On November 7, 2024 Nektar Therapeutics (Nasdaq: NKTR) and collaborators at The University of Texas MD Anderson Cancer Center reported late-breaking results from a Phase 2 study evaluating NKTR-255 for the treatment of radiation induced lymphopenia after concurrent chemoradiation in locally advanced non-small cell lung cancer (NSCLC) patients at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 39th Annual Meeting (Press release, Nektar Therapeutics, NOV 7, 2024, View Source [SID1234647982]).

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NKTR-255 is a novel polymer-conjugated IL-15 agonist, designed to activate, proliferate and expand natural killer (NK) and CD8+ T-cells, as well as to promote the survival and expansion of memory CD8+ T cells. NKTR-255 is currently being evaluated in combination with cellular therapies and immune checkpoint inhibitors. Previous pre-clinical and clinical studies have shown that NKTR-255 can proliferate a range of immune cells and augment lymphocyte trafficking.1,2,3

The results from the preplanned interim analysis from the REStoring lymphoCytes Using NKTR-255 after chemoradiothErapy in solid tumors (RESCUE) trial suggest that NKTR-255 effectively reversed radiation induced lymphopenia in patients with locally advanced NSCLC receiving consolidation therapy with durvalumab. Interim pharmacodynamic data demonstrated statistically significant superiority of the eight-week absolute lymphocyte count (ALC) with NKTR-255 post chemoradiation and in combination with durvalumab versus non-contemporaneous control groups who received either chemoradiation alone or chemoradiation in combination with durvalumab.

"Radiation induced lymphopenia is common after chemoradiation therapy and is associated with worse overall survival in multiple solid tumors including lung cancer." said Steven H. Lin, MD, PhD, Professor of Radiation Oncology at MD Anderson. "These interim results showing that NKTR-255 can rapidly restore absolute lymphocyte counts post chemoradiation suggest that NKTR-255 has the potential to confer prognostic benefits and enhanced survival in patients with locally advanced NSCLC."

"These results, combined with the body of evidence previously reported with NKTR-255 in combination with cell therapy, highlight NKTR-255’s potential to enhance clinical benefit in both hematologic malignancies and solid tumors" said Mary Tagliaferri, MD, Senior Vice President and Chief Medical Officer at Nektar.

The Phase 2 single-arm study conducted by MD Anderson is evaluating NKTR-255 (3µg/kg IV) following concurrent chemoradiation and in combination with consolidation therapy with durvalumab. NKTR-255 3µg/kg is administered intravenously every 4 weeks in combination with durvalumab (1500mg IV) for up to 1 year (NCT05632809). The primary objectives of the study are safety and ALC normalization at Week 8 after initiation of NKTR-255 and durvalumab post chemoradiation. Secondary endpoints include progression-free survival and overall survival. The trial is currently ongoing at MD Anderson.

Key details and takeaways from the presentation are as follows:

Late-breaking Abstract (LBA) 1489: " REStoring lymphoCytes Using NKTR-255 after chemoradiothErapy in solid tumors (RESCUE): Preplanned Interim Safety and Efficacy Analysis", Lin, S., et al.

The combination of NKTR-255 and durvalumab post chemoradiation was shown to be safe and tolerable with an AE profile consistent with previously reported clinical trials.
Interim pharmacodynamic data demonstrated statistically significant superiority of the eight-week absolute lymphocyte count with NKTR-255 post chemoradiation and in combination with durvalumab versus non-contemporaneous control groups who received either chemoradiation alone or chemoradiation in combination with durvalumab. Additional pharmacodynamic findings following NKTR-255 administration show increased markers of NK cell proliferation and activation.
About NKTR-255

NKTR-255 is a biologic that targets the IL-15 pathway in order to activate the body’s innate and adaptive immunity. Through optimal engagement of the IL-15 receptor complex, NKTR-255 is designed to enhance functional NK cell populations and formation of long-term immunological memory to improve the anti-tumor immune response.

In addition to studies in combination with CAR T cell therapies, NKTR-255 is being studied in a Phase 1 clinical trial sponsored by AbelZeta which is evaluating C-TIL051, a tumor-infiltrating lymphocyte therapy, in anti-PD1 resistant metastatic non-small cell lung cancer (NCT05676749). The JAVELIN Bladder Medley study (NCT05327530), sponsored by Merck KGaA, is also ongoing to evaluate NKTR-255 in combination with avelumab as a maintenance treatment in patients with locally advanced or metastatic urothelial carcinoma (NCT05327530).

On November 7, 2024 Dragonfly Therapeutics, Inc., a clinical-stage biotechnology company developing novel immunotherapies, reported the company will deliver poster presentations at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Conference, highlighting preclinical data supporting two clinical-stage assets, DF6215, its engineered IL-2 cytokine, and DF9001, its EGFR-targeting TriNKET, for the treatment of advanced solid tumors (Press release, Dragonfly Therapeutics, NOV 7, 2024, View Source [SID1234647981]).

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Data show that Dragonfly’s DF6215 IL-2 cytokine drives greater therapeutic benefit in vivo than non-alpha IL-2, with no evidence of capillary leak syndrome or cytokine release syndrome . In addition, DF6215 synergizes with PD-1 blockade cancer treatment in the "cold" B16F10 melanoma tumor model, without adding toxicity. "DF6215 is a differentiated IL-2, specifically tuned to potently stimulate anti-tumor CD8 T cells and NK cells without incurring counterproductive Treg expansion or VLS," said Ann Cheung, Chief Scientific Officer of Dragonfly Therapeutics.

Dragonfly’s DF9001 EGFR-targeting TriNKET drives efficacy via both EGFR-signal inhibition and immune-mediated mechanisms. Data show superior anti-tumor activity via EGFR signal inhibition compared to cetuximab in a xenograft mice model, and that DF9001 induces potent in vivo efficacy via immune effector cells, even in cancer models not dependent on EGFR signaling. DF9001 was well-tolerated at ≤50 mg/kg/week in a 4-week GLP study in cynomolgus monkeys. "DF9001 is the only EGFR-targeting agent that allows engagement of both innate and adaptive immune effectors," remarked Cheung, "and does so with a favorable safety profile."

SITC is being held November 6-10, 2024 in Houston, Texas, USA. Dragonfly’s poster presentations will take place on Saturday, Nov. 9, Lunch (12:15–1:45 pm), and Poster Reception (7–8:30 pm) in the George R. Brown Convention Center – Level 1 – Exhibit Halls AB.

Abstract Number 962: A novel alpha-active IL-2-Fc has expanded therapeutic index and robust monotherapy efficacy in mouse cancer models and strong synergy with PD-1 blockade. The full DF6215 poster is linked here
Abstract Number 1060: DF9001, an EGFR Targeted Immune Engager, Stimulates Innate and Adaptive Anti-Tumor Immunity with a Distinctive Safety Profile."
The full DF9001 poster is linked here
About DF6215
DF6215 is a modified, monovalent, half-life extended recombinant human IL-2 that biases toward activation of anti-tumor T and NK cells in order to improve upon the benefit-to-risk ratio of historic IL-2 drugs.

DF6215 was found to:

Increase proliferation of immune cells and preferentially expand anti-tumor effector cells compared to non-alpha IL-2 molecules (maximizing the anti-tumor effector:Treg ratio)
Increase granzyme B expression in tumor-infiltrating CD8+ T cells and NK cells
Demonstrate effective therapeutic efficacy in mouse cancer models as a single agent as well as in combination with immune checkpoint blockade
Preferentially expand activated CD8+ T cells in NHP without evidence of capillary leak syndrome or cytokine release syndrome
DF6215 is the second in a pipeline of cytokines that Dragonfly is developing to address unmet need in patients with advanced cancer and other diseases. Dragonfly’s DF6215 Phase 1/1b clinical trial is a first-in-human, multi-part, open-label study to investigate the safety, tolerability, pharmacokinetics, biological, and clinical activity of DF6215 in patients with advanced (unresectable, recurrent, or metastatic) solid tumors (NCT06108479).

About DF9001
DF9001 is an investigational first-in-class multi-specific drug candidate that targets and inhibits EGFR and potently redirects natural killer (NK) cells, gamma-delta T cells, and CD8 T cells by engaging activating receptors NKG2D and CD16.

DF9001 disrupts tumor growth by inhibiting EGFR signaling and promoting anti-tumor immunity. It has been optimized for engagement of immune cell populations that lead to the direct killing of tumor cells, while sparing healthy tissues, as well as the production of chemokines and cytokines that recruit additional effector cells to kill tumor cells. These characteristics make DF9001 a promising therapeutic agent against EGFR+ cancers, particularly those for which EGFR signal inhibition alone is ineffective.

DF9001 was discovered and developed using Dragonfly’s TriNKET platform. DF9001 is being evaluated in adult patients for the treatment of advanced solid EGFR-positive tumors (NCT05597839). DF9001 has the potential to stimulate anti-tumor immunity in patients who are not eligible or not adequately responding to current therapies. It is the second wholly owned drug candidate in a pipeline of TriNKETs Dragonfly is developing to address high unmet needs for patients across a broad range of disease areas.

On November 7, 2024 HotSpot Therapeutics, Inc., a biotechnology company pioneering the discovery and development of oral, small molecule allosteric therapies targeting regulatory sites on proteins referred to as "natural hotspots," reported it will present additional Phase 1 clinical biomarker data for HST-1011, an investigational oral, selective inhibitor of Casitas B-lineage lymphoma proto-oncogene (CBL-B), in a poster presentation at the 2024 Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting (Press release, HotSpot Therapeutics, NOV 7, 2024, View Source [SID1234647980]).

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"These biomarker data emerging from our Phase 1 clinical study of HST-1011 provide strong support for the biological activity and therapeutic potential of CBL-B inhibition, with HST-1011 treatment yielding an increase in immune activation as assessed through both peripheral blood and tumor gene expression," said Alison O’Neill, M.D., Chief Medical Officer of HotSpot Therapeutics. "Moreover, while the data are preliminary and in a small number of patients, baseline immune signature analyses suggest the potential for the prediction of clinical response. Collectively, the insights derived from these data support the further interrogation of biomarkers as HST-1011 advances through future clinical development."

The presentation describes additional clinical biomarker data from the ongoing Phase 1 monotherapy dose-escalation study of HST-1011:

An HST-1011-derived gene response signature showed a consistent dose-dependent increase in patient peripheral blood, with patients who demonstrated clinical benefit showing a higher expression of the signature in on-treatment biopsies.
Preliminary T- and B-cell receptor next-generation sequencing data showed HST-1011 impacted both immune cell populations, with changes observed in several metrics associated with clinical benefit.
At baseline, patients who benefitted from HST-1011 treatment showed higher tumor-infiltrating lymphocyte expression and a higher immune signature score, suggesting a potential for prediction of clinical benefit.

On November 7, 2024 InxMed Co., Ltd, a clinical-stage biotechnology company developing innovative therapies against tumor-treatment resistance and metastasis, reported preclinical data at 15th Annual World ADC Conference in San Diego regarding ifebemtinib (ifebe, IN10018), a highly potent and selective oral inhibitor of focal adhesion kinase (FAK), to enhance efficacy and improve safety of ADCs, and IN30758, a First-in-class ADC for treatment of multiple solid tumors including DXD resistant cancers (Press release, InxMed, NOV 7, 2024, View Source [SID1234647979]).

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The efficacy of tumor targeting ADC is limited by its exposure-related toxicity. Cancer associated fibroblasts (CAFs) surrounding tumor cells serve as a barrier for ADC access and limit its efficacy. Preclinical data demonstrated that ifebemtinib was able to reduce the fibrotic barrier, enhance the penetration of ADC, and boost efficacy.

Interstitial pneumonitis is a commonly reported dose limiting toxicity, potentially deadly side effect in some ADCs like Enhertu with a black box warning. Activation of FAK was observed in patients with interstitial pneumonitis, similarly to Enhertu induced interstitial pneumonitis in mice. InxMed demonstrated ifebemtinib is effective in preventing/treating Enhertu-induced interstitial pneumonitis in animal models.

"By increasing ADCs local exposure and reducing interstitial pneumonitis, ifebemtinib has the potential to significantly improve the therapeutic window. Clinical trials with robust design will be implemented to translate these exciting preclinical findings. Ifebemtinib could become an ideal combo partner for ADCs, leading to revolutionary advancements in cancer therapy." Said Dr. Zaiqi Wang, founder and Chief Executive Officer of InxMed.

IND for Ifebemtinib in combination with ADC will be submitted to China CDE in Nov 2024. InxMed is establishing collaborations with a number of ADC companies.

InxMed also presented preclinical data of IN30758. IN30758 is a First-in-class ADC for treatment of multiple solid tumors including DXD resistant cancers. The ADC targets a member of the integrin family that is overexpressed in vast majority of most solid tumors. Preclinically, IN30758 exhibits robust in vivo efficacy in CDX and PDX models of multiple cancers and well tolerated in cynomolgus monkeys. IN30758 will be ready for IND submission in 2025.

About Ifebemtinib

Ifebemtinib is a highly selective, orally administered, small molecule inhibitor for focal adhesion kinase, which has significant synergies with a broad spectrum of therapeutic modalities. Clinically, ifebemtinib has demonstrated therapeutic synergies with chemotherapy agents, targeted therapies, and immunotherapies. InxMed is currently pursuing a registrational trial in platinum-resistant ovarian cancer in China, and multiple proof-of-concept trials are ongoing in lung, colorectal, melanoma, and pancreatic cancers, with select tumor types to progress into pivotal clinical trials. Thus far, more than 600 patients have been treated with ifebemtinib, and a favorable safety and tolerability profile was observed.

Ifebemtinib was granted Breakthrough Therapy Designation from the China National Medical Products Administration (NMPA) and Fast-Track designation from the U.S. Food and Drug Administration (FDA). InxMed plans to submit a New Drug Application to the NMPA in early 2025.

On November 7, 2024 Akeso Biopharma (9926. HK) reported the mechanism of action (MOA) research findings of its innovative bispecific antibody, AK132, targeting both Claudin18.2 (CLDN18.2) and CD47 at the 2024 Annual Meeting of the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) (SITC 2024), held in Houston, USA, from November 6 – 10 (Press release, Akeso Biopharma, NOV 7, 2024, View Source [SID1234647978]). AK132 is an asymmetric bispecific antibody with a "1+1" valency, designed to simultaneously target and block CLDN18.2 and CD47. It features a wild-type IgG1 Fc structure and is currently in the clinical research stage.

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CD47 is overexpressed on a variety of cancer cells, where it interacts with its ligand SIRPα on innate immune cells to inhibit tumor phagocytosis. Claudin 18.2 (CLDN18.2), a tight junction protein, is abnormally activated and overexpressed in several primary malignancies. It has been recognized as a key tumor antigen target in gastric and pancreatic cancers.

Studies have demonstrated that AK132 binds with high affinity to both human CLDN18.2 and human CD47. On one hand, it competitively blocks the interaction between CD47 and its ligand SIRPα, thereby disrupting the CD47-SIRPα axis and relieving the inhibition of tumor cell phagocytosis. This enables macrophage-mediated phagocytosis of CLDN18.2+/CD47+ tumor cells, thereby enhancing the antitumor activity of immune cells. On the other hand, AK132 also induces potent tumor cell killing through Fc-mediated effector functions, such as ADCC, ADCP, and CDC, leading to superior antitumor efficacy compared to anti-CLDN18.2 monoclonal antibodies. In subcutaneous tumor xenograft models in mice, AK132 demonstrated significantly stronger antitumor activity than anti-CLDN18.2 monoclonal antibodies.

Ak132 Efficiently Binds to CLDN18.2 and CD47, Exerting Antitumor Effects through Multiple Mechanisms
Research shows that AK132 binds with high affinity and specificity to human CLDN18.2 and human CD47, competitively blocking the interaction between CD47 and its ligand SIRPα. This disruption of the CD47-SIRPα interaction releases the inhibition on tumor cell phagocytosis, enhancing immune cell anti-tumor functions. AK132 mediates macrophage phagocytosis of CLDN18.2+/CD47+ tumor cells and effectively inhibits tumor growth in subcutaneous xenograft mouse models. AK132 also efficiently kills tumor cells through Fc-mediated effector functions, such as ADCC (antibody-dependent cell-mediated cytotoxicity), ADCP (antibody-dependent cellular phagocytosis), and CDC (complement-dependent cytotoxicity).

AK132 Shows no RBC Toxicity, Does not Bind to Red Blood Cells or Induce Agglutination, Demonstrating Good Safety Profiles
Although CD47 is considered a promising target for cancer immunotherapy, the therapeutic efficacy of CD47 monoclonal antibodies is significantly limited by their considerable toxicity to red blood cells. AK132 features a unique structural design that reduces its affinity for CD47. In vitro studies have shown that AK132 binds minimally to human red blood cells, does not induce ADCP or ADCC activity against red blood cells (thus preventing red blood cell killing), and does not cause red blood cell aggregation, demonstrating an absence of erythrocyte toxicity.

Six Globally Leading Bispecific Antibodies Efficiently Propel Cancer Immunotherapy into the 2.0 Era
Akeso’s investigational New Drug application (IND) application for AK132, aimed at treating advanced malignant solid tumors, has been approved by the China NMPA. Akeso has strategically built a leading, target-rich pipeline of bispecific antibodies, establishing a competitive edge in cancer immunotherapy. Among these, cadonilimab (PD-1/CTLA-4 bispecific) and ivonescimab (PD-1/VEGF bispecific) are already market-approved. Four other bispecific antibodies, including AK129 (PD-1/LAG-3), AK130 (TIGIT/TGF-β fusion protein), AK131 (PD-1/CD73), and AK132 (CLDN18.2/CD47), are currently in clinical trials.