On November 3, 2023 Xencor, Inc. (NASDAQ: XNCR), a clinical-stage biopharmaceutical company developing engineered antibodies and cytokines for the treatment of cancer and autoimmune diseases, reported data from multiple preclinical-stage XmAb programs at the 38th Annual Meeting of the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) in San Diego (Press release, Xencor, NOV 3, 2023, View Source [SID1234636904]).

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"Xencor aims to stay on the leading edge of molecular engineering, using and improving upon our XmAb technologies to create molecules with enhanced functionality or new therapeutic mechanisms. At SITC (Free SITC Whitepaper), we are presenting new preclinical data from two research-stage programs—engineered, decoy-resistant IL18-Fc fusions and our multi-valent NK cell engagers targeted to MICA and MICB, which are tumor antigens upregulated in the tumor microenvironment," said John Desjarlais, Ph.D., executive vice president and chief scientific officer at Xencor. "Later this year, we expect to submit an investigational new drug application for XmAb541, an XmAb 2+1 format CLDN6 x CD3 bispecific antibody that we are developing for patients with ovarian cancer and other tumor types. We are also developing additional CD3 and CD28 T cell engaging bispecific antibodies against solid tumor targets."

Posters will be available in the poster hall and virtually to registrants of the SITC (Free SITC Whitepaper) Annual Meeting. In the poster hall, odd-numbered posters will be displayed on Friday, November 3, and even-numbered posters will be displayed on Saturday, November 4. Xencor’s posters will be archived under "Events & Presentations" in the Investors section of the Company’s website located at www.xencor.com.

Clinical Trials in Progress

Abstract 764, "A Phase 1, first-in-human (FIH), open-label, dose-finding and expansion study of XmAb808, a B7H3 x CD28 bispecific antibody, in combination with pembrolizumab in patients with advanced solid tumors"

Xencor is conducting a Phase 1 study of XmAb808 in patients with advanced solid tumors. XmAb808 is a tumor-selective, co-stimulatory XmAb 2+1 bispecific antibody designed to bind to the broadly expressed tumor antigen B7-H3 and selectively to the CD28 T-cell co-receptor only when bound to tumor cells, which was demonstrated in vitro. Strong potentiation of checkpoint and CD3 cytotoxic activity was also observed in vivo. XmAb808 is a wholly owned Xencor program.

The clinical trials in progress poster reviews the design of XmAb808 and the rationale of using CD28 bispecific antibodies to expand the utility of checkpoint blockade and CD3 T cell engagers. The poster also provides study objectives, key eligibility criteria and study schema.

Preclinical Programs

Abstract 1060, "Optimally engineered IL18-Fc fusion proteins balance potency and pharmacokinetics to promote strong anti-tumor activity"

IL-18 is a proinflammatory cytokine that modulates both the innate and adaptive immune responses. Preclinical studies of IL-18 have demonstrated its anti-tumor activity, including synergy with immune checkpoint inhibitors and CAR-T therapies. In contrast with other potent cytokines, IL-18 has been well tolerated in clinical trials but demonstrated a lack of efficacy despite heavy dosing. IL-18 induces a negative feedback loop with its high affinity natural inhibitor, IL18BP, which was upregulated in early phase clinical studies and may have limited IL-18’s clinical performance.

Xencor engineered stabilized, potency-modulated IL-18 cytokines fused to an XmAb heterodimeric Fc domain with Xtend Fc technology for longer half-life (IL18-Fc). In addition, Xencor engineered bispecific IL18-Fc cytokines targeted to PD-1, a checkpoint receptor on T cells. Importantly, these molecules were engineered to avoid binding IL18BP.

Xencor’s IL18-Fc fusions and PD1 x IL18-Fc bispecific inhibited tumor growth in a dose- and potency-dependent manner, outperforming a wild-type IL18-Fc fusion, in vivo. Further preclinical studies of the engineered IL18-Fc fusions demonstrated pharmacodynamic profiles similar to wild-type IL18-Fc. Notably, a set of surviving tumor-engrafted mice, which had previously received engineered IL18-Fc fusions, had no tumor growth upon rechallenge.

Abstract 1193, "Synergistic targeting of multiple activating pathways with Natural Killer cell Engagers"

Xencor’s XmAb natural killer cell engagers (NKEs) are multifunctional antibodies that target multiple activating receptors on the surface of NK cells and bind to tumor-associated antigens.

MICA and MICB (MICA/B) are stress-induced tumor antigens expressed in a range of cancers. MICA/B antigens are recognized by NKG2D, an activating receptor on NK and CD8+ T cells. While membrane-bound, MICA/B is immuno-stimulatory; however, the cleaved and soluble form, found in the tumor microenvironment, prevents NKG2D from recognizing tumor cells. Xencor engineered anti-MICA/B antibodies with enhanced effector function in order to block the cleavage of MICA/B antigens and promote NK cell engagement. These antibodies increased MICA/B membrane surface density and led to tumor cell killing with MICA/B binding to NKG2D on immune cells. To enhance the anti-tumor activity, Xencor engineered multi-specific NK cell-engaging antibodies that simultaneously target MICA/B antigens and an orthogonal activating receptor on NK cells, NKp46. These multi-specific NK cell-engaging antibodies demonstrated enhanced functional activity compared to the antibodies targeting only MICA/B.

On November 3, 2023 Werewolf Therapeutics, Inc. (the "Company" or "Werewolf") (Nasdaq: HOWL), an innovative biopharmaceutical company pioneering the development of conditionally activated therapeutics engineered to stimulate the body’s immune system for the treatment of cancer, reported preliminary first-in-human clinical data from initial monotherapy dose-escalation cohorts in the Company’s lead clinical program, WTX-124×2101 (Press release, Werewolf Therapeutics, NOV 3, 2023, View Source [SID1234636903]). This clinical program is an ongoing, multi-center Phase 1/1b clinical trial of WTX-124, Werewolf’s interleukin 2 (IL-2) INDUKINE molecule, in patients with advanced or metastatic solid tumors. The preliminary data will be presented today at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 38th Annual Meeting in San Diego, California.

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Study WTX-124×2101 is evaluating WTX-124 as a monotherapy and in combination with pembrolizumab in patients with immunotherapy sensitive advanced or metastatic solid tumors who have failed standard of care treatment, including checkpoint inhibitor therapy. The preliminary data include data collected as of October 18, 2023, from 16 heavily pretreated patients from the first four monotherapy dose escalation cohorts (1, 3, 6, 12 mg). The preliminary data established proof of mechanism for WTX-124 and proof of concept for Werewolf’s INDUKINE design.

"We are encouraged by these preliminary data demonstrating that WTX-124 was generally well tolerated while delivering a wild-type IL-2 to the tumor microenvironment and eliciting monotherapy biomarker and clinical activity including two patients with ongoing unconfirmed partial responses in the 12mg cohort," said Daniel J. Hicklin, Ph.D., President and Chief Executive Officer of Werewolf. "We look forward to sharing additional data to inform our recommended dose to proceed into monotherapy expansion arms in the first half of 2024."

The preliminary data include assessments of safety and tolerability, pharmacokinetics, relevant biomarkers and preliminary antitumor activity. Data as of the October 18, 2023, cutoff date are summarized as follows:

WTX-124 was generally well-tolerated at all doses tested up to and including 12 mg in the outpatient setting.
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All treatment-emergent adverse events (TEAEs) were Grade 1 or Grade 2, and arthralgias and fatigue were the most common TEAEs. Vascular leak syndrome was not observed, and there were no dose limiting toxicities, treatment-related serious adverse events (SAEs) or treatment-related study discontinuations.

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WTX-124 was delivered intravenously once every two weeks (Q2W).

WTX-124 showed expected pharmacokinetics with evidence of wide therapeutic index allowing for continued dose escalation.

WTX-124 demonstrated both translational biomarker activity and early evidence of monotherapy antitumor activity at 6 mg and 12 mg doses.

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CD8+ T and NK cell proliferation and activation in the tumor microenvironment and immune cell gene expression changes were seen at 6 mg and 12 mg dose levels.
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Among five patients treated at 12 mg, one patient achieved an unconfirmed partial response (uPR), one patient had a restaging scan that was consistent with a partial response as of November 1, 2023, and one other showed evidence of anti-tumor activity.

"IL-2 is a well-validated cytokine, but the challenges associated with administering high-dose IL-2 have limited its use. Next-generation approaches have not been successful to date in demonstrating monotherapy activity at well-tolerated doses," said Randi Isaacs, M.D., Chief Medical Officer of Werewolf. "Although still early in the trial, today’s presentation at SITC (Free SITC Whitepaper) of preliminary data from monotherapy dose escalation highlights WTX-124’s potential to deliver this important mechanism with limited toxicity and to provide another therapeutic option to cancer patients."

Dose escalation is ongoing in the monotherapy and combination therapy arms of the trial with additional data from monotherapy dose-escalation cohorts informing declaration of recommended dose for expansion (RDE) and opening of the monotherapy expansion arms expected in the first half of 2024.

In addition, five preclinical posters further supporting the INDUKINE hypothesis, WTX-124 properties, and other INDUKINE molecules are being presented at the meeting, including:

Title: PK/RO Modeling of WTX-124, a Tumor-Activated IL-2 Prodrug, Highlights the Potential for a Substantially Improved Therapeutic Index Compared to Other IL-2 Molecules (Abstract #1074)

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Plasma and tumor data from mice were used to perform pharmacodynamic and receptor occupancy modeling to predict IL-2 receptor occupancy on peripheral lymphocytes and tumor infiltrating lymphocytes (TILs) suggesting WTX-124 has a substantially improved, best-in-class therapeutic index as compared to other IL-2 molecules investigated, including a half-life extended non-alpha IL-2 and a non-alpha IL-2 tumor-activated prodrug.

Title: Optimal Antitumor Immunity Triggered by WTX-124, a Clinical Stage Conditionally Activated INDUKINETM Molecule that Releases Fully Potent IL-2 in the Tumor Microenvironment (Abstract #1058)
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WTX-124 generated robust anti-tumor activity in a MC38 tumor bearing mouse model and promoted the expansion and activation of tumor specific CD8+ T cells as compared to a variant Non-Alpha IL-2 containing INDUKINE molecule which failed to generate anti-tumor activity, to drive tumor specific CD8+ T cell expansion, or to activate tumor infiltrating immune cells even when dosed up to 28 times higher than the active dose of WTX-124. In addition, while both molecules protected tumor infiltrating CD8+ T cells from exhaustion, only treatment with WTX-124 was able to induce an effector phenotype in tumor specific CD8+ T cells and drive clustering of CD8+ T cells with CD103+ cross presenting dendritic cells within the tumor.

Title: Spatial Analysis of Tumor Infiltrating Lymphocyte Populations in Syngeneic Mouse Tumor Models After Treatment with IL-12 (mWTX-330) and IL-2 (WTX-124) INDUKINETM Molecules (Abstract #1059)
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Combination treatment with WTX-124 and alpha PD-1 generated robust anti-tumor activity in a CT26 model resulting in widespread tumor infiltration by CD8+ T cells driving immune activation in the tumor microenvironment. In addition, detection of structured and unstructured lymphoid aggregates, including the clustering of various adaptive and innate immune cells within the tumor microenvironment suggests a zone of cytotoxic cell education within the tumor microenvironment.

Title: The Combination of ACT and INDUKINETM Therapy Leads to Improved Antitumor Immunity in Solid Tumors (Abstract # 252)

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Systemic WTX-124 was shown to preferentially expand CD4 CAR T cells while WTX-330 expanded CD8 CAR T cells, demonstrating that the administration of INDUKINE proteins with adoptive cell therapy could reinvigorate donor cell function leading to improved immunity, engraftment and long-term responses in solid tumors.

Title: Development of WTX-712, a Conditionally Activated IL-21 INDUKINETM Molecule for the Treatment of Cancer (Abstract # 1075)

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WTX-712 was shown to be peripherally inactive in preclinical studies, releasing IL-21 selectively within the tumor microenvironment while driving CD8+ T cell polyfunctionality and promoting immune cell interactions. In addition, WTX-712 demonstrated enhanced activity when combined with immune checkpoint inhibitors, blocking PD-1/PD-L1 or CTLA-4 pathways, indicating further evaluation of WTX-712 is warranted.

The posters will be available on the ‘Scientific Resources’ section of Werewolf Therapeutics website at View Source

Conference Call Information:

Management will host a call to review the preliminary data today, November 3, at 8:30 AM ET. Details for the call can be found here and at View Source

On November 3, 2023 TG Therapeutics, Inc. (NASDAQ: TGTX) reported that Michael S. Weiss, the Company’s Chairman and Chief Executive Officer, reported that it will participate in the 5th Annual Guggenheim Inflammation, Neurology & Immunology (INI) Conference, being held at the JW Marriott Essex House, in New York City on November 6 -7, 2023 (Press release, TG Therapeutics, NOV 3, 2023, View Source [SID1234636902]). The fireside chat is scheduled to take place on Monday, November 6, 2023, at 3:10 PM ET.

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A live webcast of the fireside chat will be available on the Events page, located within the Investors & Media section, of the Company’s website at View Source

On November 3, 2023 Tallac Therapeutics, Inc., a privately held biopharmaceutical company harnessing the power of innate and adaptive immunity to fight cancer, reported the first presentation of TAC-001 Phase 1 clinical safety and efficacy data in solid tumor patients (Press release, Tallac Therapeutics, NOV 3, 2023, View Source [SID1234636901]). TAC-001 is an investigational, systemically delivered, TRAAC molecule comprised of a potent TLR9 Agonist conjugated to a CD22 antibody, designed to selectively activate B cells to drive an anti-tumor immune response.

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The findings presented in the TAC-001 poster "INCLINE-101: Preliminary Safety, Tolerability, Pharmacokinetics (PK), and Pharmacodynamics (PD) of TAC-001 (TLR9 Agonist Conjugated to a CD22 mAb) in Patients With Advanced or Metastatic Solid Tumors" demonstrate that single-agent TAC-001 (0.1 to 3 mg/kg) given systemically every 2 weeks is well tolerated, demonstrates pharmacodynamic activity consistent with its proposed MOA and resulted in preliminary clinical activity with patients achieving durable stable disease (≥6 months) and partial response per RECIST v1.1.

"These TAC-001 clinical data provide evidence that systemic administration of a TLR9 immune agonist targeting and activating B cells is generally well tolerated and induces immune activation consistent with preclinical studies. We also observed single-agent clinical benefit in late-stage metastatic cancer patients which supports the use of this novel agent for treating cancer," said Kevin N. Heller, M.D., Chief Medical Officer at Tallac Therapeutics. "The pharmacodynamic biomarker data collected from these patients is highly encouraging. We look forward to continuing TAC-001 monotherapy dose escalation and further evaluating activity in selected patient populations. We would like to thank the participants and their families for their participation in our study."

Additionally, the Company presented preclinical data in the poster titled "TAC-003, a TLR9 Agonist Antibody Conjugate for Targeted Immunotherapy of Nectin-4 Expressing Tumors" that demonstrate TAC-003 induces robust immune cell activation, leading to innate and adaptive immunity against Nectin-4 positive cancers and potent single-agent anti-tumor activity. TAC-003 single agent treatment results in durable curative responses in models with a range of low to high Nectin-4 expression, including anti-PD-1 refractory tumors, with improved efficacy compared to enfortumab vedotin. TAC-003 has completed pre-clinical testing, including exploratory toxicological studies in cynomolgus monkeys, and has been selected as the Company’s third clinical candidate.

"We are excited to see these initial clinical data with TAC-001, the first program from Tallac’s TRAAC platform," said Dr. Hong I. Wan, president, CEO and co-founder of Tallac Therapeutics. "As we advance the TAC-001 program, we are also progressing our pipeline of immunotherapy candidates. TAC-003 represents a differentiated asset with potential to address unmet medical needs in multiple cancer types."

TLR9 agonists are a class of immunotherapy that generate both innate and adaptive immune response, which may produce more robust and durable anti-cancer immunity to help overcome resistance to standard-of-care oncology treatments. TLR9 agonists have demonstrated clinical activity in melanoma patients when administered intratumorally. Tallac Therapeutic’s TRAAC platform is designed to deliver a potent and differentiated TLR9 agonist (T-CpG) for targeted immune activation via systemic administration.

About TAC-001 (CD22 TRAAC)
TAC-001 is a Toll-like Receptor Agonist Antibody Conjugate (TRAAC) comprised of a potent toll-like receptor 9 agonist (T-CpG) conjugated to an antibody against CD22, a receptor restricted to B cells, including tumor-infiltrating B cells. TAC-001 is designed to systemically deliver T-CpG to B cells by binding to CD22, leading to internalization of TAC-001, TLR9 signaling, B cell activation and a cascade of immune reactions. Preclinical studies demonstrate that the innate and adaptive immune responses triggered by TAC-001 lead to potent anti-tumor activity. TAC-001 is being developed for the treatment of solid tumors and is currently in a Phase 1/2 Study in cancer patients (NCT05399654)

About TAC-003 (Nectin-4 TRAAC)
TAC-003 is a Toll-like Receptor Agonist Antibody Conjugate (TRAAC) comprised of a T-CpG conjugated to a novel Nectin-4-targeting antibody for systemic administration and TME delivery of a potent TLR9 agonist. Nectin-4 is a cancer associated antigen over-expressed in many solid tumor types with limited expression in normal tissues. Additionally, Nectin-4 over-expression correlates with poor prognosis. Preclinical data demonstrate that TAC-003 triggers TLR9 signaling, induces myeloid and dendritic cell activation, phagocytosis, cytokine production and lymphocyte activation, resulting in potent single-agent anti-tumor efficacy.

On November 3, 2023 Sensei Biotherapeutics, Inc. (Nasdaq: SNSE), a clinical stage immuno-oncology company focused on the discovery and development of next-generation therapeutics for cancer patients, reported initial data from the monotherapy dose-escalation portion of its Phase 1/2 clinical trial for SNS-101, a conditionally active, human monoclonal antibody targeting the immune checkpoint VISTA (V-domain Ig suppressor of T cell activation) (Press release, Sensei Biotherapeutics, NOV 3, 2023, View Source [SID1234636900]). The data, to be presented in a late-breaker poster presentation at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 38th Annual Meeting, suggest a potential best-in-class safety and pharmacokinetic profile among VISTA blocking antibodies and the potential to overcome long-standing pharmacological challenges encountered by first generation approaches to blocking VISTA.

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"We are pleased to report favorable clinical data for SNS-101, a pioneering VISTA-blocking antibody that provides validation of our conditionally active approach. The data support that this highly innovative antibody is well tolerated across dose levels tested to date, shows linear, dose-dependent pharmacokinetics predicted preclinically to elicit immune-mediated anti-tumor activity, and a cytokine profile consistent with an absence of cytokine release syndrome," said John Celebi, President and Chief Executive Officer of Sensei Biotherapeutics. "Data from this clinical study to date provides important initial evidence that SNS-101 can provide clinically meaningful and mechanistic differentiation from first generation anti-VISTA approaches, as indicated by SNS-101 dose levels that are at least 10 times higher than the first clinical study of a competitor VISTA antibody that was prematurely halted due to cytokine release syndrome and poor pharmacokinetics. We believe this represents a foundational clinical achievement in the pursuit of a transformational VISTA-blocking antibody, and we look forward to building on this success with additional data readouts, including efficacy analysis, expected next year."

The multi-center Phase 1/2 clinical trial is a dose escalation study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of SNS-101 as both a monotherapy and in combination with Regeneron’s PD-1 inhibitor Libtayo (cemiplimab) in patients with advanced solid tumors.

Summary of reported data (as of the October 3, 2023 cutoff date):

A total of 13 patients were enrolled in the study.
In the monotherapy dose escalation arm, ten patients were enrolled across four dosing cohorts receiving SNS-101 treatment at 0.3, 1, 3, or 10 mg/kg.
In the combination arm, three patients were enrolled at the first dose level of 3.0 mg/kg of SNS-101 plus 350 mg of Libtayo (cemiplimab).
Safety, cytokine expression and pharmacokinetic data were presented for seven patients from the first three monotherapy cohorts, all of which have cleared the dose-limiting toxicity assessment period.
A total of 11 adverse events (including one serious adverse event not considered related to SNS-101) was reported in five patients, with no dose-limiting toxicities observed. Only one adverse event (Grade 2 dermatitis acneiform) was considered related to SNS-101.
There were no instances of cytokine release syndrome and no significant changes in key inflammatory cytokines over time, consistent with preclinical studies.
Pharmacokinetic data demonstrate dose-proportional exposure consistent with lack of target mediated drug disposition, no notable accumulation with repeat dosing, and linear elimination kinetics of SNS-101, in concordance with preclinical data.
"Too many patients remain underserved by existing immunotherapies. SNS-101 highlights the potential of targeting VISTA through an innovative concept, thoughtful approach and a well-executed study as Sensei has done," said Shiraj Sen, M.D., Ph.D., a medical oncologist at NEXT Oncology and investigator on the Phase 1/2 SNS-101 clinical trial. "I’m encouraged by the patient experience so far in the SNS-101 trial, including a potentially best-in-class safety profile and an every-three-week dosing schedule that helps alleviate the logistical burden imposed on patients by agents requiring more frequent administration due to their unfavorable PK profiles."

Sensei expects to report initial safety and pharmacokinetic combination data in Q1 2024, with topline monotherapy data in Q2 2024, and topline combination data in 2024.

Presentation at SITC (Free SITC Whitepaper):

Title: A phase 1/2 study of safety, tolerability and pharmacokinetics of SNS-101, a pH-sensitive anti-VISTA mAb, as monotherapy and in combination with cemiplimab in patients with advanced solid tumors
Presentation type: Poster (late breaking abstract)
Abstract Number: 1532
Date and time: Saturday, November 4, 2023, at 9 a.m. PT – 8:30 p.m. PT
Location: Exhibit Halls A and B1 – San Diego Convention Center
Lead authors: Shiraj Sen, M.D., Ph.D. and F. Donelson Smith, Ph.D.

A copy of the presentation materials will be added to the "Events & Presentations" section of the Company’s Investor Relations website at www.senseibio.com.