On November 9, 2021 Obsidian Therapeutics, Inc., a biotechnology company pioneering engineered cell and gene therapies, reported that the Company will present preclinical in vivo anti-tumor efficacy against melanoma data for its cytoTIL15 program at the upcoming Annual Meeting of the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) (Press release, Obsidian Therapeutics, NOV 9, 2021, View Source [SID1234594862]). The event will be hosted live in Washington, D.C. and virtually from November 10-14, 2021.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The abstract for the poster demonstrates enhanced in vivo potency of Obsidian’s cytoTIL15 product (TIL engineered with membrane-bound IL15) over conventional tumor-infiltrating lymphocytes (TILs) in PDX mouse models. The translation of previously observed in vitro and in vivo persistence of cytoTIL15 TILs, in the absence of IL2, to superior in vivo anti-tumor efficacy in PDX models supports the potential for increased efficacy of cytoTIL15 therapy over conventional TIL therapy in solid tumor malignancies. The abstract is also published in the Annual Meeting Abstract Book, in the Journal for ImmunoTherapy of Cancer (JITC)supplement and in the Poster Hall of the Conference location.

Details of the poster presentation:

Title: Genetically engineered tumor-infiltrating lymphocytes (cytoTIL15) exhibit IL2-independent persistence and anti-tumor efficacy against melanoma in vivo

Abstract Number: 166

Category: Cellular Therapy

Abstract Summary:

Adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) has demonstrated tremendous promise in clinical trials for patients with solid tumors. However, current TIL therapy requires systemic administration of IL2 to promote TIL survival, and IL2-associated toxicities greatly limit patient eligibility and reduce the long-term clinical benefit of TIL therapy. Obsidian Therapeutics designed genetically engineered TILs to express a regulated form of membrane-bound IL15 for tunable long-term persistence, leading to enhanced persistence and efficacy in vitro and in PDX tumor models. cytoTIL15 TILs demonstrated enhanced potency over conventional TILs in vitro, and persisted without IL2 at greater frequencies compared to conventional TILs + IL2 in a 10-day antigen-independent in vitro assay. cytoTIL15 TILs adoptively transferred into naïve NSG mice demonstrated long-term persistence without antigen or exogenous IL-2, and importantly, cytoTIL15 TILs achieved significant tumor control in a human PDX model, which correlated with increased TIL accumulation in secondary lymphoid organs.

"We are pleased with the superior persistence, potency and anti-tumor activity of cytoTIL15 therapy in the absence of IL2," commented Jan ter Meulen, M.D., Ph.D., Chief Scientific Officer of Obsidian. "These results highlight the clinical potential of cytoTIL15 TILs as a novel TIL product with enhanced safety and efficacy for patients with solid tumors."

About OBX-115

OBX-115 is Obsidian’s lead cytoTIL15 program, currently in preclinical development for the treatment of patients with metastatic melanoma and other solid tumors. OBX-115 is a novel engineered tumor infiltrating lymphocyte therapy engineered with regulated membrane-bound IL15 that does not require patients to receive concomitant IL2 therapy, a toxic and costly requirement for conventional TILs. The Company expects to submit an IND for OBX-115 in mid-2022.

On November 9, 2021 Fate Therapeutics, Inc. (NASDAQ: FATE), a clinical-stage biopharmaceutical company dedicated to the development of programmed cellular immunotherapies for patients with cancer, reported that the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Communications Committee selected an abstract featuring preclinical data from the Company’s FT538 and FT573 programs for showcase at the SITC (Free SITC Whitepaper) 2021 Annual Meeting Press Conference (Press release, Fate Therapeutics, NOV 9, 2021, View Source [SID1234594878]). The selected abstract entitled "Off-the-shelf, engineered iPSC-derived NK cells mediate potent cytotoxic activity against primary glioblastoma cells and promote durable long-term survival in vivo" will be presented by Jeffrey S. Miller, M.D., Professor of Medicine, University of Minnesota and Deputy Director, Masonic Cancer Center. The press conference is being held on Wednesday, November 10 from 12:30-2 pm ET.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Dr. Miller’s presentation will describe the anti-tumor activity of the Company’s FT538 clinical product candidate as monotherapy and in combination with an NK cell engager targeting B7-H3, an immune checkpoint transmembrane protein overexpressed on many human cancer cells and commonly associated with poor prognosis. The presentation will also describe the integration of a novel chimeric antigen receptor (CAR) construct targeting B7-H3 into the master induced pluripotent stem cell (iPSC) line of FT538 to create the Company’s preclinical product candidate FT573, a B7-H3-targeted CAR NK cell incorporating multiple anti-tumor modalities.

In a recently published peer-reviewed article in Cell Stem Cell entitled "Harnessing features of adaptive NK cells to generate iPSC-derived NK cells for enhanced immunotherapy", FT538 was shown to share metabolic, transcriptional, and functional features with adaptive NK cells, a rare subset of NK cells with memory-like properties that have a genome-wide epigenetic profile and recall response that parallel cytotoxic effector CD8+ T cells. The published data demonstrate that FT538 exhibits significantly enhanced serial killing and functional persistence compared to peripheral blood NK cells. The superior anti-tumor activity of FT538 was attributable to its novel engineered components, including the knockout of CD38 and the expression of IL-15/IL-15R fusion protein, which were shown to improve metabolic fitness, increase resistance to oxidative stress, and induce a protein expression program that enhanced NK cell activation and effector function. The studies in the Cell Stem Cell publication were conducted as part of a collaboration between scientists at Fate Therapeutics and the laboratory of Dr. Miller, and were led by Frank Cichocki, Ph.D., University of Minnesota.

Investor Event Webcast and Conference Call

The Company will host a live audio webcast on Monday, November 15, 2021 at 4:30 p.m. ET to highlight its emerging pipeline of off-the-shelf, multiplexed-engineered, iPSC-derived NK cell programs for the treatment of solid tumors. In order to participate in the conference call, please dial (877) 303-6235 (domestic) or (631) 291-4837 (international) and refer to conference ID 2793475. The live webcast can be accessed under "Events & Presentations" in the Investors section of the Company’s website at www.fatetherapeutics.com. The archived webcast will be available on the Company’s website beginning approximately two hours after the event.

About Fate Therapeutics’ iPSC Product Platform
The Company’s proprietary induced pluripotent stem cell (iPSC) product platform enables mass production of off-the-shelf, engineered, homogeneous cell products that can be administered with multiple doses to deliver more effective pharmacologic activity, including in combination with other cancer treatments. Human iPSCs possess the unique dual properties of unlimited self-renewal and differentiation potential into all cell types of the body. The Company’s first-of-kind approach involves engineering human iPSCs in a one-time genetic modification event and selecting a single engineered iPSC for maintenance as a clonal master iPSC line. Analogous to master cell lines used to manufacture biopharmaceutical drug products such as monoclonal antibodies, clonal master iPSC lines are a renewable source for manufacturing cell therapy products which are well-defined and uniform in composition, can be mass produced at significant scale in a cost-effective manner, and can be delivered off-the-shelf for patient treatment. As a result, the Company’s platform is uniquely capable of overcoming numerous limitations associated with the production of cell therapies using patient- or donor-sourced cells, which is logistically complex and expensive and is subject to batch-to-batch and cell-to-cell variability that can affect clinical safety and efficacy. Fate Therapeutics’ iPSC product platform is supported by an intellectual property portfolio of over 350 issued patents and 150 pending patent applications.

About FT538
FT538 is an investigational, universal, off-the-shelf natural killer (NK) cell cancer immunotherapy derived from a clonal master induced pluripotent stem cell (iPSC) line engineered with three functional components: a novel high-affinity 158V, non-cleavable CD16 (hnCD16) Fc receptor, which has been modified to prevent its down-regulation and to enhance its binding to tumor-targeting antibodies; an IL-15 receptor fusion (IL-15RF) that augments NK cell activity; and the deletion of the CD38 gene (CD38KO), which promotes persistence and function in high oxidative stress environments. FT538 is designed to enhance innate immunity in cancer patients, where endogenous NK cells are typically diminished in both number and function due to prior treatment regimens and tumor suppressive mechanisms. In preclinical studies, FT538 has shown superior NK cell effector function, as compared to peripheral blood NK cells, with the potential to confer significant anti-tumor activity to patients through multiple mechanisms of action. FT538 is being investigated in a multi-dose Phase 1 clinical trial for the treatment of acute myeloid leukemia (AML) and in combination with daratumumab, a CD38-targeted monoclonal antibody therapy, for the treatment of multiple myeloma (NCT04614636). FT538 is also being investigated in a multi-dose Phase 1 clinical trial in combination with one of an array of tumor-targeting monoclonal antibodies for the treatment of advanced solid tumors (NCT05069935).

On November 9, 2021 FibroGen, Inc. (NASDAQ: FGEN) reported financial results for the third quarter 2021 and provided an update on the Company’s recent developments (Press release, FibroGen, NOV 9, 2021, View Source [SID1234594894]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"We and our partner Astellas are excited to be making Evrenzo available to patients in Europe," said Enrique Conterno, Chief Executive Officer, FibroGen. "In addition to continuously looking at opportunities to maximize the value of our portfolio of assets, following the complete response letter for roxadustat in the U.S., we are implementing a comprehensive plan which includes a cost reduction effort that will enable us to focus on our strategic priorities of development of pamrevlumab, roxadustat, and advancing our pipeline."

Recent Key Events and Other Developments

Regulatory:

The European Commission approved EVRENZO (roxadustat) for the treatment of adult patients with symptomatic anemia associated with chronic kidney disease (CKD). Astellas has launched in Germany, the United Kingdom, Netherlands, and Austria.
The U.S. Food and Drug Administration (FDA) issued a complete response letter regarding the New Drug Application (NDA) for roxadustat for the treatment of anemia of CKD.
Clinical:

Announced positive topline results from WHITNEY, the Company’s Phase 2 clinical study of roxadustat, for the treatment of chemotherapy-induced anemia (CIA). The results of the study will be presented at an upcoming medical meeting.
China:

Roxadustat net transfer price from sales to the distribution entity (JDE) jointly owned by FibroGen and AstraZeneca was $19.1 million for the third quarter. From the net transfer price, FibroGen defers a certain portion for revenue recognition purposes under US GAAP. FibroGen reported $13.4 million in roxadustat net product revenue for the quarter.
Total roxadustat net sales in China of $57.8 million by FibroGen and the distribution entity jointly owned by FibroGen and AstraZeneca, compared to $22.7 million in the third quarter of 2020.
Clinical Presentations / Publications:

FibroGen and its partners presented 15 presentations at the American Society of Nephrology (ASN) Kidney Week 2021 Virtual Conference.
One additional roxadustat Phase 3 manuscripts on the treatment of anemia of CKD was published in a peer-reviewed medical journal, bringing the total to 8:
Roxadustat for the Maintenance Treatment of Anemia in Patients with End-Stage Kidney Disease on Stable Dialysis: A European Phase 3, Randomized, Open-Label, Active-Controlled Study (PYRENEES) Advances in Therapy
Upcoming Data Milestones:

Topline data from the Phase 3 MATTERHORN study of roxadustat in anemia of myelodysplastic syndromes (MDS) expected 2H 2022 / 1H 2023.
Interim analysis of event free survival of Phase 3 LAPIS study of pamrevlumab in locally advanced pancreatic cancer (LAPC) expected in 2H 2022.
Topline data from the Phase 3 LELANTOS-1 study of pamrevlumab in non-ambulatory Duchenne muscular dystrophy (DMD) expected 1H 2023.
Topline data from the Phase 3 ZEPHYRUS-1 study of pamrevlumab in idiopathic pulmonary fibrosis (IPF) expected mid-2023.
Corporate

Appointed Juan Graham as Chief Financial Officer.
Implemented a plan to reduce our projected expenses by approximately $100 million per year, for each of the next 3 years.
Financial:

Total revenue for the third quarter of 2021 was $156.0 million, as compared to $44.0 million for the third quarter of 2020. To highlight, current quarter revenue includes $120 million of milestone payments from Astellas related to the EU approval of roxadustat.
Net income for the third quarter of 2021 was $49.8 million, or $0.54 net income per basic and diluted share, compared to a net income of $33.0 million, or $0.36 net income per basic and $0.35 per diluted share one year ago.
At September 30, FibroGen had $665.0 million in cash, cash equivalents, investments, and accounts receivable.
Based on our latest forecast, we estimate our 2021 ending balance of cash, cash equivalents, investments, and accounts receivable to be in the range of $580-610 million.
Conference Call and Webcast Details
FibroGen will host a conference call and webcast today, Tuesday, November 9, 2021, at 5:00 p.m. Eastern Time (2:00 p.m. Pacific Time) to discuss financial results and provide a business update. A live audio webcast of the call may be accessed in the investor section of the Company’s website, www.fibrogen.com. To participate in the conference call by telephone, please dial 1 (877) 658-9081 (U.S. and Canada) or 1 (602) 563-8732 (international), reference the FibroGen third quarter 2021 financial results conference call, and use confirmation number 1747879. A replay of the webcast will be available shortly after the call for a period of 7 days. To access the replay, please dial 1 (855) 859-2056 (domestic) or 1 (404) 537-3406 (international), and use passcode 1747879.

About Roxadustat
Roxadustat, an oral medication, is the first in a new class of medicines comprising HIF-PH inhibitors that promote erythropoiesis, or red blood cell production, through increased endogenous production of erythropoietin, improved iron absorption and mobilization, and downregulation of hepcidin. Roxadustat is also in clinical development for anemia of chronic kidney disease (CKD) and anemia associated with myelodysplastic syndromes (MDS), and for chemotherapy-induced anemia (CIA).

Roxadustat is approved in European Union (EU) member states, including the European Economic Area (EEA) countries, as well as in Japan, China, Chile, and South Korea for the treatment of anemia of CKD in adult patients on dialysis (DD) and not on dialysis (NDD). Several other licensing applications for roxadustat have been submitted by partners, Astellas and AstraZeneca to regulatory authorities across the globe, and are currently under review.

Astellas and FibroGen are collaborating on the development and commercialization of roxadustat for the potential treatment of anemia in territories including Japan, Europe, Turkey, Russia and the Commonwealth of Independent States, the Middle East, and South Africa. FibroGen and AstraZeneca are collaborating on the development and commercialization of roxadustat for the potential treatment of anemia in the U.S., China, other markets in the Americas, in Australia/New Zealand, and Southeast Asia.

About Pamrevlumab
Pamrevlumab is a first-in-class antibody developed by FibroGen that inhibits the activity of connective tissue growth factor (CTGF), an important biological mediator in fibrotic and proliferative disorders. Pamrevlumab is in Phase 3 clinical development for the treatment of idiopathic pulmonary fibrosis (IPF), locally advanced unresectable pancreatic cancer (LAPC), and Duchenne muscular dystrophy (DMD). For information about pamrevlumab studies currently recruiting patients, please visit www.clinicaltrials.gov.

On November 9, 2021 Aethlon Medical, Inc. (Nasdaq: AEMD), a company developing medical technology to treat cancer and life-threatening infectious diseases, reported financial results for its second quarter ended September 30, 2021 and provided an update on recent developments (Press release, Aethlon Medical, NOV 9, 2021, View Source [SID1234594910]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Company Updates

Aethlon Medical is continuing the research and clinical development of the Hemopurifier, our therapeutic blood filtration system that can bind and remove life-threatening viruses and harmful exosomes from blood. This action has potential applications in cancer, where cancer associated exosomes may promote immune suppression and metastasis, and in life-threatening infectious diseases, including removal of COVID-19 virus, associated variants, and related exosomes.

As disclosed in our last earnings release on August 9, 2021, the Aethlon Hemopurifier has demonstrated binding of SARS-CoV-2 spike protein and, as reported in a peer reviewed publication, the binding and removal from circulation of SARS-CoV-2 virus from a human patient. This is in addition to the Hemopurifier’s previously demonstrated binding of numerous pathogenic viruses. The new information about the Hemopurifier in COVID-19 has stimulated clinical researchers to express interest in joining our ongoing clinical trial investigating the Hemopurifier for the treatment of patients with SARS-CoV-2/COVID-19 infection. This trial is being conducted under the open Investigational Device Exemption (IDE) for the Hemopurifier in life threatening viral infections. The trial is designed to allow for up to 40 of these patients to be treated under an Early Feasibility Study protocol at up to 20 clinical sites in the U.S.

During the recent quarter, we entered into an agreement with PPD, Inc., a leading global contract research organization (CRO), to oversee our U.S. clinical studies investigating the Hemopurifier for critically ill COVID-19 patients.

Together with PPD, we continue to advance site readiness at Cooper Medical Center, Loma Linda Medical Center, University of California Davis, Virginia Commonwealth University Medical Center, LSU Health Shreveport, University of Miami Medical Center, and Thomas Jefferson Medical Center. Additionally, we obtained institutional research board approval and have entered into a clinical trial agreement with Stanford Hospital. We are in discussions to bring on board other key U.S. medical centers.

We also recently obtained ethics review board approval and entered into a clinical trial agreement with Medanta Medicity Hospital, a multi-specialty hospital in Delhi NCR, India, for a COVID-19 clinical trial at that location. On-site training is expected to take place in November 2021.

"The opportunity to help critically ill, ICU patients with COVID-19 continues in both the U.S. and India," said Steven LaRosa, M.D., Chief Medical Officer.

"In addition to our work with COVID-19, we remain very optimistic about the use of our Hemopurifier for the treatment of Head and Neck Cancer. We acknowledge that the enrollment of our Head and Neck Cancer trial has been delayed, primarily due to the COVID-19 pandemic. We are exploring additional avenues to investigate our Hemopurifier in patients with cancer," said Charles J. Fisher, Jr., M.D., CEO.

Financial Results for the Second Quarter Ended September 30, 2021

At September 30, 2021, Aethlon Medical had a cash balance of approximately $23.2 million.

Aethlon recorded approximately $115,000 of government contract revenue on its Phase 2 Melanoma Cancer Contract in the three months ended September 30, 2021. We also recorded approximately $17,000 of revenue related to our cost reimbursable subaward arrangement with the University of Pittsburgh in connection with an NIH contract entitled "Depleting Exosomes to Improve Responses to Immune Therapy in HNNCC." As a result, the Company recorded total government contract revenue of approximately $132,000 in the three months ended September 30, 2021. Aethlon did not record any government contract revenue in the three months ended September 30, 2020.

Consolidated operating expenses for the three months ended September 30, 2021 were approximately $2.1 million, compared to approximately $1.8 million for the three months ended September 30, 2020. This increase of approximately $300,000, or 20%, in the 2021 period was due to increases in payroll and related expenses of approximately $200,000 and in general and administrative expenses of approximately $100,000.

The $200,000 increase in payroll and related expenses was primarily due to the combination of a $101,000 increase in our research and development payroll as the result of hiring additional scientists and, a $100,000 increase in general and administrative payroll expense as the result of additional headcount.

The $100,000 increase in general and administrative expenses was primarily due to a $72,000 increase in our rent expense, a $54,000 increase in our amortization expense and a $46,000 increase in our insurance expenses, which were partially offset by a $57,000 decrease in our clinical trial expenses.

As a result of the changes in revenues and expenses noted above, the Company’s net loss before noncontrolling interests increased to approximately $2.0 million for the three months ended September 30, 2021, from approximately $1.8 million for the three months ended September 30, 2020.

The unaudited condensed consolidated balance sheet for September 30, 2021 and the unaudited condensed consolidated statements of operations for the three and six month periods ended September 30, 2021 and 2020 follow at the end of this release.

Conference Call

The Company will hold a conference call today, Tuesday, November 9, 2021 at 4:30 p.m. Eastern Time to review financial results and recent corporate developments. Following management’s formal remarks, there will be a question and answer session.

Interested parties can register for the conference by navigating to View Source

Please note that registered participants will receive their dial in number upon registration.

Interested parties without internet access or unable to pre-register may dial in by calling:
PARTICIPANT DIAL IN (TOLL FREE): 1-844-836-8741
PARTICIPANT INTERNATIONAL DIAL IN: 1-412-317-5442

All callers should ask for the Aethlon Medical, Inc. conference call.

A replay of the call will be available approximately one hour after the end of the call through December 9, 2021. The replay can be accessed via Aethlon Medical’s website or by dialing 1-877-344-7529 (domestic) or 1-412-317-0088 (international) or Canada Toll Free at 1-855-669-9658. The replay conference ID number is 10162862.

On November 9, 2021 HotSpot Therapeutics, Inc., a biotechnology company pioneering the discovery and development of first-in-class allosteric therapies targeting regulatory sites on proteins referred to as "natural hotspots," reported new data validating its Smart Allostery platform in the elucidation and preclinical evaluation of a novel allosteric inhibitor of the E3 ubiquitin ligase CBL-B (Press release, HotSpot Therapeutics, NOV 9, 2021, View Source [SID1234594926]). The data will be presented at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 36th Annual Meeting, which is being held from November 10-14, 2021.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"CBL-B’s role as a master negative regulator of T cells and NK cells makes it a very attractive target for cancer immunotherapy, but it has proven difficult to inhibit with traditional small molecules," said Geraldine Harriman, Ph.D., Co-Founder and Chief Scientific Officer at HotSpot Therapeutics. "We’re thrilled to share these new data showing that we can successfully inhibit CBL-B with a novel allosteric inhibitor identified through our Smart Allostery platform and promote T cell responses in vitro and in mice. To better treat patients, we need new mechanisms to enhance and sustain effective anti-tumor immunity and to address suboptimal responses. Our small molecule allosteric inhibitor of CBL-B may bring such benefit with the added advantage of convenient oral delivery."

CBL-B sits at a pivotal node in immune cell activation, and its inhibition holds the potential to address several key mechanisms where translational data supports a causative role in suboptimal response to current immunotherapies. Because inhibition of CBL-B lowers the threshold for T cell and NK cell activation, even in the absence of co-stimulatory signals, it may bring benefit to patients with low antigen levels (e.g., low TMB), low inflammation (e.g., low PDL-1) and/or sub-par co-stimulation (e.g., low CD28).

HotSpot’s Smart Allostery approach offers a diversity of advantages in delivering highly selective and differentiated orally bioavailable medicines against proteins that are undruggable or poorly druggable targets, including CBL-B. The platform utilizes a suite of computational algorithms powered by machine learning to uncover natural hotspots that control protein function, employs an array of specialized assays to identify hotspot binders and subsequently uses chemistry to selectively drug these sites with allosteric inhibitors.

SITC Presentation Overview:

Title: Identification of A Novel Allosteric Oral CBL-B Inhibitor that Augmented T Cell Response and Enhanced NK Cell Killing in vitro and in vivo
Authors: Jun Kuai, Yingzhi Bi, Yilin Qi, Deborah G Conrady, Rajiv G Govindaraj, Graham Hone, R. Aldrin Denny, Ken Carson, Geraldine Harriman, Fang Wang
Poster Number: 864
Session: Novel Single-Agent Immunotherapies

Summary of Poster

CBL-B is activated by tyrosine kinases and undergoes a large conformational change from closed inactive form to open active form.
Through the utilization of HotSpot’s proprietary Smart Allostery platform, including its AI-powered SpotFinder technology, a druggable phosphoregulatory pocket was identified in the inactive form of CBL-B.
HotSpot identified an inhibitor that binds to a regulatory hotspot on CBL-B, locking it in its inactive form, as confirmed by co-crystal structures.
This molecule prevents CBL-B phosphorylation, inhibits E3 ligase activity, promotes cytokine release, enhances T cell proliferation, and stimulates NK cell activation/killing.
In vivo, the molecule enhances T cells responses in anti-CD3 treated mice.