On December 7, 2021 ATP (Apple Tree Partners), a leader in life sciences venture capital, reported the launch of Adendra Therapeutics Ltd. ("Adendra"), a company that will discover and develop treatments for cancers and autoimmune diseases by applying new insights into regulation of adaptive immune responses by dendritic cells (Press release, ATP, DEC 7, 2021, View Source [SID1234596533]). Adendra is funded with a $53 (£40) million Series A investment from ATP and founded by ATP as a spin-out of breakthrough biology conducted at the Francis Crick Institute in London in the lab of immunologist Caetano Reis e Sousa, D.Phil., whose research on ways in which dendritic cells orchestrate immune responses to cell death has been published in leading scientific journals.

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Adendra’s proprietary technology is based on the work of Professor Caetano Reis e Sousa’s Immunobiology Laboratory at The Francis Crick Institute in collaboration with Raj Mehta, Ph.D., an Entrepreneur-in-Residence (EIR) at ATP who has previously founded and led companies including GammaDelta Therapeutics (recently acquired by Takeda) and Revitope Oncology. Adendra aims to design and develop novel immunotherapies focused on modulation of dendritic and other immune cells to augment immunological control of cancer or curtail T cell-driven autoimmunity.

"We are delighted to partner with Caetano and the Francis Crick Institute to form Adendra, to translate their pioneering work in dendritic cell biology into novel therapeutics," said Dr. Mehta, ATP EIR and Adendra co-founder and Chief Executive Officer. "Building on the leading scientific knowledge and expertise coming from Caetano’s lab and applying ATP’s capabilities in therapeutics development and life sciences strategy and operations, Adendra is uniquely positioned to improve the current treatment paradigm in cancer and other diseases."

"I am delighted to have the backing of ATP to enable the clinical translation of research in the field of innate immune recognition of dead cells and am excited about the prospect of offering meaningful clinical benefit to patients suffering from cancer or autoimmune diseases," said Professor Reis e Sousa, Adendra co-founder and Senior Group Leader and Assistant Research Director at the Francis Crick Institute.

Adendra will use proceeds from the financing to generate developmental candidates for new molecular and biological therapeutics against solid cancers and T cell-based autoimmune disorders. Beyond these areas of focus, Adendra welcomes approaches from potential research partners interested in accessing the company’s specialized capabilities and tools to address other urgent unmet medical needs.

"Adendra exemplifies ATP’s model of creating and building companies through ongoing partnership with leading scientific experts to develop first- and best-in-class therapies," said Seth Harrison, M.D., ATP founder and managing partner. "We are pleased to launch ATP’s first UK-based enterprise, we anticipate more transformational ventures emerging from our scientific collaborations in the UK and Europe, and we look forward to establishing Adendra at the forefront of the next leading wave of immune-oncology and immunotherapy companies."

In conjunction with the Series A, Professor Reis e Sousa and Drs. Mehta and Harrison have joined the Adendra Board of Directors, along with Raj Chopra, M.D., Ph.D., ATP’s Head of Oncology who is also a venture partner at the firm. Donna Hackett, Head of Commercial Translation at the Francis Crick Institute, is a Board Observer

On December 6, 2021 Bolt Biotherapeutics, Inc. (Nasdaq: BOLT), a clinical-stage biotechnology company pioneering a new class of immuno-oncology agents that combine the targeting precision of antibodies with the power of both the innate and adaptive immune systems, reported the presentation of interim clinical data from the company’s ongoing Phase 1/2 study of BDC-1001, the company’s lead immune-stimulating antibody conjugate (ISAC) in a poster session at the European Society for Medical Oncology Immuno-Oncology (ESMO I-O) Congress 2021, being held virtually from Dec. 6-11, 2021 (Press release, Bolt Biotherapeutics, DEC 6, 2021, View Source [SID1234618691]). The lead author for the poster is Manish Sharma, M.D., START Midwest, with contributions from Ecaterina Dumbrava, M.D., MD Anderson Cancer Center, and other colleagues from the U.S. and South Korea.

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The company reported data from 57 subjects participating in an ongoing Phase 1/2 study of BDC-1001, across 16 different types of HER2-expressing solid tumors. BDC-1001 demonstrated a favorable safety and tolerability profile at all evaluated doses and schedules, showing early signs of clinical activity with corresponding biomarker changes in the tumor microenvironment of post-treatment tumor biopsies. BDC-1001 is an immune-stimulating antibody conjugate (ISAC) comprising a HER2-targeting biosimilar of trastuzumab conjugated with a non-cleavable linker to an innovative TLR7/8 agonist.

"The favorable safety profile and early indications of clinical disease control in the BDC-1001 study are encouraging," said Dr. Sharma, Associate Director of Clinical Research at START Midwest. "There is a clear need for well tolerated, durable treatments in the fight against cancer and I’m excited to see if BDC-1001 can deliver on that potential as we explore higher drug exposure levels."

The poster presentation at ESMO (Free ESMO Whitepaper) I-O reported new safety, pharmacokinetic/pharmacodynamic, and efficacy results for the ongoing Phase 1 dose-escalation portion of the BDC-1001 monotherapy trial. Fifty-seven subjects have been treated at increasing dose levels up to 20 mg/kg every three weeks and 12 mg/kg every two weeks, and data from these subjects demonstrate that:

BDC-1001 continues to have a favorable safety and tolerability profile with mild (grade 1/grade 2) infusion related reactions in some patients and no dose-limiting toxicities at dose levels up to 20 mg/kg every three weeks and 12 mg/kg every two weeks. There was no indication of cytokine release syndrome (CRS), and a maximum tolerated dose (MTD) has not been reached.
Early signs of clinical activity are noted in 13 of 40 tumor evaluable subjects with one durable partial response maintained through 52 weeks and multiple subjects achieving stable disease for >12 weeks.
The pharmacokinetic (PK) data demonstrate increasing peak drug levels with increasing dose, and linearity of PK above the 5 mg/kg dose level. Clinical PK modeling predicts that target exposure levels can be achieved with weekly dosing.
Plasma and tissue biomarker results show increase in multiple biomarkers indicative of myeloid cell and TLR 7/8 activation that is consistent with BDC-1001’s mechanism of action. Increasing drug exposure correlates with increases in plasma cytokines and corresponding biomarker changes in the tumor microenvironment of multiple post-treatment tumor biopsies, with intriguing signs of clinical disease control.
These encouraging data point to the need for increased drug exposure to optimize clinical benefit. The favorable safety profile of BDC-1001 allows for continued enrollment in the dose escalation portion of the study, and the Company’s refined PK model based on data from more than 50 patients predicts that weekly administration will provide BDC-1001 exposures at or above the target exposure threshold. The data also support initiation of the combination therapy study with nivolumab (PD-1 inhibitor).

"Bolt Biotherapeutics is committed to agile clinical development based on data. In this Phase 1/2 study of BDC-1001, we have gained tremendous insight into the ability of this novel candidate to mobilize the patient’s immune system in targeting the tumor and its microenvironment. The increases in myeloid cell infiltration and repolarization of macrophages we’ve seen in multiple post-treatment biopsies are provocative and consistent with our proposed mechanism of action," said Edith Perez, M.D., Chief Medical Officer of Bolt Biotherapeutics. "We look forward to exploring weekly dosing as we get closer to determining the recommended Phase 2 dose for BDC-1001 as monotherapy, and to initiating combination therapy with a checkpoint inhibitor."

Presentation Details
Title: Preliminary results from a phase 1/2 study of BDC-1001, a novel HER2 targeting TLR7/8 immune-stimulating antibody conjugate (ISAC), in patients (pts) with advanced HER2-expressing solid tumors
Lead author: Manish R. Sharma, M.D.
Presentation Number: 164P
Timing: On-demand access beginning Dec. 6 at 12:00 p.m. CET.

The poster presentation will be available on the ESMO (Free ESMO Whitepaper) I-O conference website and on Bolt’s website.

Conference Call and Webcast Details

Bolt Biotherapeutics management will host a conference call for the investment community, in conjunction with the now virtual ESMO (Free ESMO Whitepaper) Immuno-Oncology Congress 2021, to discuss emerging clinical data and insights from the ongoing Phase 1/2 study today, Monday, December 6, 2021, at 8:00 a.m. ET/5 a.m. PT.

The conference call can be accessed by dialing +1 (833) 665-0609 within the U.S. or Canada or by dialing +1 (929) 517-0400 from international locations. The passcode for the call is 2633068. A live webcast, including slides, will be available on the Events & Presentations page of Bolt Biotherapeutic’s website at www.boltbio.com. An archived replay can be accessed for 30 days following the webcast.

About the Boltbody Immune-Stimulating Antibody Conjugate (ISAC) Platform
ISACs are a new category of immunotherapy that combines the precision of antibody targeting with the strength of the innate and adaptive immune systems. Boltbody ISACs comprise three primary components: a tumor-targeting antibody, a non-cleavable linker, and a proprietary immune stimulant to activate the patient’s innate immune system. By initially targeting a single marker on the surface of a patient’s tumor cells, an ISAC can create a new immune response by activating and recruiting myeloid cells. The activated myeloid cells start a feed-forward loop by releasing cytokines and chemokines, chemical signals that attract other immune cells and lower the activation threshold for an immune response. This reprograms the tumor microenvironment and invokes an adaptive immune response that targets the tumor, with the goal of durable responses for patients with cancer.

On December 6, 2022 Chimeric reported that it has entered into an exclusive option agreement to license the clinically validated, off the shelf, robust, enhanced natural killer (CORE-NK) cell platform from Case Western Reserve University for the treatment of cancer (Press release, Chimeric Therapeutics, DEC 6, 2021, View Source [SID1234598461]). The CORE-NK platform was designed to overcome the hurdles associated with NK cell development and enables the production of large numbers of highly active universal donor NK cells that are active in the body. The company expects to rapidly move to complete full licensing of the platform.

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Improving NK cells
NK cells are naturally found within the body and are able to recognise and kill cancer cells, but efficacy when used in a therapeutic setting is often limited due to challenges in manufacturing enough of them to halt the growth of many cancers. CORE-NK cells are made by activating and expanding NK cells to make them more active and robust in large numbers.

Enabling an expansion of the pipeline
Besides using CORE-NK cells to target cancer directly, this licensure would allow for the creation of CAR-NK programs to augment the current CLTX CAR T and CDH17 CAR T programmes that are focused on solid tumours. Four new pipeline programmes are expected to be started in 2023 following the anticipated acquisition of the CORE-NK platform. Positive low dose CHM 1101 data from Phase I Data from the low dose cohort of four patients from the Phase I trial of CHM 1101 (CLTX CAR T) was presented in November at the Society for Neuro-Oncology (SNO) annual meeting. Three out of four patients achieved stable disease that was durable for five to eight weeks. In one patient, there was no evidence of progression in the part of the brain in which CHM 1101 was infused intratumourally and progression was only seen in an area of the brain where it was not infused intertumourally. Valuation: A$322m or $0.97 per share We have adjusted our valuation from A$327m or A$0.99 per share to A$322m or A$0.97 per basic share, mainly due to lower net cash. Because the CORE-NK platform is not fully licensed and its associated products are not yet in the clinic, we are not including them in our valuation yet, in accordance with Edison methodology. Once included, they may have a meaningful impact upon the valuation due to the size of the markets targeted by the company.

Chimeric Therapeutics Development update Acquiring an exciting new NK cell technology Price A$0.27 Market cap A$90m A$1.40/US$ Net cash (A$m) at 30 June 2021 17.4 Shares in issue 333.4m Free float 39.2% Code CHM Primary exchange ASX Secondary exchange N/A Share price performance % 1m 3m 12m Abs (13.3) (24.6) N/A Rel (local) (11.4) (21.8) N/A 52-week high/low A$0.39 A$0.24 Business description Chimeric Therapeutics is an oncology-focused Australian-based company that recently went public on the ASX. The lead programme is CHM 1101, currently in Phase I for the treatment of GBM. Beyond GBM, the technology may have applicability for other tumours such as melanoma. The company recently in-licensed a CDH17 CAR T for use in solid tumours and the CORE-NK platform, which may have broad applicability in cancer. Next events Updated CHM 1101 data CY22 CHM 2101 Phase I initiation CY22 Analysts Maxim Jacobs +1 646 653 7027 Jyoti Prakash +91 981 880 393 [email protected] Edison profile page Pharma & biotech Chimeric Therapeutics is a research client of Edison Investment Research Limited Chimeric Therapeutics | 6 December 2021 2 The CORE-NK platform Chimeric has announced that it has entered into an exclusive option agreement to license the CORE-NK platform from Case Western Reserve University. NK cells are found in the body naturally and are able to recognise and kill cancer cells without affecting healthy cells. They are also able to produce cytokines that use the immune system to mount an additional response to kill tumours.

However, efficacy when used in a therapeutic setting is often limited due to challenges in manufacturing enough of them to halt the growth of many cancers. Through the platform, CORENK cells are made by activating and expanding NK cells to make them more active and robust in large numbers. 1 The company expects to rapidly move to complete full licensing of the platform. Financial terms are likely to include development milestones, industry standard royalties (likely single digit in our view) and an upfront payment. The anticipated licensure would enable a significant expansion of the product pipeline past CHM 1101 and CHM 2101, the CLTX and CDH17 CAR T therapies, respectively, currently in development.

The company plans to develop CAR NK versions of both those programmes, develop therapies using the current and next generation CORE-NK platform and an additional CAR NK with an undisclosed target. CAR NK products would be made by inserting CARs into the CORE-NK platform cells. Adding the CARs improves the delivery of the NK cells to specific antigen-expressing tumours. Exhibit 1: Planned Chimeric pipeline post-CORE-NK licensure Programme Construct Type Indication focus Status CHM 1101 CLTX CAR T Autologous Glioblastoma multiforme (GBM), melanoma, colorectal, prostate Phase I ongoing in GBM, second trial in another indication planned for 2022 CHM 2101 CDH17 CAR T Autologous Neuroendocrine, colorectal, pancreatic, gastric Phase I expected 2022 CHM 0201 CORE-NK Platform Allogeneic Both hematologic and solid tumours Phase I complete (9 patients completed all three dose levels with data expected in 2022), further technological enhancements planned for development as combination therapy CHM 0301 Next Generation CORE-NK platform Allogeneic Hematologic tumours Phase I planned 2023 CHM 1301 CLTX CAR-NK Allogeneic Glioblastoma multiforme (GBM), melanoma, colorectal, prostate Phase I planned 2023 CHM 2301 CDH17 CAR-NK Allogeneic Neuroendocrine, colorectal, pancreatic, gastric Phase I planned 2023 CHM 3301 Undisclosed CAR-NK Allogeneic Undisclosed Phase I planned 2023 Source: Chimeric Therapeutics As NK cells are not thought to cause graft-versus-host-disease (GVHD), all these CORE-NK based therapies have the potential to be allogeneic, where cells from a single donor could be used to treat multiple patients.

This is in contrast to autologous therapies where treatments are based on a patient’s own cells. Allogeneic therapies hold the promise of starting with healthier material, lowering manufacturing costs and being rapidly available to patients (the bespoke nature of autologous treatments can delay treatment for weeks). Besides these announced programmes, Chimeric will be seeking additional collaboration and licensing opportunities for the platform. CHM 1101 data from the low-dose cohort At the SNO conference in November, data from the CHM 1101 Phase I was presented. The data focused the four patients who were enrolled at the lowest dose level of 44m CLTX CAR T cells 1 Ojo et al., Membrane bound IL-21 based NK cell feeder cells drive robust expansion and metabolic activation of NK cells. Scientific Reports 2019 Oct 17;9(1):14916. Chimeric Therapeutics | 6 December 2021 3 (which were injected intratumourally in a single injection). Stable disease was achieved in three out of the four patients with durability of five to eight weeks. Importantly, in one patient, there was no observed tumour recurrence in the left frontal lobe where the CLTX CAR T cells were administered.

Tumour progression in that patient occurred in the left temporal lobe, which did not receive the infusion. Also, with regards to safety, therapy was generally well tolerated and there were no cytokine release syndrome (CRS) events due to therapy. Dose escalation is planned across four dose levels up to 440m cells through dual intratumoural and intraventricular routes of administration (intraventricular administration only starts at the 88m cell dose level). Valuation We have adjusted our valuation from A$327m or A$0.99 per share to A$322m or A$0.97 per basic share, mainly due to lower net cash. Because the CORE-NK platform is not fully licensed and its associated products are not yet in the clinic, we are not including them in our valuation yet, in accordance with Edison methodology. Once included, they may have a meaningful impact upon the valuation due to the size of the markets targeted by the companyFinancials In the quarterly cash flow report for the first quarter of FY22 (the period ending 30 September 2021), Chimeric reported A$17.4m in cash at Q122.

In FY21 the company had an operating loss of A$15.1m. We have not made any meaningful changes to our financial model following these results and have introduced FY23 estimates, which feature A$14.5m in operating expenses. We may increase our R&D expense estimates once we have more clarity on the clinical programme post the closure of the licensing of the CORE-NK platform. We continue to project a financing need of A$80m through 2026, with A$20m expected to be raised in FY22 and modelled as illustrative debt.

On December 6, 2021 Cancer Advances, Inc., a clinical stage biopharmaceutical company developing therapeutics for gastrointestinal cancers, reported a new publication in Frontiers in Oncology, section Gastrointestinal Cancers: Gastric & Esophageal Cancers (Press release, Cancer Advances, DEC 6, 2021, View Source [SID1234597367]).

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The gastrointestinal peptide gastrin has been shown to stimulate growth of gastric cancer through the cholecystokinin-B receptor (CCK-BR), a receptor that is expressed in at least 56.6% of human gastric cancers. The researchers evaluated the effects of PAS (Polyclonal Antibody Stimulator), a Phase 3 ready cancer vaccine that induces antibodies to gastrin, alone or in combination with a Programed Death-1 antibody (PD-1 Ab) in immune competent mice bearing YTN-16 gastric tumors.

Tumor growth was significantly slower than controls in PAS-treated mice, and tumor growth rate was decreased even more in combination-treated mice.
There were no metastases in any of the mice treated with PAS either alone or in combination with PD-1 Ab.
PAS monotherapy or combined with PD-1 Ab increased tumor CD8+ T-lymphocytes and decreased the number of immunosuppressive M2-polarized tumor-associated macrophages.
PAS monotherapy or combined with PD-1 Ab significantly decreased fibrosis in the tumor microenvironment.
These results show that the addition of PAS to therapy with an immune checkpoint antibody may decrease growth and metastases of gastric cancer by altering the tumor microenvironment and interrupting the autocrine pathway between gastrin and the CCKB receptor.

The study was conducted in collaboration with the manuscript’s lead author, Jill P. Smith, MD, professor of medicine and oncology at Georgetown University Medical Center, through a sponsored agreement with Cancer Advances, Inc. Cancer Advances plans to seek approval for PAS in the treatment of gastric and pancreatic cancers.

Link to publication:
https://www.frontiersin.org/articles/10.3389/fonc.2021.788875/full

On December 6, 2021 OBI Pharma, a Taiwan biopharma company (TPEx: 4174), reported that the first patient has been enrolled on the Phase 2 study of OBI-999 (Press release, OBI Pharma, DEC 6, 2021, View Source [SID1234596935]).

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OBI-999 is a novel antibody drug conjugate (ADC) cancer therapy targeting cancer with overexpression of Globo H. By releasing a small molecule chemotherapeutic drug through the specificity of the antibody, it directly deploys cytotoxic therapy at the targeted cancer cells. The Phase 2 study enrolls Globo H expressing patients with pancreatic, colorectal and other high Globo H expression solid tumors. The study will evaluate the safety and therapeutic activity of OBI-999.

OBI-999-001 study (ClinicalTrials.gov Identifier: NCT04084366) has been initiated in more than ten medical centers in the US and in Taiwan. OBI Pharma’s Chief Medical Officer, Tillman Pearce, M.D., noted, "this clinical trial enrolls late-stage cancer patients who lack effective therapeutic options. We look forward to validating OBI-999 as a safe and effective novel treatment for the cancer patients with high unmet medical needs."

Dr Pearce also noted, "the safety and tolerability of OBI-999 has been validated in the Phase I study. High potency across multiple xenograft models and the prescreening of a Globo H immunohistochemistry assay for selection of patients with high Globo H expression in the Phase II study support our enthusiasm for OBI-999."

Apostolia Tsimberidou, MD, PhD. noted, "The aberrant expression of the glycolipid Globo-H in epithelial tumors makes it an attractive target. We are excited to explore the ADC, OBI-999, that holds the promise to induce clinically meaningful responses."

OBI anticipates completing the enrollment of the Phase II study in the second half of 2023.

【About OBI-999】

OBI-999 is a novel first-in-class Antibody Drug Conjugate (ADC) with a proprietary linker technology that provides a consistent Drug-to-Antibody ratio (DAR) for cancer treatment that is based on Globo H, an antigen expressed in up to 15 epithelial cancers. OBI-999 uses a Globo H antibody to target cancer cells of high Globo H expression. By releasing a small molecule chemotherapeutic drug through the specificity of the antibody, it directly deploys cytotoxic therapy at the targeted cancer cells. OBI-999 is currently in a Phase 1/2 clinical trial (ClinicalTrials.gov Identifier: NCT04084366) to test its safety and efficacy as an oncology ADC therapy. In pre-clinical xenograft animal models in multiple tumor types (gastric, pancreatic, lung and breast), OBI-999 has demonstrated profound tumor shrinkage at various doses. In pre-clinical single and repeated dose toxicology studies, OBI-999 was well-tolerated, and achieved a favorable safety margin which warrants further clinical development. OBI Pharma owns global rights to OBI-999.