On November 8, 2019 Rubius Therapeutics, Inc. (Nasdaq: RUBY), a clinical-stage biopharmaceutical company that is genetically engineering red blood cells to create an entirely new class of cellular medicines, reported that the Company presented preclinical data supporting its lead artificial antigen presenting cell program, RTX-321, for the potential treatment of HPV 16-positive tumors at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 34th Annual Meeting (Press release, Rubius Therapeutics, NOV 8, 2019, View Source [SID1234550760]). Last month at the AACR (Free AACR Whitepaper)-NCI-EORTC International Conference on Molecular Targets and Cancer, Rubius Therapeutics presented data demonstrating that its Red Cell Therapeutics can be engineered to create a loadable system for personal neoantigens, unlocking a potential new use of our RED PLATFORM.

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"Current cell therapy approaches are limited by a number of challenges – they require harvesting and engineering a patient’s own T cells, undergo a lengthy manufacturing process, are limited in the number of targets that can be pursued, and, once administered to patients, can elicit unpredictable immune responses, including severe side effects. Today at SITC (Free SITC Whitepaper), we presented additional preclinical proof of concept data demonstrating that Rubius Therapeutics can engineer allogeneic artificial antigen presenting cells against a tumor-associated antigen that significantly expand antigen-specific T cells and nearly eliminates lung metastases in a melanoma mouse model with minimal, reversible toxicity," said Pablo J. Cagnoni, M.D., chief executive officer of Rubius Therapeutics. "Separately, current personalized neoantigen approaches are promising, but do not adequately stimulate and expand the right subset of T cells to the levels required to achieve robust efficacy. Last month at AACR (Free AACR Whitepaper)-NCI-EORTC, Rubius Therapeutics presented data showing that we can engineer our red cells to create a loadable system for personal neoantigens and dramatically expand primary T cells to induce an immune response, unlocking a potential new use of our RED PLATFORM."

Data Summaries

Red Cell Therapeutic Artificial Antigen Presenting Cells (aAPCs) at SITC (Free SITC Whitepaper)

(P233) RTX-321, an Allogeneic Artificial Antigen Presenting Red Cell Therapeutic, Expressing MHC I-Peptide, 4-1BBL and IL-12, Promotes Antigen-Specific T Cell Expansion and Anti-Tumor Activity in HPV16+ Tumors

Allogeneic Red Cell Therapeutic artificial antigen presenting cells (RTX-aAPCs) are engineered to induce a tumor-specific response by expanding antigen-specific T cells.
As preclinical proof of concept, mouse red cells were chemically engineered with hundreds of thousands of copies of the major histocompatibility complex (MHC) I loaded with the gp100 peptide, a melanoma antigen, 4-1BBL and IL-12 on the cell surface and were tested in a B16-F10 melanoma mouse model.
These cells (mRBC-gp100-4-1BBL-IL-12 ) nearly eliminated lung metastases at the highest dose levels.
mRBC-gp100-4-1BBL-IL-12 promoted gp100-specific T cell expansion in the circulation, secondary lymphoid organs and lungs.
RTX-aAPC was engineered with a cytomegalovirus (CMV) antigen, 4-1BBL and IL-12 and expanded CMV-specific T cells from healthy donor peripheral blood mononuclear cells (PBMCs).
RTX-321 (HPV+) was engineered to express an HPV peptide antigen bound to MHC I, 4-1BBL and IL-12 on the cell surface to mimic human T cell-APC interactions.
Expression of IL-12 as signal 3 on an aAPC resulted in more robust antigen-specific T cell expansion, memory formation and cytotoxicity against tumor cells when compared to IL-7 or IL-15, leading the Company to select IL-12 as signal 3 for RTX-321.
RTX-321 is selectively directed against an HPV dominant epitope and promoted T cell receptor (TCRs), 4-1BB and IL-12 receptor signaling in engineered cell lines.
RTX-321 expanded HPV-specific TCR-transduced primary human T cells.
RTX-321 is currently in IND-enabling studies.
Loadable Red Cell Therapeutic Artificial Antigen Presenting Cells for Neoantigens at AACR (Free AACR Whitepaper)-NCI-EORTC

(B062) Enabling the Rapid Generation of Allogeneic Artificial Antigen Presenting Cell (aAPC) Red Cell Therapeutics with a Loadable MHC System

Allogeneic Red Cell Therapeutic artificial antigen presenting cells (RTX-aAPCs) are engineered to induce an tumor-specific response by expanding antigen-specific T cells.
A loadable MHC system was engineered to enable the rapid generation of aAPCs targeting personal neoantigens.
Antigenic peptides can be loaded onto empty MHC constructs, which can be stably expressed at high levels.
RTX-aAPCs with peptide-loaded MHC constructs functionally engaged TCRs and achieved robust expansion of primary CMV-specific T cells in healthy donor PBMCs with prior exposure to CMV.
Rubius Therapeutics’ loadable aAPC system has the potential to generate aAPCs containing multiple neoantigens in a single therapeutic.
Further development of a loadable aAPC system may enable effective personalized neoantigen therapies.

On November 8, 2019 Boston Biomedical, Inc. reported the presentation of new data from a phase 1 study evaluating DSP-7888, an investigational WT1 cancer peptide vaccine, in patients with advanced malignancies (Press release, Boston Biomedical, NOV 8, 2019, View Source [SID1234550776]). Findings from the phase 1 study investigating the safety, tolerability, and determination of the recommended phase 2 dose of DSP-7888 in patients with recurrent or progressive advanced malignancies will be presented in a poster presentation at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 34th Annual Meeting, held in National Harbor, Maryland, on November 6-10, 2019. Patients enrolled in the study have progressed on standard therapy, were intolerant to standard therapy, or were patients for whom no standard therapy existed for their cancer.

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"The data presented at the SITC (Free SITC Whitepaper) Annual Meeting demonstrate our unwavering commitment to advancing a pipeline of novel cancer therapeutics to address unmet patient needs," said Patricia S. Andrews, Chief Executive Officer, Boston Biomedical, Inc. "We are excited to share more about the progress of our pipeline, including DSP-7888, with the scientific community."

Findings from the multicenter, open-label, dose-escalation study showed that DSP-7888 was well tolerated, with no dose-limiting toxicities identified in patients with advanced malignancies. In this study, 24 patients received escalating doses of intradermal (n=10) or subcutaneous (n=14) DSP-7888. Of the 24 patients, four had stable disease and 21 patients were evaluable for WT1-specific cytotoxic T-lymphocyte (CTL) detection. In the evaluable population, WT1-specific CTL induction was observed in six of nine intradermal patients (66.7%) and five of 12 subcutaneous patients (41.7%). An intradermal dose of 10.5 mg was determined as the recommended phase 2 dose, consistent with the findings of a separate phase 1/2 study of DSP-7888 in patients with myelodysplastic syndrome. The most frequently observed adverse event was Grade 1 or 2 injection site reaction.1

"We believe the WT1 antigen is a promising target for immunotherapy, as it is expressed across a range of cancer types and plays a key role in the proliferation, differentiation and apoptotic process of cells," said Alexander Spira, MD, PhD, FACP, lead author, and Director of Virginia Cancer Specialists Research Institute. "The findings from this study support the continuation of evaluating DSP-7888 in advanced cancers."

The company will also present background information on an ongoing phase 1/2 clinical study evaluating DSP-0509, an investigational toll-like receptor (TLR) 7 agonist, for the treatment of solid tumors.

Below are the details for the Boston Biomedical presentations:

Abstract Title

Details

Lead Author

Multicenter, open-label,
phase 1 study of DSP-7888
Dosing Emulsion (DSP-7888)
in patients with advanced
malignancies

Abstract #355

November 8, 2019

7:00 a.m. – 8:00 p.m. ET

Poster Presentation

Alexander Spira, MD, PhD,
FACP, Virginia Cancer
Specialists Research Institute
and The US Oncology
Network

A first-in-human phase 1/2,
multicenter trial of toll-like
receptor (TLR) 7 agonist
DSP-0509 as monotherapy
and in combination with
pembrolizumab in adult
patients with advanced solid
tumors

Abstract #426

November 9, 2019

7:00 a.m. – 8:00 p.m. ET

Poster Presentation

Shadia Jalal, MD, Indiana
University School of Medicine

About DSP-7888 (ombipepimut-S*)
DSP-7888 is an investigational cancer vaccine containing two peptides that induce WT1-specific cytotoxic T lymphocytes (WT1-CTL) and helper T cells to attack WT1-expressing cancerous cells found in various types of hematologic and solid tumors. Researchers have identified that by adding helper T cell inducing peptides, improved outcomes may be achieved compared to a killer peptide treatment regimen alone.

DSP-7888 is currently being investigated in combination with bevacizumab in a phase 2 trial in patients with recurrent or progressive glioblastoma (NCT03149003) and in a phase 1/2 trial in combination with nivolumab or pembrolizumab in patients with advanced solid tumors (NCT03311334). DSP-7888 is currently being investigated in two monotherapy studies: a phase 1/2 trial in myelodysplastic syndrome (MDS) (NCT02436252) and a phase 1/2 trial in pediatric patients with relapsed or refractory high grade gliomas (NCT02750891). In 2017, the U.S. Food and Drug Administration granted Orphan Drug Designations for DSP-7888 in MDS and brain cancer.

*Adegramotide/nelatimotide is also assigned as the international nonproprietary name (INN).

About DSP-0509
DSP-0509 is an investigational synthetic toll-like receptor (TLR) 7 agonist. In preclinical models, DSP-0509 was shown to promote the cytokine induction and cytotoxic T lymphocyte activation mediated by agonistic effect of TLR 7 expressed in plasmacytoid dendritic cells. DSP-0509 is hypothesized to sustain the immune-mediated anticancer activity by induction of immune system memory cells and is currently being evaluated in a phase 1/2 clinical trial in patients with advanced solid tumors (NCT03416335).

On November 8, 2019 Aptevo Therapeutics Inc. (Nasdaq: APVO), a biotechnology company focused on developing novel immuno-oncology and hematology therapeutics and Alligator Bioscience (Nasdaq Stockholm: ATORX), a biotechnology company developing antibody-based pharmaceuticals for tumor-directed immunotherapy reported that new preclinical data for ALG.APV-527 are being presented at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 34th Annual Meeting at the National Harbor, Maryland, November 6-10, 2019.

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ALG.APV-527 is a novel immunotherapeutic candidate intended for the treatment of a variety of 5T4-positive solid tumors. It is designed to induce signaling through the co-stimulatory receptor 4-1BB (CD137), which is present on activated cytotoxic T cells and natural killer (NK) cells. Once activated, it is designed to promote potent and selective tumor-directed immune activation in the presence of the tumor associated antigen, 5T4, which is present on many different types of solid tumors.

The preclinical data presented at SITC (Free SITC Whitepaper) show that ALG.APV-527 selectively enhances T cell and NK cell responses in the presence of 5T4 in vitro and displays potent and sustained tumor suppression in vivo. The preclinical studies demonstrate that ALG.APV-527:

Enhances CD8+ T cell and NK function and proliferation preferentially over that of CD4+ T cells, upon 5T4-mediated crosslinking
In preliminary in vivo studies in a human 4-1BB knock in model, induces rejection of established murine bladder cancer cells expressing human 5T4 at doses of 20 µg in mice and induces anti-tumor immunological memory responses
Is well tolerated after repeated dosing in a GLP toxicology study above the expected human dose and displays an antibody-like half-life of up to 9.5 days
"We’re pleased that ALG.APV-527 continues to show promising preclinical results," said Jane Gross, Ph.D., Chief Scientific Officer for Aptevo. "The ability of ALG.APV-527 to induce potent anti-tumor T cell and NK cell activity suggests 4-1BB is an attractive target for designing new immuno-oncology therapeutics. Monospecific 4-1BB-directed antibodies have been challenged by dose-limiting liver toxicities. As a novel bispecific antibody ALG.APV-527 may circumvent these challenges and minimize systemic toxicity by stimulating 4-1BB function only when co-engaged with the tumor antigen, 5T4."

"The presented preclinical data strongly support a potent effect of ALG.APV-527 without compromising on safety. The data further strengthens our CTA package and we are eagerly looking forward to discuss this candidate with potential partners to take this exciting asset further into clinical development," commented Christina Furebring, Ph.D., Vice President Preclinical Development at Alligator.

The Alligator/Aptevo poster presentation, entitled "Potent Tumor-Directed T Cell Activation and Tumor Inhibition Induced by a 4-1BB x 5T4 ADAPTIR Bispecific Antibody" is being presented on Saturday, November 9, 2019 from 7:00 am – 8:30 pm ET.

About ALG.APV-527
ALG.APV-527 is a bispecific antibody (4-1BB x 5T4) intended for tumor-directed treatment of solid cancers. ALG.APV-527 was built using Aptevo’s ADAPTIR bispecific platform and combines binding domains sourced from the ALLIGATOR-GOLD human scFv library. The ALG.APV-527 bispecific antibody consists of two parts, one part activating tumor-specific T cells through the co-stimulatory receptor 4-1BB, the other part binding to the 5T4 protein displayed on the surface of tumor cells. This enables the immune-activating effect of ALG.APV-527 to be directed specifically to the tumor and not against normal tissue.

On November 8, 2019 Alpine Immune Sciences, Inc. (NASDAQ:ALPN), a leading clinical-stage immunotherapy company focused on developing innovative treatments for cancer, autoimmune/inflammatory, and other diseases, today presented new preclinical data on ALPN-202, a conditional CD28 costimulator and dual checkpoint inhibitor for the treatment of advanced malignancies, at The Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 34th Annual Meeting (Press release, Alpine Immune Sciences, NOV 8, 2019, View Source [SID1234550761]). ALPN-202 is Alpine’s lead oncology program and remains on track to initiate a first-in-human clinical trial by the first quarter of 2020.

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ALPN-202 is designed to improve upon the safety and efficacy of existing combination checkpoint and/or costimulation therapeutic strategies. One poster presents mechanistic data supporting that ALPN-202 inhibits both the PD-L1 and CTLA-4 checkpoint pathways while also providing PD-L1-dependent CD28 costimulation, as intentionally designed. A second poster demonstrates the ability of ALPN-202 to improve significantly upon the activity of existing cancer therapeutics when given alone and/or in combination in preclinical models. In addition, crystallographic study suggests that ALPN-202 binds PD-L1 and CD28 at distinct, non-overlapping epitopes enabling its potentially unique functionality:

P793. ALPN-202, a Conditional CD28 Costimulator and Dual Checkpoint Inhibitor, Utilizes Multiple Mechanisms to Elicit Potent Anti-Tumor Immunity Superior to Checkpoint Blockade

P467. ALPN-202, a Conditional CD28 Costimulator and Dual Checkpoint Inhibitor, Enhances the Activity of Multiple Standard of Care Modalities

Immune checkpoint inhibitors targeting the PD-1/PD-L1 and/or CTLA-4 pathways have demonstrated clinical activity in multiple cancers, but many patients still experience inadequate anti-tumor responses and/or relapse, which may be in part due to insufficient anti-tumor T cell activation and/or exhaustion. At the same time, combinations of checkpoint inhibitors and/or costimulatory agents can result in excessive immune-related toxicities. "ALPN-202 is engineered to address both of these issues by promoting T cell activity, but primarily only in a tumor-specific fashion, to produce specific, durable anti-tumor immune responses," said Stanford Peng, MD PhD, Alpine’s President and Head of Research and Development. "These data continue to encourage us regarding the potential for ALPN-202 as a new, first-in-class cancer immunotherapy. We continue to look forward to initiating our first clinical trial of ALPN-202."

The full poster presentations can be found at: View Source and View Source

About ALPN-202

ALPN-202 is a first-in-class, conditional CD28 costimulator and dual checkpoint inhibitor, which has the potential to improve upon the efficacy of combined checkpoint inhibition while limiting significant toxicities. Preclinical studies of ALPN-202 have successfully demonstrated superior efficacy in tumor models compared to checkpoint inhibition alone. We anticipate initiation of the first-in-human clinical study of ALPN-202 to begin by the first quarter of 2020.

On November 8, 2019 Zimmer Biomet Holdings, Inc. (NYSE and SIX: ZBH), a global leader in musculoskeletal healthcare, reported that it will participate in the Evercore ISI HealthCONx Conference at the Four Seasons Hotel in Boston (Press release, Zimmer Holdings, NOV 8, 2019, https://www.prnewswire.com/news-releases/zimmer-biomet-holdings-to-present-at-the-2nd-annual-evercore-isi-healthconx-conference-300954357.html [SID1234550777]). Suky Upadhyay, Executive Vice President and Chief Financial Officer and Cole Lannum, CFA, Senior Vice President Investor Relations, will present for the Company on Tuesday, December 3, 2019, at 1:15 p.m. Eastern Time.

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A live webcast of the presentation can be accessed via Zimmer Biomet’s Investor Relations website at https://investor.zimmerbiomet.com. The webcast will be archived for replay following the conference.