On March 7, 2022 Tollys, a biopharmaceutical company developing TL-532, the first anti-cancer immunotherapy based on a synthetic toll-like receptor 3 (TLR3) specific agonist, reported that it has entered into a sponsored research agreement with Gustave Roussy, the leading cancer center in Europe (Press release, Tollys, MAR 7, 2022, View Source [SID1234609589]).

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Professor Guido Kroemer’s team will evaluate the effects of TL-532 in the context of FPR1 deficiency using methods similar to those recently published in the original research article entitled ‘A TLR3 Ligand reestablishes chemotherapeutic responses in the context of FPR1 deficiency’. These studies were conducted with polyinosinic:polycytidylic acid (pIC), a research grade TLR3 agonist. In comparison with agonists of TLR 2, 4, 5, 6, 7, 8 and 9, only the TLR3 agonist pIC was able to restore deficient chemotherapeutic responses in mice lacking FPR1, suggesting a personalized strategy for compensating for the FPR1 defect with a TLR3 agonist.

TL-532 is developed by Tollys and is a specific TLR3 agonist with a defined 70 base pair sequence of double-stranded RNA (dsRNA), produced by chemical synthesis, which can meet today’s quality manufacturing standards for new molecular entities.

"We are very eager to show that TL-532 can restore deficient chemotherapeutic responses in the model of Prof Kroemer’s team, because FPR1 deficiency is a common genetic disorder and there is a good chance that, in the future, patients with FPR1 deficiency may derive critical benefits from a treatment with TL-532," said Vincent Charlon, CEO of Tollys.

About FPR1 Deficiency
For anthracycline-based chemotherapy to be immunogenic, dying cancer cells must release annexin A1 (ANXA1) that subsequently interacts with the pattern recognition receptor, formyl peptide receptor 1 (FPR1), on the surface of dendritic cells (DC). Approximately 30% of individuals bear loss-of-function alleles of FPR1, calling for strategies to ameliorate their anticancer immune response. Le Naour et al. (Cancer Discovery 2021;11:408-23), showed that immunotherapy with a ligand of Toll-like receptor-3, polyinosinic:polycytidylic acid (pIC), restores the deficient response to chemotherapy in tumors lacking ANXA1 developing in immunocompetent mice or those of normal cancers growing in FPR1-deficient mice. This effect was accompanied by improved DC-and T-lymphocyte–mediated anticancer immunity. Of note, carcinogen-induced breast cancers precociously developed in FPR1-deficient mice as compared with wild-type controls. A similar tendency for earlier cancer development was found in patients carrying the loss-of-function allele of FPR1. These findings have potential implications for the clinical management of FPR1-deficient patients.

About TL-532
TL-532 is the first synthetic specific TLR3 agonist with a proprietary defined doublestranded RNA sequence. As such, TL-532 has the potential to be the best-in-class and firstto-market TLR3 agonist. TL-532 was shown to have a triple mechanism of action inducing 1) death by apoptosis selective to cancer cells-not in normal cells-, leading to the in-situ release of tumor specific antigens, 2) activation of the myeloid dendritic cells of the immune system to mount a specific T-cell response against the tumor antigens and 3) a switch of the tumor microenvironment by producing cytokines and chemokines which are unfavorable to tumor development. The result is the immunogenic cell death of tumor cells, accompanied by an auto-vaccination preventing the recurrence of cancer.

On March 7, 2022 Chugai Pharmaceutical Co., Ltd. (TOKYO: 4519) and Nippon Shinyaku Co., Ltd. (TOKYO: 4516) reported that Chugai filed a regulatory application with the Ministry of Health, Labour and Welfare (MHLW), for approval of an anti-cancer agent/humanized anti-CD20 monoclonal antibody Gazyva Intravenous Infusion 1000 mg [generic name; obinutuzumab (genetical recombination)] for the treatment of chronic lymphocytic leukemia (CLL) (Press release, Chugai, MAR 7, 2022, View Source [SID1234609587]).

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"Ensuring safety during long-term treatment is increasingly important as the recent expansion in treatment options may lead to longer survival for patients with CLL. As a result, there is a growing unmet medical need for treatments that control disease and have an acceptable safety profile," said Chugai’s President and CEO, Dr. Osamu Okuda. "We are working towards approval of Gazyva so the drug can contribute to treatment as a new therapeutic option for CLL."

"We are very pleased that Gazyva was applied for marketing approval for a new indication in CLL," said Nippon Shinyaku’s President, Toru Nakai. "We believe that the addition of the CLL indication to Gazyva will help medical needs and further contribute to the treatment of patients in the field of hematologic malignancies, which is one of our focus field."

The filing is based on the results including Phase III ELEVATE-TN study (ACE-CL-007) conducted by AstraZeneca, evaluating the efficacy and safety of Gazyva and acalabrutinib (Bruton’s tyrosine kinase (BTK) inhibitor, brand name Calquence) in patients with untreated CLL.

About ELEVATE-TN study
ELEVATE-TN (ACE-CL-007, NCT02475681) study is a randomized, multicenter, open-label Phase III trial evaluating the safety and efficacy of acalabrutinib in combination with obinutuzumab or alone versus chlorambucil (unapproved) in combination with obinutuzumab in previously untreated patients with CLL. In the study, patients are randomized 1:1:1 to following groups;

Chlorambucil plus obinutuzumab
Acalabrutinib plus obinutuzumab
Acalabrutinib monotherapy
The primary endpoint is IRC-assessed progression-free survival (PFS) with acalabrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab. Secondary endpoint is IRC-assessed PFS with acalabrutinib monotherapy versus chlorambucil plus obinutuzumab. Other secondary endpoints are objective response rate, time to next treatment and overall survival etc 1).

About Gazyva (obinutuzumab)
Gazyva is a glycoengineered type II anti-CD20 monoclonal antibody designed to bind to CD20, a protein expressed on certain B cells, but not on stem cells or plasma cells. Gazyva is designed to attack and destroy targeted B cells both directly and together with the body’s immune system. Chugai and Nippon Shinyaku jointly develop and market the product in Japan.

About chronic lymphocytic leukemia (CLL)
Chronic lymphocytic leukemia (CLL) a rare type of lymphoma accounting for less than one case in 100,000 population annually 2). In CLL, blood stem cells in the bone marrow become excessive abnormal lymphocytes and these abnormal cells have difficulty fighting infections. As the number of abnormal cells grows there is less room for healthy white blood cells, red blood cells, and platelets. This could result in anemia, infection, and bleeding 3). B-cell receptor signaling through BTK is one of the essential growth pathways for CLL.

On March 7, 2022 Curis, Inc. (NASDAQ: CRIS), a biotechnology company focused on the development of innovative therapeutics for the treatment of cancer, reported that a manuscript has been published in the peer-reviewed journal Gastroenterology, authored by Curis collaborators at Washington University School of Medicine in St. Louis, on the role of IRAK4 in pancreatic ductal adenocarcinoma (PDAC) and the preclinical efficacy of emavusertib (CA-4948), a novel, small molecule IRAK4 inhibitor, in combination with checkpoint immunotherapy (Press release, Curis, MAR 7, 2022, View Source [SID1234609586]).

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"Through our emavusertib clinical trials, we have seen the potential of targeting IRAK4 in indications like non-Hodgkin’s lymphoma, acute myeloid leukemia and myelodysplastic syndromes," said James Dentzer, President and Chief Executive Officer of Curis. "Given the early, but compelling preclinical data outlined in Gastroenterology, IRAK4 targeting may have a broader application in treating solid tumors such as pancreatic cancer. We are thrilled to continue to identify new opportunities to potentially expand the development of emavusertib into additional cancer types as we work towards our goal of delivering novel, innovative cancer therapeutics in areas with significant unmet patient need."

The manuscript titled "IRAK4 signaling drives resistance to checkpoint immunotherapy in pancreatic ductal adenocarcinoma" concluded that tumor IRAK4 drives T-cell exhaustion in PDAC and is a promising therapeutic target when combined with checkpoint immunotherapy. Specifically, the experiments demonstrated that IRAK4 controls the NF-kB pathway and production of multiple checkpoint ligands, suppressive chemokines/cytokines, as well as hyaluronan synthase 2, all of which suppress T cell immune function against cancer. The study demonstrated that in a genetic mouse model that develops highly aggressive pancreatic cancer, IRAK4 can be targeted to overcome the immunosuppressive tumor microenvironment and drive response to checkpoint immunotherapy and validate the study of CA-4948 as a means to improve immunotherapeutic response in pancreatic cancer. The study team further confirmed this finding by generating a genetic mouse model in which the IRAK4 gene is deleted from the pancreatic cancer, providing firm evidence that IRAK4 is a promising therapeutic target in this deadly disease.

"Historically, the tumor microenvironment’s strong defense mechanisms have made cancers such as PDAC nearly impossible to treat effectively. Checkpoint immunotherapies, which have had a groundbreaking impact on other areas of oncology, are largely ineffective in PDAC," said Dr. Kian-Huat Lim, MD, PhD, Associate Professor of Medicine at Washington University School of Medicine, and Director of the GI Oncology Program. "Given the role of IRAK4 in NF-kB activation, we sought to explore whether there could be a translational benefit to targeting IRAK4 in PDAC. The results of our preclinical study show the promising effects of targeting IRAK4 in combination with chemotherapy and checkpoint immunotherapy, highlighting the potential of emavusertib to deliver effective therapeutic options to pancreatic cancer patients, who continue to have very limited therapeutic options."

The manuscript is available online at View Source(22)00201-3/pdf.

About Emavusertib (CA-4948)

Emavusertib is an IRAK4 kinase inhibitor and IRAK4 plays an essential role in the toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathways, which are frequently dysregulated in patients with AML and MDS. Third parties have recently discovered that the long form of IRAK4 (IRAK4-L) is oncogenic and preferentially expressed in over half of patients with AML and MDS. The overexpression of IRAK4-L is believed to be driven by a variety of factors, including specific spliceosome mutations such as SF3B1 and U2AF1.

On March 7, 2022 Lonza reported that it has expanded its renowned human stem cell offerings to provide human cord blood CD34+ hematopoietic stem cells (CB-CD34+ HSCs) in large batch sizes, meeting a critical and rapidly expanding market need (Press release, Lifescience Newswire, MAR 7, 2022, View Source [SID1234609585]). Lots in a range of sizes are also now available with high-resolution HLA-type information, removing the requirement for cumbersome HLA screening after lot purchase. CB-CD34+ HSCs are the preferred cell choice for creating humanized mouse models, which are critical for preclinical safety testing of a range of immunotherapies. The new offering enables mouse model developers and researchers to increase cohort sizes for bolstered model-creating capacity, simplify HLA-matched model creation, and unlock unprecedented cost and time efficiencies.

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Humanized mice are a powerful tool for exploring how novel cancer biotherapies interact with a human-specific immune system comprising different and interacting cell types. Across the market, there is a lack of large batch sizes of these cells, restricting the number of humanized mice that can be generated per cell lot. In addition, to maximize in vivo predictivity and accuracy of results, it is beneficial for mouse models to be carefully HLA matched to the grafted tumor tissue. Without ready-typed cells available, companies face lengthy in-house HLA screening that can add weeks to timelines, with no guarantee that an unscreened batch will contain the desired HLA type.

Now, leveraging its longstanding expertise and heavy investment in primary cell isolation, Lonza is able to offer a reliable and consistent supply of large-batch CB-CD34+ HSCs, as well as ready-typed cell lots in various sizes. As a result, customers can create larger mouse model cohorts of the exact HLA-type they need, expanding testing throughput capabilities and unlocking predictive results more quickly and at a significantly lower cost. The breadth of Lonza’s inventory will also allow researchers to obtain all their CB-CD34+ HSCs from a single supplier, ensuring consistency and reliable quality in their processes.

Aurita Menezes, Global Product Manager, Lonza, commented: "Isolating high-purity CD34+ stem cells from cord blood is incredibly complex, leaving most vendors unable to deliver the lot size and continuous supply required — even without HLA typing. Lonza’s technological know-how in this domain means it is leading the market with this new offering. Through this, we’re uniquely placed to accelerate routes to success for customers, further bolstering our ability to help deliver safe and affordable biotherapies to patients faster."

Lonza’s large cell lots are guaranteed to be >90% purity, contain ≥2 million viable cells in the lot, and come complete with a certificate of analysis. HLA-typed CB-CD34+ HSC lots are screened using gold-standard next-generation sequencing, providing higher-resolution HLA information that minimizes the risk of mismatches common with standard, low-resolution serological typing methods. Cell customers will also receive Lonza’s renowned global technical support, ensuring they can quickly overcome hurdles and achieve optimal outcomes in their mouse model creation.

Find out more about Lonza’s HLA-typed human cord blood CD34+ hematopoietic stem cells here: View Source

On March 7, 2022 AnaptysBio, Inc. (Nasdaq: ANAB), a clinical-stage biotechnology company developing first-in-class antibody product candidates focused on emerging immune control mechanisms applicable to inflammation and immuno-oncology indications, reported operating results for the fourth quarter and year ended December 31, 2021 and provided pipeline updates (Press release, AnaptysBio, MAR 7, 2022, View Source [SID1234609583]).

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"We advanced our wholly-owned antibody product pipeline and completed a $250 million royalty monetization transaction during 2021," said Hamza Suria, president and chief executive officer of AnaptysBio. "We look forward to multiple clinical data readouts during 2022 and remain focused on developing first-in-class therapeutic antibodies using a capital-efficient business model."
Imsidolimab (Anti-IL-36 Receptor) Program
•Following an end-of-Phase 2 meeting with the FDA, we initiated our GEMINI-1 Phase 3 trial of imsidolimab in generalized pustular psoriasis (GPP) where the primary endpoint is the proportion of patients achieving a score of clear (0) or almost clear (1) skin on the Generalized Pustular Psoriasis Physician’s Global Assessment (GPPPGA) at week 4 in 45 patients randomized against placebo. These same patients will subsequently be enrolled into GEMINI-2, which will assess 6 months of monthly subcutaneous dosing and safety follow-up.
•We anticipate top-line data from the ACORN Phase 2 trial of imsidolimab in moderate-to-severe acne in H1 2022 and from the HARP Phase 2 trial in moderate-to-severe hidradenitis suppurativa in H2 2022.
Rosnilimab (Anti-PD-1 Agonist) Program
•We announced positive top-line data from a randomized placebo-controlled healthy volunteer single and multiple ascending dose Phase 1 trial of rosnilimab, our investigational wholly-owned anti-PD-1 agonist therapeutic antibody, previously known as ANB030. Top-line data demonstrated favorable safety, pharmacokinetics and pharmacodynamic results, which supported initiation of our Phase 2 AZURE clinical trial of rosnilimab in alopecia areata.
ANB032 (Anti-BTLA Modulator) Program
•We are advancing ANB032, our wholly-owned BTLA modulator antibody, in a healthy volunteer Phase 1 single and multiple ascending dose clinical trial where top-line data is anticipated during the first half of 2022.

GSK Partnered Programs
•We completed a royalty monetization agreement with Sagard Healthcare Royalty Partners where AnaptysBio received a $250 million payment in exchange for JEMPERLI royalties due to AnaptysBio on annual commercial sales below $1 billion and certain future milestones starting October 2021. The aggregate JEMPERLI royalties and milestones to be received by Sagard under this Agreement is capped at certain fixed multiples of the upfront payment.
Fourth Quarter Financial Results
•Cash, cash equivalents and investments totaled $615.2 million as of December 31, 2021, compared to $411.2 million as of December 31, 2020, for an increase of $204.0 million. The increase relates primarily to cash received from the royalty monetization transaction with Sagard Healthcare Partners offset by cash used for operating activities.
•Collaboration revenue was $1.0 million and $63.2 million for the three and twelve months ended December 31, 2021. The $1.0 million earned during the fourth quarter primarily relates to royalty revenue earned for sales of JEMPERLI (dostarlimab) and Zejula by GSK, compared to $60.0 million and $75 million of milestone revenue for the three and twelve months ended December 31, 2020.
•Research and development expenses were $26.8 million and $98.5 million for the three and twelve months ended December 31, 2021, compared to $21.6 million and $80.0 million for the three and twelve months ended December 31, 2020. The increase was due primarily to continued advancement of the Company’s clinical programs.
•General and administrative expenses were $5.4 million and $21.5 million for the three and twelve months ended December 31, 2021, compared to $5.1 million and $18.9 million for the three and twelve months ended December 31, 2020. The increase was due primarily to personnel-related expenses, including share-based compensation.
•Net loss was $32.5 million and $57.8 million for the three and twelve months ended December 31, 2021, or a net loss per share of $1.18, and $2.11, compared to net income of $33.6 million for the three months ended December 31, 2020 or net income per share of $1.23 and a net loss of $19.9 million for the twelve months ended December 31, 2020, or net loss per share of $0.73.