001’s upcoming clinical development, with a Phase 1 clinical trial expected to start before the end of 2020.

BT-001 is a next-generation oncolytic virus (OV) being co-developed by Transgene and BioInvent. It was generated using Transgene’s Invir.IO platform and its patented large-capacity VVcopTK-RR- oncolytic virus, which has been engineered to encode a Treg-depleting, anti-CTLA4 antibody generated by BioInvent’s proprietary n-CoDeR/F.I.R.S.T platforms, as well as the cytokine GM-CSF.

BT-001 has multiple mechanisms of action. It has been designed to combine the killing of cancer cells (oncolysis), and the production of the anti-CTLA4 antibody and GM-CSF directly in the tumor site, while also generating an immune response against tumor cells.

These data indicate that BT-001 has the potential to make a significant difference in the treatment of solid tumors and as such, underpin the effectiveness of both Transgene’s and BioInvent’s technology platforms.

Main points from the presentation included:

The anti-CTLA4 antibody and GM-CSF accumulate in tumors with low systemic exposure. Concentrations of the anti-CTLA4 antibody in the tumor after intratumoral injection of BT-001 is more than 10-fold higher than after intraperitoneal injection of 3 mg/kg of the recombinant antibody in a xenograft tumor model.
When tumor cells were re-implanted in mice that had been cured after a first BT-001 treatment, a strong tumor-specific response and long-lasting immune memory were developed by these mice.
BT-001, even at sub-optimal dose, reinforced the therapeutic activity of an anti-PD-1 antibody – opening up potential combinations for powerful dual checkpoint blockade treatment regimens.
These promising findings are available in a poster being presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting II, on June 22-24, 2020. It can be downloaded from the AACR (Free AACR Whitepaper) website and from both Transgene’s and BioInvent’s websites.

Title of the poster: "BT-001, an oncolytic Vaccinia virus armed with a Treg-depletion-optimized recombinant human anti-CTLA4 antibody and GM-CSF to target the tumor microenvironment."
Authors: Jean-Baptiste Marchand, Monika Semmrich, Laetitia Fend, Matilda Rehn, Nathalie Silvestre, Ingrid Teige, Johann Foloppe, Linda Mårtensson, Eric Quéméneur, Björn Frendeus
Session Date: June 22-24, 2020
Poster Session Title: Inflammation, Immunity, and Cancer / Modifiers of the Tumor Microenvironment 2
Poster Number: 5602// Abstract Number: 2902

Xencor Presents Data from Four Preclinical XmAb® 2+1 Bispecific Antibody and Cytokine Programs at AACR Virtual Annual Meeting II

On June 22, 2020 Xencor, Inc. (NASDAQ: XNCR), a clinical-stage biopharmaceutical company developing engineered monoclonal antibodies for the treatment of cancer and autoimmune diseases, reported the presentation of new preclinical data from three XmAb 2+1 bispecific antibody programs and its IL-12-Fc cytokine program during the second session of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting (Press release, Xencor, JUN 22, 2020, View Source [SID1234561353]). Poster presentations and audio descriptions are available to registrants of the AACR (Free AACR Whitepaper) Virtual Annual Meeting.

"Compared to many therapeutic targets for blood cancers like CD19 or CD20, which are generally restricted to specific cell populations, solid tumor targets often are expressed on a range of normal tissues, including critical organs, which can limit the therapeutic index for drug candidates," said John Desjarlais, Ph.D., senior vice president and chief scientific officer at Xencor. "The XmAb 2+1 bispecific antibody format has two domains that bind the tumor target, and this bivalent binding can preferentially bind tumor cells with high target expression, potentially sparing low-expression normal tissues. This selectivity and potency tuning of T-cell activation may provide for higher efficacy and tolerability compared to other bispecific antibody formats.

"We have also presented data from our IL-12-Fc cytokine program, which builds off of our prior work with IL-15 and IL-2. IL-12 is a potent immune signaling protein that can have a dramatic effect on shrinking tumors; however, prior clinical studies have demonstrated IL-12 to have a narrow therapeutic window, limiting potential response rates. We created an IL-12 Fc-fusion with reduced potency in order to improve tolerability, slow receptor-mediated clearance and prolong the molecule’s half-life," said Dr. Desjarlais.

XmAb 2+1 Bispecific Antibodies

Poster: 2286, "XmAb30819, an XmAb 2+1 ENPP3 x CD3 bispecific antibody for RCC, demonstrates safety and efficacy in in-vivo preclinical studies"
Poster: 5663, "Affinity tuned XmAb 2+1 PSMA x CD3 bispecific antibodies demonstrate selective activity in prostate cancer models"
Poster: 5654, "Affinity tuned XmAb 2+1 anti-mesothelin x anti-CD3 bispecific antibody induces selective T cell directed cell cytotoxicity of human ovarian cancer cells"
ENPP3, PSMA and MSLN are tumor-associated antigens associated with renal cell carcinoma (RCC), prostate cancer and ovarian cancer, respectively, but they are not restricted to tumors and exhibit base level expression on normal tissues. Xencor has expanded its T-cell redirecting CD3 class of bispecific antibodies to create an XmAb 2+1 bispecific antibody format, utilizing an engineered heterodimeric Fc domain, two identical tumor targeting domains and one CD3 targeting domain. The affinities for antigen binding are reduced, which allows for selective engagement of high antigen-expressing tumor cells over low antigen-expressing normal cells. In preclinical models, XmAb 2+1 bispecific antibodies bound preferentially to tumor cells compared to normal cells and effectively recruited T cells to kill tumor cells selectively. Additional data presented on XmAb 2+1 PSMA x CD3 bispecific antibody candidates and XmAb30819, a first-in-class XmAb 2+1 ENPP3 x CD3 bispecific antibody, demonstrated strong reversal of tumor growth in human-cell engrafted mouse models of disease. Further data presented from preclinical studies of XmAb30819 in non-human primates demonstrated it was well-tolerated with expected pharmacodynamics and an antibody-like half-life.

IL-12-Fc Cytokine

Poster: 5549, "Potency-reduced IL-12 heterodimeric Fc-fusions exhibit strong anti-tumor activity"
IL-12 is a heterodimeric proinflammatory cytokine produced by activated antigen-presenting cells, and it leads to proliferation of T cells and NK cells and increased cytotoxicity through high levels of interferon gamma signaling. IL-12-Fc fusions were engineered with potency-reduced IL-12 to improve its potential tolerability, slow receptor-mediated clearance and prolong its half-life in vivo. In preclinical models, these potency-reduced IL-12-Fc fusions demonstrated significant anti-tumor activity concurrent with activation and proliferation of CD8+ T cells, increased PD-1 checkpoint expression and increased levels of interferon gamma in serum. Anti-tumor activity was enhanced when combined with an anti-PD-1 antibody.

The posters will be archived under "Events & Presentations" in the Investors section of the Company’s website located at www.xencor.com.

ImmunoGen Presents Preclinical Data on IMGN151 at Virtual AACR Annual Meeting

On June 22, 2020 ImmunoGen, Inc. (Nasdaq: IMGN), a leader in the expanding field of antibody-drug conjugates (ADCs) for the treatment of cancer, reported preclinical data for its next generation anti-folate receptor alpha (FRα) ADC, IMGN151, which is being investigated in tumors with a broad range of FRα expression (Press release, ImmunoGen, JUN 22, 2020, View Source [SID1234561352]). The findings were shared via poster presentation at the virtual American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting II.

"Engineered to include multiple antibody and linker-payload innovations, IMGN151 targets tumors with a broad range of FRα expression," said Eric Westin, MD, Vice President of Clinical Development and Translational Sciences at ImmunoGen. "IMGN151 demonstrated enhanced anti-tumor activity in both in vitro and in vivo preclinical models, with complete regression of human tumor xenograft models induced in those with high, medium, and low levels of FRα expression. Based on these data, we look forward to exploring IMGN151 in the clinic in multiple FRα-positive epithelial malignancies, including ovarian, endometrial, triple negative breast, and non-small cell lung cancer."

IMGN151 PRECLINICAL DATA
Poster Presentation, Abstract 2890

IMGN151 comprises an asymmetric, bivalent, biparatopic antibody targeting two independent epitopes of FRα, linked to a highly potent maytansinoid derivative, DM21, via a cleavable peptide linker with enhanced stability, longer half-life, and increased bystander activity. The average drug per antibody ratio is 3.5. IMGN151 activity was characterized against cell lines and xenograft models with a wide range of FRα expression and compared to mirvetuximab soravtansine (IMGN853). Cell lines and xenograft models originated from ovarian, endometrial, breast, and cervical cancer.

Key findings include:

The protease-cleavable linker deployed in IMGN151 improves stability and ADC exposure; as compared to IMGN853, pharmacokinetic studies in cynomolgus monkeys showed increased ADC half-life by 60 hours and conjugate exposure in vivo by 40%.
The IMGN151 biparatopic format boosted antibody binding events and DM21 payload delivery in tumor cell lines; the increased payload delivery and greater membrane permeability of DM21 enhanced bystander killing activity.
In vitro, IMGN151 was more active against FRα-positive cell lines, with the most pronounced effect in cells with low to medium levels of FRα.
In vivo, IMGN151 demonstrated better activity over IMGN853 against low and medium levels of FRα, and equivalent activity to IMGN853 against FRα high tumors with lower effective dose; all tested doses were well tolerated.
Additional information can be found at www.aacr.org.

ABOUT IMGN151

IMGN151 is a next-generation ADC, designed to address the unmet needs of cancer patients with tumor types expressing lower levels of folate receptor alpha (FRα). IMGN151 comprises an asymmetric, bivalent, biparatopic antibody targeting two independent epitopes of FRα, linked to a highly potent maytansinoid derivative, DM21, via a cleavable peptide linker with enhanced stability, longer half-life, and increased bystander activity.

Ikena Oncology Presents New Preclinical Data Highlighting the Anti-Cancer Effects of TEAD Inhibition on the Hippo Signaling Pathway

On June 22, 2020 Ikena Oncology, a clinical-stage biotechnology company that discovers and develops patient-directed, biomarker-driven therapies, reported the presentation of new preclinical research highlighting the anti-proliferative and anti-tumor effects of Ikena-developed compounds targeting the Hippo signaling pathway through the inhibition of TEAD at the 2020 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting II, taking place June 22-24, 2020 (Press release, Ikena Oncology, JUN 22, 2020, View Source [SID1234561351]).

The TEAD (TEA domain) family of transcription factors downstream of the Hippo signaling pathway elicits a gene expression signature that plays a prominent role in cancer development, progression, and metastasis. Increased Hippo pathway activity sustains proliferation, inhibits apoptosis, promotes angiogenesis, and is associated with resistance to multiple therapies. Inhibition of TEAD has been and remains an attractive opportunity for a novel targeted cancer therapy.

"The Hippo pathway is highly mutated across many cancer types, including in mesothelioma, ovarian and breast cancers, and its activation is correlated with an overall poor prognosis in patients. Therefore, we have insights into which patients will most likely benefit from a TEAD-targeted therapy," said Jeffrey Ecsedy, Ph.D., Chief Scientific Officer of Ikena Oncology. "The AACR (Free AACR Whitepaper) presentation this year highlights promising pharmacokinetic, pharmacodynamic, and in vivo efficacy results in mesothelioma models for multiple lead TEAD inhibitor candidates identified by Ikena. These compounds are in studies to narrow in on a development candidate that we look forward to progressing into IND-enabling studies during the second half of 2020."

Ikena’s Novel Small Molecule TEAD Inhibitors

Ikena researchers rationally designed and developed multiple novel, potent, orally bioavailable small molecule inhibitors that reversibly and irreversibly bind to the central lipid (palmitate) binding pocket of TEAD family members. These inhibitors prevent TEAD palmitoylation, a process that is essential for the interaction between the transcriptional co-regulators YAP (Yes-associated protein) or TAZ (transcriptional co-activator with PDZ-binding motif) with TEAD, and lead to downregulation of the YAP/TAZ-TEAD-dependent transcription. Binding of these TEAD inhibitors to the central lipid binding pocket was observed using crystallography.

The Effects of TEAD Inhibition In Vitro and In Vivo

When evaluated in vitro, Ikena’s TEAD inhibitors demonstrated anti-proliferative properties in Hippo pathway-driven cancer cell lines, but not in Hippo pathway wildtype cancer cell lines. Subsequent in vivo experiments in human tumor xenograft mouse models demonstrated that oral administration of these TEAD inhibitors was well tolerated and that TEAD-dependent transcription in the tumors was inhibited. Robust anti-tumor activity was observed in two separate Hippo pathway-mutated mesothelioma xenografts. Translational studies to identify additional tumor types that are Hippo pathway-driven and dependent on TEAD function are in progress.

"The Hippo pathway is hijacked in many cancer types and we believe that by disrupting TEAD transcription, we can prevent tumors from proliferating and evading the body’s immune system," said Mark Manfredi, Ph.D., President and Chief Executive Officer of Ikena Oncology. "We believe our TEAD inhibitor candidates have the potential to be active across several types of Hippo-driven cancers, both as single-agent therapy and in combination with other standard of care oncology agents to overcome therapeutic resistance."

Details for the AACR (Free AACR Whitepaper) 2020 Virtual Meeting II presentation are as follows:

Title: Potent small molecule TEAD inhibitors targeting the Hippo pathway exhibit antiproliferation in vitro and anti-tumor effect in vivo
Lead author: Ben Amidon, Ikena Oncology
Abstract #: 2474
Poster Board #: 18
Session: PO.MCB04.02 – Gene Regulation and Transcription Factors 2
Date and Time: Monday, June 22, 2020; 9:00 a.m. to 6:00 p.m. ET
URL: View Source!/9045/presentation/6122

Minerva Biotechnologies Announces License Agreement with Memorial Sloan Kettering Cancer Center for 1XX Technology

On June 22, 2020 Minerva Biotechnologies (Minerva) reported that it has licensed from Memorial Sloan Kettering Cancer Center (MSK) "1XX" technology for use with Minerva’s proprietary anti-MUC1* antibodies to increase CAR T cell persistence in patients (Press release, Minerva Biotechnologies, JUN 22, 2020, View Source [SID1234561350]).

"This promises to be a great step forward for CAR T cell treatment of solid tumors," said Minerva CEO Dr. Cynthia Bamdad. "We are combining Minerva’s demonstrated cancer-specific antibodies with MSK’s innovative T cell signaling technology that sustains CAR T cell function and persistence."

Minerva is currently in a first-in-human clinical trial for metastatic breast cancers with a CAR T (huMNC2-CAR44) targeting a cleaved form of MUC1 called MUC1* (NCT04020575). MUC1* is the growth factor receptor form of MUC1 that is aberrantly expressed on over 75% of all solid tumors and on over 90% of breast cancers.

CAR T cell persistence, which is the amount of time that infused CAR T cells have the potential to kill tumor cells, is a recognized problem in the revolutionary field of cancer immunotherapy. Since over-activation drives CAR T cell exhaustion, calibrating their activation potential through 1XX mutations in their signaling domain staves off expression of exhaustion molecules that turn CAR T cells off. With this agreement, Minerva will gain non-exclusive access to two of MSK’s innovative CAR T technologies, including the 1XX CAR T cell signaling construct, whose activation potential more closely resembles that of naturally occurring T cells. Minerva expects its next-generation anti-MUC1* CAR T cell therapies to have enhanced therapeutic profiles due to their extended persistence.

Michel Sadelain, M.D., Ph.D., Director, Center for Cell Engineering at MSK and inventor of the 1XX technology said, "We are excited by the prospect of targeting MUC1* with MSK’s 1XX CAR technology."