On April 10, 2021 Jounce Therapeutics, Inc. (NASDAQ: JNCE), a clinical-stage company focused on the discovery and development of novel cancer immunotherapies and predictive biomarkers, reported new preclinical data on JTX-8064, the first tumor-associated macrophage program from their Translational Science Platform, at the 2021 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting being held April 10-15, 2021 (Press release, Jounce Therapeutics, APR 10, 2021, View Source [SID1234577840]). The poster presentation includes data showing a high Leukocyte Immunoglobulin Like Receptor B2 (LILRB2) to interferon gamma (IFNγ) ratio is associated with resistance to PD-(L)1 inhibitor treatment in humans, JTX-8064’s ability to bridge innate and adaptive immunity, and how Jounce’s Translational Science Platform informed indication selection for the Phase 1 INNATE trial.

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"The translational analyses presented at AACR (Free AACR Whitepaper) link JTX-8064’s mechanism to tumor types that may respond better to LILRB2 inhibition," said Elizabeth Trehu, M.D., chief medical officer of Jounce Therapeutics. "The Phase 1 INNATE trial is designed to move as quickly as possible to proof of concept and this new data enabled the prioritization of tumor-specific expansion cohorts, which are on track to start enrolling in the second half of 2021. Furthermore, the negative prognostic implications of a high LILRB2 to IFNγ ratio support the role of LILRB2 in resistance to PD-(L)1 inhibitors and highlight the potential for JTX-8064 to reverse this resistance."

In a poster titled "Tumor associated macrophages and resistance to immune checkpoint blockade: Consideration of cancer indications for the clinical development of JTX-8064, an anti-LILRB2/ILT4 monoclonal antibody" Jounce demonstrated:

JTX-8064 can induce T cell activation in co-culture with macrophages, demonstrating its potential to bridge the gap between innate and adaptive immune responses;
CD163+ M2 macrophages co-localize with T cells in the tumor microenvironment, and patients with high levels of LILRB2 or a proprietary tumor-associated macrophage (TAM) signature score relative to an IFNγ signature score are less responsive to PD-(L)1 inhibitors, providing evidence that LILRB2+ macrophages may be involved in mechanisms of primary resistance to PD-(L)1 inhibitors; and
Expression profiles of LILRB2 mRNA, TAM signatures, and other inflammatory cell signatures were used to identify tumor types that may benefit most from JTX-8064 treatment and used to inform indication selection for expansion cohorts of the Phase 1 INNATE trial.
The poster is available on the "Our Pipeline" section of the Jounce Therapeutics website at www.jouncetx.com.

About JTX-8064

JTX-8064 is a humanized IgG4 monoclonal antibody designed to specifically bind to Leukocyte Immunoglobulin Like Receptor B2 (LILRB2/ILT4) and block interactions with its ligands. JTX-8064 is the first tumor-associated macrophage candidate developed from Jounce’s Translational Science Platform. Preclinical data presented at the 2020 Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s Annual Meeting and the 2019 and 2021 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meetings support the development of JTX-8064 as a novel immunotherapy to reprogram immune-suppressive macrophages and enhance anti-tumor immunity. A Phase 1 clinical trial named INNATE (NCT04669899), of JTX-8064 as a monotherapy and in combination with either JTX-4014, or pembrolizumab, is currently enrolling patients with advanced solid tumors.

On April 10, 2021 ImmunoGen Inc. (Nasdaq: IMGN), a leader in the expanding field of antibody-drug conjugates (ADCs) for the treatment of cancer, reported that a poster highlighting preclinical data for its novel ADAM9-targeting ADC, IMGC936, which is being investigated in multiple solid tumor types, is being presented at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting April 10-15, 2021 (Press release, ImmunoGen, APR 10, 2021, View Source [SID1234577856]).

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"ADAM9 is overexpressed in a wide range of solid tumors and minimally expressed on normal tissue, which makes it an ideal ADC target," said Eric Westin, MD, Vice President, Clinical Development and Translational Sciences at ImmunoGen. "IMGC936 showed compelling anti-tumor activity against multiple patient-derived xenograft models with clinically relevant levels of ADAM9 and was well-tolerated across all models tested. We continue to enroll patients in our Phase 1 dose-escalation study of IMGC936 in multiple tumor types and look forward to sharing initial data by the end of 2021 or early 2022."

POSTER PRESENTATION

Title: "IMGC936, an investigational ADAM9-targeting antibody-drug conjugate, is active against patient-derived ADAM9-expressing xenograft models"
Day/Time: Saturday, April 10, 2021 at 8:30 AM ET
Session Category: Immunology
Session Title: PO.IM02.10 – Therapeutic Antibodies, Including Engineered Antibodies
Abstract: 1841
Additional information can be found at www.aacr.org.

ABOUT IMGC936
IMGC936 is a first-in-class ADAM9-targeting antibody-drug conjugate (ADC) that is comprised of a humanized antibody engineered to include a YTE mutation for enhanced exposure through improved recycling, a tri-peptide cleavable linker stable in circulation, and a next-generation DM21 maytansinoid payload, which is more potent and hydrophobic, resulting in increased bystander activity.

ADAM9 is a cell surface protein that belongs to the ADAM (a disintegrin and metalloproteinase) family of proteases, which have been implicated in cytokine and growth factor shedding and cell migration. Dysregulation of ADAM9 has been involved in tumor progression and metastasis, as well as pathological neovascularization. ADAM9 is overexpressed in multiple solid tumor types (e.g., non-small cell lung, gastric, pancreatic, triple-negative breast, and colorectal cancers) and minimally expressed on normal tissue, making ADAM9 an attractive target for ADC development.

IMGC936 is being co-developed with MacroGenics and is currently in a Phase 1 study enrolling patients with solid tumors that express ADAM9.

On April 10, 2021 Jubilant Therapeutics Inc., a biopharmaceutical company advancing oral, small molecule modulators to address unmet medical needs in oncology and autoimmune diseases, reported that preclinical data from two programs evaluating the company’s PRMT5 inhibitor and PD-L1 inhibitor as anti-cancer agents, will be presented today in a poster session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2021 Annual Meeting taking place virtually from April 10-15, 2021 (Press release, Jubilant Therapeutics, APR 10, 2021, View Source [SID1234577872]).

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"We are excited to announce these important data from our PRMT5 and our PD-L1 programs that show efficacy and tolerability in preclinical models," said Syed Kazmi, President and Chief Executive Officer of Jubilant Therapeutics Inc. "Our oral PRMT5 inhibitor has good plasma and sustained brain exposure which results in strong target inhibition, tumor growth delay and survival advantage in both xenografts and orthotopic brain models. Our oral anti-PDL1 immunotherapeutics, with a shorter half-life, are an attractive alternative to current intravenous antibody therapies especially in the maintenance settings with potential to limit immune-mediated toxicities and side effects via innovative dosing approaches, while maintaining the class-based wide anti-tumor efficacy. We look forward to continuing our work on these programs as we see great potential for treating multiple cancers."

A link to the e-posters, listed below, is available through the AACR (Free AACR Whitepaper) website.

Title: Novel, small molecule PRMT5 inhibitors for treatment of cancer
Poster Number: 1128
Date and Time: April 10, 2021 at 8:30 a.m. Eastern Daylight Time (EDT)
Session Title: Epigenetic Targets
Presenter: Dhanalakshmi Sivanandhan, et al.

Title: Novel, small molecule inhibitors of PD-L1/PD-1 interaction
Poster Number: 1630
Date and Time: April 10, 2021 at 8:30 a.m. Eastern Daylight Time (EDT)
Session Title: Immune Checkpoints
Presenter: Dhanalakshmi Sivanandhan, et al.

PRMT5 over-expression, shown in several cancers including lymphoid, lung, breast, glioblastoma, gastric etc., is thought to be an important factor in its tumorigenicity due to its repressive function on tumor suppressor gene expression. Key highlights from an evaluation which examined the tumor growth inhibition of PRMT5 inhibitor JBI-778 in multiple cancer cell lines as well as glioblastoma, include the following:

JBI-778 is a potent PRMT5 inhibitor that is selective against other PRMTs;
JBI-778 shows potent anti-proliferative activity against a number of cancers;
This oral small molecule demonstrated anti-tumor efficacy in a Mantle Cell lymphoma model with an ED50 of < 10 mg/Kg and a complete tumor growth inhibition (97%) at a dose of 50mg/kg; and
JBI-778 exhibited sustained brain exposure and significant tumor growth inhibition in an orthotopic glioblastoma model, translating into substantial survival advantage.
JBI-778 is currently being evaluated for the treatment of multiple cancers and IND-enabling studies have commenced.

PD-L1 expression is an immune evasion mechanism exploited by many cancers, such as melanoma, non-small cell lung cancer and breast cancer, which permits cancer progression and metastasis. Key highlights from the PD-L1/PD-1 study which examined the ability of JBI-1527 to inhibit PD-L1 and restore T-cell proliferation and function, include the following:

JBI-1527 is a potent, selective inhibitor of PD-L1 which induces dimerization of the protein thereby alleviating PD-L1-induced suppression of T cell activation;
The inhibitor shows similar modulation of cytokines as Pembrolizumab in BioMAP assay and competes with anti-PD-L1 blocking antibody suggesting similar binding site on PD-L1; and
In CT-26 and MC38-hPD-L1 syngeneic models, the small molecule showed strong tumor growth inhibition comparable to anti-PD-L1 mAb/Atezolizumab, and was well tolerated.
Studies to further assess JBI-1527 and additional compounds are underway.

Jubilant Therapeutics Inc. is developing a pipeline of novel, differentiated therapeutic assets; for partnership opportunity inquiries please contact [email protected].

On April 10, 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 that an online oral presentation with live Q&A and a Trial in Progress poster presentation for lead agent BDC-1001 are being presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021 being held virtually from April 10-15th (Press release, Bolt Biotherapeutics, APR 10, 2021, View Source [SID1234618697]).

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The oral presentation explores immunosuppression mediated by various cells in the tumor microenvironment (TME), as well as the tumor-supportive nature of antigen presenting cells (APCs) in the TME in preclinical models. Reawakening these immunosuppressed APCs may result in a productive and durable anti-tumor immune response. Bolt is utilizing its Boltbody platform to create immune-stimulating antibody conjugates (ISACs), such as BDC-1001, that invoke this mechanism and provided complete tumor regression in preclinical tumor models.

"In murine models we have seen efficacy in a variety of tumors that are immunologically cold and well-established. Furthermore, consistent with our proposed mechanism of action for ISACs, we see evidence of increased myeloid and T cell infiltration in the tumor microenvironment mediated by BDC-1001 surrogate ISACs," said David Dornan, Ph.D., Chief Scientific Officer at Bolt Biotherapeutics. "We’re excited to share our rationale for selecting the linker-payload for BDC-1001 to optimize anti-tumor activity while minimizing the potential for the formation of anti-drug antibodies."

BDC-1001 is comprised of a tumor antigen-targeting monoclonal antibody (mAb), a trastuzumab biosimilar and an immune-stimulating agent (a TLR7/8 agonist) conjugated to each other with a non-cleavable linker. In a series of preclinical studies with BDC-1001, Bolt demonstrated the mechanism of action for their HER2-targeted ISAC. BDC-1001 surrogate was able to eliminate established, treatment-resistant tumors through the engagement of both innate and adaptive immunity. There were no adverse findings in toxicology studies of BDC-1001.

A Trial in Progress poster is also being presented by Manish R. Sharma, M.D. of START Midwest, a principal investigator in Bolt’s ongoing BDC-1001 Phase 1/2 trial. The poster details the design of the study: a four-part study with two dose-escalation parts and two dose-expansion parts. The study is evaluating BDC-1001 administered intravenously with or without an immune checkpoint inhibitor targeting PD-1 in up to 390 patients with HER2-expressing or HER2-amplified advanced or metastatic solid tumors. The dose escalation parts will evaluate sequential doses of BDC-1001 as a monotherapy or in combination with a PD-1 checkpoint inhibitor in a 3+3 design, with the ability to backfill up to an additional 12 patients in each dose cohort. The dose expansion parts will evaluate the recommended Phase 2 dose as monotherapy or in combination with a PD-1 checkpoint inhibitor in four cohorts of patients.

The primary objective of the dose escalation portion of the study is to assess safety as measured by the incidence of adverse events and serious adverse events; dose-limiting toxicities within the 3+3 design; and potential immune-related toxicities and determine the recommended phase 2 dose. Secondary objectives will evaluate pharmacokinetic parameters and pharmacodynamic biomarkers in tumor tissue and in peripheral blood associated with drug exposure. These exploratory studies will help reinforce the ISAC mechanism of action in humans and seek to identify biomarkers associated with BDC-1001 biological activity with or without an immune checkpoint inhibitor.

In January, Bolt presented a preliminary clinical update on the first 20 patients that showed early signs of clinical activity, including stable disease in several patients and a confirmed partial response by RECIST, and acceptable safety with all 20 patients completing their dose-limiting toxicity (DLT) evaluation period without DLTs or drug-related serious adverse events. Treatment-emergent adverse events deemed to be related to BDC-1001 have been mild or moderate in severity, including mild infusion-related reactions without interruption to dosing. Bolt expects to provide an update on the trial sometime in the second half of 2021.

About Bolt Biotherapeutics’ Immune Stimulating Antibody Conjugate (ISAC) Platform Technology
The Boltbody ISAC platform technology harnesses the ability of innate immune agonists to convert cold tumors into immunologically hot tumors, thereby illuminating tumors to the immune system and allowing them to be invaded by tumor killing cells. Boltbody ISACs have demonstrated the ability to eliminate tumors following systemic administration as monotherapy in preclinical models and have also led to the development of immunological memory, which is predicted to translate into more durable clinical responses for patients.

About the Ongoing BDC-1001 Phase 1/2 Study in Patients with HER2-Expressing Solid Tumors
The Phase 1/2, multi-center, open-label study is evaluating the safety, pharmacokinetics, pharmacodynamics and proof of mechanism of BDC-1001 in patients with HER2-expressing solid tumors. The first portion of the study includes a monotherapy dose-escalation phase in which cohorts of patients will receive ascending intravenous doses of BDC-1001 to determine the maximum tolerated dose and/or the recommended dose to advance into expansion cohorts and Phase 2 based on safety and tolerability. The second portion of the study is a dose expansion phase in which patients will receive BDC-1001 monotherapy to further evaluate the safety, tolerability and clinical antitumor activity of the recommended Phase 2 dose. Please refer to www.clinicaltrials.gov NCT04278144 for additional clinical trial information.

On April 10, 2021 Black Diamond Therapeutics, Inc. (Nasdaq: BDTX), a precision oncology medicine company pioneering the discovery and development of small molecule, MasterKey therapies, reported the presentation of preclinical data on BDTX-189 and BDTX-1535 at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (AACR) (Free AACR Whitepaper), taking place April 9-14, 2021 (Press release, Black Diamond Therapeutics, APR 10, 2021, View Source [SID1234584639]).

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"These preclinical data demonstrate achievement of a key goal of our pharmacokinetic (PK)/pharmacodynamic (PD) strategy for BDTX-189 with a preclinical PK/PD profile designed for rapid and sustained target inhibition with rapid clearance," said Elizabeth Buck, Ph.D., Executive Vice President, Discovery and Translational Sciences at Black Diamond Therapeutics. "We look forward to presenting preliminary clinical data, including detailed PK data, from the Phase 1 dose-escalation portion of the MasterKey-01 study in the first half of this year."

Dr. Buck continued: "Additionally, these data illustrate the MasterKey profile of BDTX-1535 as a brain-penetrant, epidermal growth factor receptor (EGFR) mutant selective inhibitor. BDTX-1535 has been shown to potently and selectively inhibit the family of EGFR variants implicated in glioblastoma multiforme (GBM), as well as Exon 18 mutations and the C797S mutations evident in non-small cell lung cancer (NSCLC). This breadth of coverage, coupled with a brain-penetrant PK profile, supports the potential to develop a novel and differentiated candidate for GBM and solid tumors expressing un-drugged EGFR mutations, including NSCLC."

The presentations describe the following data:

Preclinical PK BDTX-189 Data:

Black Diamond employed a novel physiologically based pharmacokinetic (PBPK) modeling strategy, accounting for compound-specific determinants of BDTX-189 metabolism and disposition, to prospectively predict the clinical PK profile and active dose range of BDTX-189.
Preclinical PBPK modeling indicated that BDTX-189 would be readily orally absorbed with a short elimination half-life (approximately two hours) while maintaining suppression of ErbB pathway biomarkers over the dosing interval, consistent with the irreversible mechanism of action and the desired PK/PD profile.
Active dose levels in humans were projected to be in the 400–800 mg QD range based on the exposure-tumor growth inhibition relationship in multiple mouse patient-derived xenograft (PDX) models harboring ErbB allosteric mutations.
Enrollment and dosing of patients in the Phase 1/2 MasterKey-01 study of BDTX-189 is ongoing, and the Company is on track to complete the dose-escalation portion of the Phase 1 clinical trial in the first half of 2021.
Preclinical BDTX-1535 Data:

GBM tumors express a family of allosteric oncogenic EGFR variants that often appear together in GBM and, as shown by the Company’s preclinical work, must all be effectively inhibited to secure a meaningful anti-tumor response. In cell-based assays, BDTX-1535 achieved potent and selective inhibition of all members of the family of oncogenic EGFR variants expressed in GBM.
BDTX-1535 demonstrated a favorable brain-penetrant PK profile in mouse, rat, and dog models.
Tumor growth inhibition in mouse models bearing intracranial GBM6 patient-derived tumors expressing allosteric EGFR mutants was achieved.
BDTX-1535 demonstrated potent and selective inhibition of rare Exon 18 mutations and the C797S mutation, supporting the potential for utility beyond GBM, such as in NSCLC.
Black Diamond expects to file an Investigational New Drug (IND) application for BDTX-1535 in the first half of 2022.
"Collectively, these data support the differentiated profiles of both BDTX-189 and BDTX-1535, the foundation of our ErbB franchise, and our ability to develop novel therapies for patients with genetically defined cancers," said David M. Epstein, Ph.D., President and Chief Executive Officer of Black Diamond Therapeutics.

The presentations from the AACR (Free AACR Whitepaper) meeting are available on the "Scientific Presentations and Publications" section of the Black Diamond Therapeutics website.

About BDTX-189
BDTX-189 is an orally available, irreversible small molecule inhibitor that is designed to block the function of family of oncogenic proteins defined by driver mutations across a range of tumor types, and which affect both of the epidermal growth factor receptor (EGFR) and the tyrosine-protein kinase, ErbB-2, or human epidermal growth factor receptor 2 (HER2). BDTX-189 is designed as a MasterKey inhibitor targeting a family of previously undrugged and functionally similar mutations in a tumor-agnostic manner. These mutations include extracellular domain allosteric mutations of HER2, as well as EGFR and HER2 kinase domain Exon 20 insertions, and additional activating oncogenic drivers of ErbB. The ErbB receptors are a group of receptor tyrosine kinases involved in key cellular functions, including cell growth and survival. BDTX-189 is also designed to spare normal, or wild-type, EGFR, which we believe has the potential to improve upon the toxicity profiles of current ErbB kinase inhibitors. Currently, there are no medicines approved by the U.S. Food and Drug Administration (FDA) to target all of these oncogenic mutations with a single therapy.

BDTX-189 is currently being evaluated in a Phase 1/2 clinical trial (MasterKey-01) in adult patients with advanced solid tumors with at least one MasterKey mutation who have no standard therapy available or for whom standard therapy is considered unsuitable or intolerable. In July 2020, the FDA granted Fast Track designation to BDTX-189 for the treatment of adult patients with solid tumors harboring an allosteric HER2 mutation or an EGFR or HER2 Exon 20 insertion mutation who have progressed following prior treatment and who have no satisfactory treatment options.