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Xencor Presents Data from Four Preclinical XmAb® 2+1 Bispecific Antibody and Cytokine Programs at AACR Virtual Annual Meeting II

On June 22, 2020 Xencor, Inc. (NASDAQ: XNCR), a clinical-stage biopharmaceutical company developing engineered monoclonal antibodies for the treatment of cancer and autoimmune diseases, reported the presentation of new preclinical data from three XmAb 2+1 bispecific antibody programs and its IL-12-Fc cytokine program during the second session of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting (Press release, Xencor, JUN 22, 2020, View Source [SID1234561353]). Poster presentations and audio descriptions are available to registrants of the AACR (Free AACR Whitepaper) Virtual Annual Meeting.

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"Compared to many therapeutic targets for blood cancers like CD19 or CD20, which are generally restricted to specific cell populations, solid tumor targets often are expressed on a range of normal tissues, including critical organs, which can limit the therapeutic index for drug candidates," said John Desjarlais, Ph.D., senior vice president and chief scientific officer at Xencor. "The XmAb 2+1 bispecific antibody format has two domains that bind the tumor target, and this bivalent binding can preferentially bind tumor cells with high target expression, potentially sparing low-expression normal tissues. This selectivity and potency tuning of T-cell activation may provide for higher efficacy and tolerability compared to other bispecific antibody formats.

"We have also presented data from our IL-12-Fc cytokine program, which builds off of our prior work with IL-15 and IL-2. IL-12 is a potent immune signaling protein that can have a dramatic effect on shrinking tumors; however, prior clinical studies have demonstrated IL-12 to have a narrow therapeutic window, limiting potential response rates. We created an IL-12 Fc-fusion with reduced potency in order to improve tolerability, slow receptor-mediated clearance and prolong the molecule’s half-life," said Dr. Desjarlais.

XmAb 2+1 Bispecific Antibodies

Poster: 2286, "XmAb30819, an XmAb 2+1 ENPP3 x CD3 bispecific antibody for RCC, demonstrates safety and efficacy in in-vivo preclinical studies"
Poster: 5663, "Affinity tuned XmAb 2+1 PSMA x CD3 bispecific antibodies demonstrate selective activity in prostate cancer models"
Poster: 5654, "Affinity tuned XmAb 2+1 anti-mesothelin x anti-CD3 bispecific antibody induces selective T cell directed cell cytotoxicity of human ovarian cancer cells"
ENPP3, PSMA and MSLN are tumor-associated antigens associated with renal cell carcinoma (RCC), prostate cancer and ovarian cancer, respectively, but they are not restricted to tumors and exhibit base level expression on normal tissues. Xencor has expanded its T-cell redirecting CD3 class of bispecific antibodies to create an XmAb 2+1 bispecific antibody format, utilizing an engineered heterodimeric Fc domain, two identical tumor targeting domains and one CD3 targeting domain. The affinities for antigen binding are reduced, which allows for selective engagement of high antigen-expressing tumor cells over low antigen-expressing normal cells. In preclinical models, XmAb 2+1 bispecific antibodies bound preferentially to tumor cells compared to normal cells and effectively recruited T cells to kill tumor cells selectively. Additional data presented on XmAb 2+1 PSMA x CD3 bispecific antibody candidates and XmAb30819, a first-in-class XmAb 2+1 ENPP3 x CD3 bispecific antibody, demonstrated strong reversal of tumor growth in human-cell engrafted mouse models of disease. Further data presented from preclinical studies of XmAb30819 in non-human primates demonstrated it was well-tolerated with expected pharmacodynamics and an antibody-like half-life.

IL-12-Fc Cytokine

Poster: 5549, "Potency-reduced IL-12 heterodimeric Fc-fusions exhibit strong anti-tumor activity"
IL-12 is a heterodimeric proinflammatory cytokine produced by activated antigen-presenting cells, and it leads to proliferation of T cells and NK cells and increased cytotoxicity through high levels of interferon gamma signaling. IL-12-Fc fusions were engineered with potency-reduced IL-12 to improve its potential tolerability, slow receptor-mediated clearance and prolong its half-life in vivo. In preclinical models, these potency-reduced IL-12-Fc fusions demonstrated significant anti-tumor activity concurrent with activation and proliferation of CD8+ T cells, increased PD-1 checkpoint expression and increased levels of interferon gamma in serum. Anti-tumor activity was enhanced when combined with an anti-PD-1 antibody.

The posters will be archived under "Events & Presentations" in the Investors section of the Company’s website located at www.xencor.com.

ImmunoGen Presents Preclinical Data on IMGN151 at Virtual AACR Annual Meeting

On June 22, 2020 ImmunoGen, Inc. (Nasdaq: IMGN), a leader in the expanding field of antibody-drug conjugates (ADCs) for the treatment of cancer, reported preclinical data for its next generation anti-folate receptor alpha (FRα) ADC, IMGN151, which is being investigated in tumors with a broad range of FRα expression (Press release, ImmunoGen, JUN 22, 2020, View Source [SID1234561352]). The findings were shared via poster presentation at the virtual American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting II.

"Engineered to include multiple antibody and linker-payload innovations, IMGN151 targets tumors with a broad range of FRα expression," said Eric Westin, MD, Vice President of Clinical Development and Translational Sciences at ImmunoGen. "IMGN151 demonstrated enhanced anti-tumor activity in both in vitro and in vivo preclinical models, with complete regression of human tumor xenograft models induced in those with high, medium, and low levels of FRα expression. Based on these data, we look forward to exploring IMGN151 in the clinic in multiple FRα-positive epithelial malignancies, including ovarian, endometrial, triple negative breast, and non-small cell lung cancer."

IMGN151 PRECLINICAL DATA
Poster Presentation, Abstract 2890

IMGN151 comprises an asymmetric, bivalent, biparatopic antibody targeting two independent epitopes of FRα, linked to a highly potent maytansinoid derivative, DM21, via a cleavable peptide linker with enhanced stability, longer half-life, and increased bystander activity. The average drug per antibody ratio is 3.5. IMGN151 activity was characterized against cell lines and xenograft models with a wide range of FRα expression and compared to mirvetuximab soravtansine (IMGN853). Cell lines and xenograft models originated from ovarian, endometrial, breast, and cervical cancer.

Key findings include:

The protease-cleavable linker deployed in IMGN151 improves stability and ADC exposure; as compared to IMGN853, pharmacokinetic studies in cynomolgus monkeys showed increased ADC half-life by 60 hours and conjugate exposure in vivo by 40%.
The IMGN151 biparatopic format boosted antibody binding events and DM21 payload delivery in tumor cell lines; the increased payload delivery and greater membrane permeability of DM21 enhanced bystander killing activity.
In vitro, IMGN151 was more active against FRα-positive cell lines, with the most pronounced effect in cells with low to medium levels of FRα.
In vivo, IMGN151 demonstrated better activity over IMGN853 against low and medium levels of FRα, and equivalent activity to IMGN853 against FRα high tumors with lower effective dose; all tested doses were well tolerated.
Additional information can be found at www.aacr.org.

ABOUT IMGN151

IMGN151 is a next-generation ADC, designed to address the unmet needs of cancer patients with tumor types expressing lower levels of folate receptor alpha (FRα). IMGN151 comprises an asymmetric, bivalent, biparatopic antibody targeting two independent epitopes of FRα, linked to a highly potent maytansinoid derivative, DM21, via a cleavable peptide linker with enhanced stability, longer half-life, and increased bystander activity.

Ikena Oncology Presents New Preclinical Data Highlighting the Anti-Cancer Effects of TEAD Inhibition on the Hippo Signaling Pathway

On June 22, 2020 Ikena Oncology, a clinical-stage biotechnology company that discovers and develops patient-directed, biomarker-driven therapies, reported the presentation of new preclinical research highlighting the anti-proliferative and anti-tumor effects of Ikena-developed compounds targeting the Hippo signaling pathway through the inhibition of TEAD at the 2020 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting II, taking place June 22-24, 2020 (Press release, Ikena Oncology, JUN 22, 2020, View Source [SID1234561351]).

The TEAD (TEA domain) family of transcription factors downstream of the Hippo signaling pathway elicits a gene expression signature that plays a prominent role in cancer development, progression, and metastasis. Increased Hippo pathway activity sustains proliferation, inhibits apoptosis, promotes angiogenesis, and is associated with resistance to multiple therapies. Inhibition of TEAD has been and remains an attractive opportunity for a novel targeted cancer therapy.

"The Hippo pathway is highly mutated across many cancer types, including in mesothelioma, ovarian and breast cancers, and its activation is correlated with an overall poor prognosis in patients. Therefore, we have insights into which patients will most likely benefit from a TEAD-targeted therapy," said Jeffrey Ecsedy, Ph.D., Chief Scientific Officer of Ikena Oncology. "The AACR (Free AACR Whitepaper) presentation this year highlights promising pharmacokinetic, pharmacodynamic, and in vivo efficacy results in mesothelioma models for multiple lead TEAD inhibitor candidates identified by Ikena. These compounds are in studies to narrow in on a development candidate that we look forward to progressing into IND-enabling studies during the second half of 2020."

Ikena’s Novel Small Molecule TEAD Inhibitors

Ikena researchers rationally designed and developed multiple novel, potent, orally bioavailable small molecule inhibitors that reversibly and irreversibly bind to the central lipid (palmitate) binding pocket of TEAD family members. These inhibitors prevent TEAD palmitoylation, a process that is essential for the interaction between the transcriptional co-regulators YAP (Yes-associated protein) or TAZ (transcriptional co-activator with PDZ-binding motif) with TEAD, and lead to downregulation of the YAP/TAZ-TEAD-dependent transcription. Binding of these TEAD inhibitors to the central lipid binding pocket was observed using crystallography.

The Effects of TEAD Inhibition In Vitro and In Vivo

When evaluated in vitro, Ikena’s TEAD inhibitors demonstrated anti-proliferative properties in Hippo pathway-driven cancer cell lines, but not in Hippo pathway wildtype cancer cell lines. Subsequent in vivo experiments in human tumor xenograft mouse models demonstrated that oral administration of these TEAD inhibitors was well tolerated and that TEAD-dependent transcription in the tumors was inhibited. Robust anti-tumor activity was observed in two separate Hippo pathway-mutated mesothelioma xenografts. Translational studies to identify additional tumor types that are Hippo pathway-driven and dependent on TEAD function are in progress.

"The Hippo pathway is hijacked in many cancer types and we believe that by disrupting TEAD transcription, we can prevent tumors from proliferating and evading the body’s immune system," said Mark Manfredi, Ph.D., President and Chief Executive Officer of Ikena Oncology. "We believe our TEAD inhibitor candidates have the potential to be active across several types of Hippo-driven cancers, both as single-agent therapy and in combination with other standard of care oncology agents to overcome therapeutic resistance."

Details for the AACR (Free AACR Whitepaper) 2020 Virtual Meeting II presentation are as follows:

Title: Potent small molecule TEAD inhibitors targeting the Hippo pathway exhibit antiproliferation in vitro and anti-tumor effect in vivo
Lead author: Ben Amidon, Ikena Oncology
Abstract #: 2474
Poster Board #: 18
Session: PO.MCB04.02 – Gene Regulation and Transcription Factors 2
Date and Time: Monday, June 22, 2020; 9:00 a.m. to 6:00 p.m. ET
URL: View Source!/9045/presentation/6122

Minerva Biotechnologies Announces License Agreement with Memorial Sloan Kettering Cancer Center for 1XX Technology

On June 22, 2020 Minerva Biotechnologies (Minerva) reported that it has licensed from Memorial Sloan Kettering Cancer Center (MSK) "1XX" technology for use with Minerva’s proprietary anti-MUC1* antibodies to increase CAR T cell persistence in patients (Press release, Minerva Biotechnologies, JUN 22, 2020, View Source [SID1234561350]).

"This promises to be a great step forward for CAR T cell treatment of solid tumors," said Minerva CEO Dr. Cynthia Bamdad. "We are combining Minerva’s demonstrated cancer-specific antibodies with MSK’s innovative T cell signaling technology that sustains CAR T cell function and persistence."

Minerva is currently in a first-in-human clinical trial for metastatic breast cancers with a CAR T (huMNC2-CAR44) targeting a cleaved form of MUC1 called MUC1* (NCT04020575). MUC1* is the growth factor receptor form of MUC1 that is aberrantly expressed on over 75% of all solid tumors and on over 90% of breast cancers.

CAR T cell persistence, which is the amount of time that infused CAR T cells have the potential to kill tumor cells, is a recognized problem in the revolutionary field of cancer immunotherapy. Since over-activation drives CAR T cell exhaustion, calibrating their activation potential through 1XX mutations in their signaling domain staves off expression of exhaustion molecules that turn CAR T cells off. With this agreement, Minerva will gain non-exclusive access to two of MSK’s innovative CAR T technologies, including the 1XX CAR T cell signaling construct, whose activation potential more closely resembles that of naturally occurring T cells. Minerva expects its next-generation anti-MUC1* CAR T cell therapies to have enhanced therapeutic profiles due to their extended persistence.

Michel Sadelain, M.D., Ph.D., Director, Center for Cell Engineering at MSK and inventor of the 1XX technology said, "We are excited by the prospect of targeting MUC1* with MSK’s 1XX CAR technology."

RGENIX Presents Biomarker and Efficacy Results from Phase 1 Dose Escalation Cohorts of RGX-104 at the 2020 AACR Annual Meeting

On June 22, 2020 RGENIX, Inc., a clinical stage biopharmaceutical company developing first-in-class small molecule and antibody cancer therapeutics, reported it is presenting an abstract on RGX-104, RGENIX’s lead therapy in development (Press release, Rgenix, JUN 22, 2020, View Source [SID1234561349]). RGENIX’s abstract, "Correlative analysis of pharmacokinetics and pharmacodynamics of RGX-104, a first-in-class Liver-X-Receptor (LXR) agonist, and clinical outcomes in patients with advanced solid tumors" was accepted for the 2020 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, which this year was scheduled as two virtual meetings. The abstract results will be presented as a virtual poster presentation (#LB-133/7) in the Late-Breaking Research: Clinical Research 1 session on June 22, by clinical investigator Dr. Monica Mita, Co-Director, Experimental Therapeutics Program, Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center, who is lead author on the study.

RGX-104 is a small-molecule LXR agonist that modulates innate immunity via transcriptional activation of the ApoE gene. RGX-104 inhibits tumor angiogenesis and depletes myeloid derived suppressor cells (MDSC), thereby activating cytotoxic T-lymphocytes. MDSCs are associated with resistance to both checkpoint inhibitors (CPI) and chemotherapy, providing a rationale for combination therapy with RGX-104.

For the dose escalation stage of the Phase 1 study, RGX-104 was tested as a monotherapy or in combination with either nivolumab, ipilimumab, or docetaxel in heavily pre-treated patients with refractory or relapsed solid tumors, including patients who had progression on prior checkpoint inhibitors (CPI). As outlined in the presentation, objective clinical activity was observed in all treatment arms, including the monotherapy arm, with partial responses achieved in patients with NSCLC, SCLC, melanoma, SCCHN, and endometrial cancer.

Of note, in the combination arms, a 28.6% objective response rate was observed in all evaluable patients who had previously progressed on CPI, with 4 of 14 evaluable patients achieving PRs. Responses included ongoing durable PRs – some exceeding 11 months – in CPI refractory/resistant patients whose tumors were PD-L1 low/negative.

Importantly, clinical activity across all treatment arms was associated with RGX-104 related pharmacodynamic effects, including ApoE activation, MDSC depletion, and CD8 T cell activation with associated induction of IFNγ. Robust ApoE induction was achieved with BID dosing of RGX-104 and was correlated with the magnitude of MDSC depletion. Additionally, in comparison to PD-L1 positive tumors, PD-L1 negative tumors were found to have significantly lower baseline (pre-treatment) levels of ApoE, a feature associated with higher likelihood of clinical benefit to RGX-104. The data demonstrate that MDSC depletion via ApoE induction with RGX-104 can overcome resistance to CPI or chemotherapy, resulting in durable clinical activity.

As a result, RGX-104 is being evaluated in combination with the front-line standard-of-care regimen of pembrolizumab plus carboplatin/pemetrexed in a phase 1b/2 study currently enrolling patients with advanced non-squamous non-small cell lung cancer (NSCLC) whose tumors are PD-L1 negative. RGX-104 is also being evaluated in combination with docetaxel in a phase 1b/2 expansion study that has begun enrolling patients with relapsed/refractory extensive stage small-cell lung cancer (ES-SCLC) or high grade-neuroendocrine tumors (HG-NET).

Monica Mita, M.D., principal investigator from Cedars-Sinai Medical Center and lead author and presenter of the poster, said, "These exciting results provide clinical validation of the novel MDSC-targeting mechanism of RGX-104. The durable clinical responses observed in patients who have previously progressed on checkpoint inhibitors are very promising."

Masoud Tavazoie, M.D., Ph.D., and Chief Executive Officer of RGENIX, said, "We are very encouraged by the results presented today as they demonstrate that our first-in-class drug candidate RGX-104 can robustly target MDSCs, a key drug resistance mechanism, to provide durable clinical benefit to patients. The findings further strengthen the foundation for our ongoing Phase 1b/2 studies. We look forward to sharing results from these ongoing studies."