On December 11, 2021 Ichnos Sciences Inc., a global biotechnology company developing innovative biologics in oncology, reported that preclinical data that support the potential for ISB 1442, a first-in-class 2+1 biparatopic bispecific antibody that targets both CD38 and CD47, as a treatment for relapsed/refractory multiple myeloma and other CD38+ hematological malignancies (Press release, Ichnos Sciences, DEC 11, 2021, View Source [SID1234596808]). The data were presented today by Stefano Sammicheli, Ph.D., Director of Innate Cell Engagers, during an oral session at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

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ISB 1442 includes three arms in a 2+1 biparatopic BEAT 2.0 bispecific[1] format:

Two proprietary high-affinity anti-CD38 binding arms, each targeting different CD38 epitopes, neither of which competes functionally with daratumumab, drive the binding of this molecule to CD38 expressing tumor cells.
A third, lower affinity arm masks CD47 and disrupts binding to SIRPα on macrophages, blocking the "do not eat me signal."
Engineering of the fragment crystallizable (Fc) region enhances antibody dependent cell phagocytosis (ADCP), antibody dependent cell cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC).
Ichnos’ proprietary BEAT 2.0 platform is among the most innovative multispecific platforms: it mimics the natural full length antibody format, the BEAT interface enables high yield for heavy chain pairing, and light chains are assembled via common light chain Fab technique.
The data presented today demonstrate the potency and anti-tumor activity of ISB 1442 in multiple in vitro and in vivo tumor models relative to daratumumab and magrolimab. Specifically, the results show that:

ISB 1442 induces comparable blockade of CD47/SIRPα interactions to the clinical benchmark magrolimab, an antibody that targets CD47.
ISB 1442 enables a significant increase in phagocytosis in CD38 low tumor cells relative to that of daratumumab, an antibody that targets CD38.
ISB 1442 shows higher ADCC relative to daratumumab.
ISB 1442 improved tumor growth inhibition in an in vivo preclinical model compared to daratumumab.
"We are excited to present data on Ichnos’ first-in-class biparatopic CD38 x CD47 bispecific antibody at ASH (Free ASH Whitepaper)," said Mario Perro, Ph.D., Vice President Oncology, Interim Head of Discovery at Ichnos. "ISB 1442 has demonstrated high potency in multiple in vitro tumor models, including one that assessed multiple antibody-dependent mechanisms of actions simultaneously, and higher tumor growth inhibition in vivo. We believe that this asset has the potential to effectively treat patients with multiple myeloma who have relapsed or are refractory to daratumumab as well as other CD38 expressing hematological malignancies."

"Today’s presentation represents another step forward as Ichnos works to bring this novel multispecific approach that co-targets CD38 and CD47 to patients with hematologic malignancies," said Cyril Konto, M.D., President and Chief Executive Officer of Ichnos. "With its unique design and mechanisms of action, data suggest that ISB 1442 may enhance anti-tumor activity relative to approved anti-CD38 targeted therapies by overcoming primary and acquired tumor mechanisms of resistance. We look forward to submitting the IND to FDA in early 2022 and initiating our first-in-human clinical study in patients with relapsed/refractory multiple myeloma, acute myeloid leukemia and T-cell acute lymphoblastic leukemia in the middle of 2022."

The video presentation is available to registered meeting attendees on the ASH (Free ASH Whitepaper) platform. Additional details are also included in the abstract.

Ichnos continues to advance its pipeline of agents based on the proprietary BEAT technology platform. Using this platform, Ichnos is exploring the full design space for treating cancer and engineering multispecific antibodies capable of simultaneously engaging tumor and immune cells.

On December 11, 2021 Schrödinger, Inc. (Nasdaq: SDGR), whose physics-based software platform is transforming the way therapeutics and materials are discovered, reported that new preclinical data from its mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) inhibitor program in B-cell lymphomas in a poster session at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition in Atlanta, Georgia (Press release, Schrodinger, DEC 11, 2021, View Source [SID1234596853]). MALT1 is considered a potential therapeutic target for several non-Hodgkin’s B-cell lymphomas as well as chronic lymphocytic leukemia. Schrödinger has identified novel MALT1 inhibitors that demonstrate strong anti-tumor activity across multiple tumor models, including cell- and patient-derived xenograft models, and combination potential with other agents, including standards of care such as ibrutinib.

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"We are pleased that our data strongly underscore the therapeutic potential of our MALT1 inhibitors and present an opportunity to advance a potential best-in-class MALT1 inhibitor into the clinic," said Karen Akinsanya, Ph.D., executive vice president, chief biomedical scientist and head of discovery R&D at Schrödinger. "We are on track to submit the IND for our MALT1 development candidate to the FDA in the first half of 2022."

The data presented suggest that targeting MALT1 may expand therapeutic options for patients with selected B-cell lymphomas, such as activated B-cell (ABC) subtype of diffuse large B cell lymphoma (DLBCL), with the possibility of expanding into other B-cell lymphomas such as mantle cell lymphoma (MCL). Furthermore, these small molecule MALT1 inhibitors demonstrate potential in combination with Bruton’s tyrosine kinase (BTK) inhibitors to overcome drug-induced resistance in patients with relapsed/refractory B-cell lymphomas.

Additional Details About the Study

The presentation, "Characterization of Potent Paracaspase MALT1 Inhibitors for Hematological Malignancies," highlighted preclinical data with multiple lead molecules discovered using Schrodinger’s proprietary physics-based free energy perturbation (FEP+) modeling technology. These molecules demonstrate potent inhibition of MALT1 enzymatic activity and anti-proliferative activity in the ABC-DLBCL cell lines, such as OCI-LY3 and OCI-LY10. In combination with approved agents, these inhibitors demonstrate strong combination potential with Bruton’s tyrosine kinase (BTK) inhibitors such as ibrutinib in ABC-DLBCL cell lines. In ABC-DLBCL cell line-derived xenograft (CDX) models, the company’s representative MALT1 inhibitor induces tumor regression as a single agent and complete tumor regression in combination with ibrutinib. The representative MALT1 inhibitor, when tested in LY2298 patient-derived xenograft (PDX) models, demonstrates similar results. In addition, the representative MALT1 inhibitor was explored in a CDX model derived from a mantle cell lymphoma REC-1 cell line, and demonstrates strong anti-tumor activity of ~78% tumor growth inhibition as a single agent. Taken together, these data strongly underscore the therapeutic potential of Schrödinger’s MALT1 inhibitors and support further evaluation of a potential best-in-class MALT1 inhibitor in clinical trials.

On December 11, 2021 Cellectis (Euronext Growth: ALCLS – Nasdaq: CLLS), a clinical-stage biotechnology company employing its pioneering TALEN gene-editing platform to develop innovative therapeutics for the treatment of serious diseases, reorted that preliminary results from the BALLI-01 Phase 1 study of UCART22, its allogeneic CAR-T cell therapy candidate targeting CD22, in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (r/r B-ALL), and preclinical data on TALGlobin01, its autologous cell therapy product candidate for homozygous SCD patients (HbSS) at the 63rd Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) in Atlanta, Georgia (Press release, Cellectis, DEC 11, 2021, View Source [SID1234596809]).

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"We are excited by the encouraging preliminary results obtained from patients administered UCART22 after fludarabine, cyclophosphamide and alemtuzumab (FCA) lymphodepletion in the BALLI-01 study. The addition of alemtuzumab to fludarabine and cyclophosphamide (FC) was demonstrated to be safe, improve host-lymphocyte suppression, and promote UCART22 expansion, which was associated with anti-leukemic activity," said Carrie Brownstein, MD, Chief Medical Officer. "We believe these initial data support our mission to develop UCART22 for patients with r/r B-ALL, who remain in dire need of additional treatment options, particularly those who have failed CD19 therapy."

BALLI-01 investigating UCART22 product candidate in R/R B-ALL

BALLI-01, a phase 1 open-label dose-escalation study, is designed to assess the safety, maximum tolerated dose (MTD), and preliminary anti-leukemia activity of UCART22 in patients with r/r B-ALL. Additional endpoints include characterization of the expansion, trafficking, and persistence of UCART22 cells.

The poster presentation includes preliminary data from patients who received UCART22 at dose level 2 (DL2) and intermediate dose level 2 (DL2i) after lymphodepletion with FCA. Alemtuzumab was added to FC to deepen and sustain host lymphocyte suppression and thereby promote UCART22 expansion and persistence.

As of the clinical cut-off date of October 1, 2021, 12 patients received lymphodepletion; 11 were administered UCART22, of which 6 received UCART22 and FCA. Enrolled patients were predominantly male [n=7], young (median age 30 [range 20-61]), and most had recurrent genetic abnormalities including the CRFL2 (cytokine receptor-like factor 2) rearrangement. Additionally, enrolled patients were heavily pretreated with a median of 3 prior lines of therapy [range 2-6]. Three-fourths of patients had received prior blinatumomab, approximately half had received prior inotuzumab, and 3 had received prior CD19 autologous CAR-T therapy.

Safety Data
The FCA lymphodepletion regimen was well tolerated, and most treatment-emergent adverse events (TEAEs) were mild to moderate in intensity and manageable. Importantly, no patients experienced protocol-defined dose limiting toxicities (DLTs), immune effector cell-associated neurotoxicity syndrome (ICANS), nor UCART22-related severe (grade ≥3) TEAEs. Three patients experienced mild to moderate cytokine release syndrome (CRS), and one patient reported grade II GvHD with skin involvement only, that required hospitalization.

Activity Data
Encouraging anti-leukemic activity was observed in two (2/6) patients in the FCA cohorts. Both patients, one at DL2 and one at DL2i, achieved blast reductions to < 5% (0.4% and 0%, respectively) by day 28, accompanied by measurable UCART22 expansion and changes in relevant inflammatory cytokines.

Overall, UCART22 after FCA lymphodepletion regimen demonstrated promising signs of anti-leukemic activity at DL2 and DL2i, without unexpected or significant treatment-related toxicity. The addition of alemtuzumab to the FC lymphodepletion regimen was safe and promoted sustained host T-cell suppression and expansion of UCART22. These data are encouraging and support the further development of UCART22 for patients with r/r B- ALL. BALLI-01 is currently enrolling patients at dose level 3 with FCA lymphodepletion.

TALGlobin01; an autologous ex vivo TALEN-edited hematopoietic stem and progenitor cell gene therapy for the treatment of Sickle Cell Disease

Initial pre-clinical data from Cellectis’ .HEAL platform’s product candidate, TALGlobin01 demonstrates that TALEN is specific and efficient in correcting the mutated beta-globin gene, the underlying cause of sickle cell disease.

The data, presented in a poster, demonstrate that TALEN-based engineering could be used to correct the beta-globin gene mutation in HbSS patient-derived hematopoietic stem and progenitor cells. The data show up to 70% of HBB allelic correction, with only 9% of HBB biallelic inactivation and a low level of TALEN off-target cleavage. Genetic correction of HBB translates into high level of hemoglobin A expression (up to 47% HbA detected among total hemoglobin) and reversion of the sickling phenotype in differentiated red blood cells. Preclinical data show the capacity of TALGlobin01 edited cells to engraft in vivo using an NSG mouse model.

Collectively, the preclinical data demonstrate high efficiency and safety of TALEN treatment in HbSS patient-derived hematopoietic stem and progenitor cells.

A copy of each poster presentation is available on Cellectis’ website, linked here.

About UCART22

UCART22 is an allogeneic T-cell product manufactured from healthy donor cells. T-cells are transduced using a lentiviral vector to express the anti-CD22 chimeric antigen receptor (CAR) and are genetically modified using TALEN gene-editing technology to disrupt the T-cell receptor alpha constant (TRAC) gene to minimize risk of graft-vs-host disease (GvHD) and the CD52 gene to eliminate sensitivity to anti-CD52–directed agents used in lymphodepletion regimens. UCART22 is being developed for the treatment of R/R B-cell ALL.

About TALGlobin01

TALGlobin01, is an autologous ex vivo TALEN-edited CD34+ HSC gene therapy for the treatment of SCD. TALGlobin01 is developed using both TALEN technology to induce a double strand DNA break in the SCD-causing hemoglobin subunit beta (HBB) gene and adeno-associated virus (AAV) particles containing a DNA repair template designed to correct the faulty HBB gene via endogenous homology directed repair.

On December 11, 2021 Aleta Biotherapeutics, a privately held immuno-oncology company focused on transforming cellular therapeutics to allow a broad spectrum of cancer indications to be targeted, reported a summary of ALETA-001 preclinical results from a poster being presented at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, held in Atlanta, Georgia and in a virtual platform on December 11-14, 2021 (Press release, Aleta Biotherapeutics, DEC 11, 2021, View Source [SID1234596854]).

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The presentation featured preclinical data that support the upcoming Phase 1/2 clinical trial of ALETA-001 being run in collaboration with Cancer Research UK. ALETA-001 is a multifunctional biologic for injection that contains an anti-CD20 llama VHH linked to an optimized CD19 protein and further linked to an anti-albumin llama VHH. Extensive preclinical in vitro modeling demonstrated that ALETA-001 specifically binds to CD20-positive/CD19 negative lymphoma cells with high affinity, thereby densely coating these cancer cells with the CD19 protein. In the presence of anti-CD19 CAR T cells, ALETA-001 mediated cytotoxicity against CD19 negative lymphoma cells at sub-nM concentrations. The administration of ALETA-001 and anti-CD19 CAR T cells in vivo eliminated systemic CD19 negative lymphoma that otherwise produced lethal disease at doses of ALETA-001 as low as 0.5mg/kg. Further, upon stopping dosing in the in vivo lymphoma model, 40% of ALETA-001-treated animals did not relapse through day 43, more than 2 weeks after the last dose, suggesting apparent cures. Additionally, excess ALETA-001 did not interfere with cytotoxicity. ALETA-001 is designed to be administered to patients who have received CAR19 T cell therapy and who fail to achieve a complete response at the time of their first clinical evaluation, or who relapse from a complete response thereafter. Clinical trial development is underway in collaboration with Cancer Research UK.

On December 11, 2021 Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) reported new results for higher dose level cohorts of its investigational REGN5458 (BCMAxCD3) bispecific antibody, which were presented in an oral session at the 2021 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Atlanta, GA (Press release, Regeneron, DEC 11, 2021, View Source [SID1234596810]). The new results from the Phase 1 portion of the Phase 1/2 trial in patients with relapsed/refractory multiple myeloma found a 51% overall response rate (ORR) across all dose groups, rising to 75% in patients who received higher doses of REGN5458 (200-800 mg).

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"Patients with multiple myeloma often face a long and challenging journey, with most becoming refractory to multiple lines of therapy over time," said Jeffrey Zonder, M.D., Professor of Oncology at the Karmanos Cancer Institute, MI, and a trial investigator. "Today’s REGN5458 data show promising response rates, particularly at the higher dose levels, in patients with a high disease burden and highly refractory disease who otherwise would have very limited options available."

REGN5458 is a bispecific antibody designed to bind to BCMA on multiple myeloma cells and the CD3 receptor on T-cells in order to bridge them together and activate T-cells to kill the cancer cells. It is currently being assessed in the potentially registrational Phase 2 portion of the trial, which is expected to complete recruitment in 2022.

In results presented at ASH (Free ASH Whitepaper) today, 73 patients were treated with REGN5458 doses ranging from 3-800 mg for up to 21 months at the time of data cutoff. Patients had received a median of 5 prior lines of therapy, with 38% (n=28) being penta-refractory and 90% (n=66) being refractory to the last line of therapy.

The ORR was 75% at the highest dose levels (200-800 mg, n=18/24), and 51% among all enrolled patients (n=37/73). Most responses occurred within the first month of treatment and deepened over time. Among responders across all dose groups:

86% (n=32/37) achieved a very good partial response (VGPR) or better.
43% (n=16/37) achieved a complete response (CR), with 40% of evaluable CR patients (n=4/10) being minimal residual disease (MRD) negative.
8 months from the time of response, there was a 90% probability of being event-free (95% CI: 73%, 97%), defined by the absence of disease progression or death. The estimated median duration of response had not yet been reached at the time of data cutoff.
Responses occurred rapidly, usually within the first month of treatment, and continue to deepen with longer treatment; the higher dose groups currently have substantially shorter follow up.
The safety profile was generally consistent across all dose levels. Cytokine release syndrome (CRS) was reported in 38% of patients (n=28), the majority of which were Grade 1 (n=25), with no cases >Grade 3. The other most common treatment-emergent adverse events (TEAEs) were fatigue (n=33), pyrexia (n=26), nausea (n=24) and anemia (n=23). The most common >Grade 3 TEAEs were anemia (n=17), neutropenia (n=16), lymphopenia (n=14), thrombocytopenia (n=10) and pneumonia (n=9). There were 5 deaths in the trial, all due to infection; none were considered related to the underlying disease by investigators.

"In multiple myeloma, the highest treatment response rates are typically seen earlier in the course of the disease, using multi-drug regimens. It is very encouraging that we observed a 75% response rate with higher doses of REGN5458 monotherapy in patients with more advanced disease," said L. Andres Sirulnik, M.D., Ph.D., Senior Vice President, Clinical Development, Hematology at Regeneron. "This adds to the growing body of encouraging data across our investigational CD3 bispecifics, supporting the continued development of this class across a diverse range of blood cancers."

REGN5458 is currently under clinical development and its safety and efficacy have not been fully evaluated by any regulatory authority.

Investor Webcast Information
Regeneron will host a conference call and simultaneous webcast to share updates on the company’s hematology portfolio on Monday, December 13 at 4:30 PM ET. To access this call, dial (888) 660-6127 (U.S.) or (973) 890-8355 (International); conference ID 2668896. A link to the webcast may be accessed from the ‘Investors and Media’ page of Regeneron’s website at View Source A replay of the conference call and webcast will be archived on the company’s website for at least 30 days.

About the Dose-escalation Trial
The open-label Phase 1/2 dose-escalation trial is investigating REGN5458 (BCMAxCD3) in patients with relapsed/refractory multiple myeloma who had received at least three prior lines of therapy or were double refractory. All patients had received prior treatment with proteasome inhibitors, immunomodulatory drugs and CD38 antibody treatments.

The Phase 1 portion of the trial is primarily assessing safety, tolerability and dose-limiting toxicities of REGN5458, with efficacy as secondary endpoints. The Phase 2 portion will further assess REGN5458 anti-tumor activity and safety. If you are interested in learning more about this trial, please contact us ([email protected], +1 844 734 6643), or visit our clinical trial website.

About Multiple Myeloma
Multiple myeloma is the second most common blood cancer with approximately 30,192 and 168,765 new diagnoses in the U.S. and the world, respectively, in 2020. It is characterized by the proliferation of cancerous plasma cells (multiple myeloma cells) that crowd out healthy blood cells in the bone marrow, infiltrate other tissues and cause potentially life-threatening organ injury. Multiple myeloma is not curable despite treatment advances, and while current treatments are able to slow the progression of the cancer, most patients will ultimately experience cancer progression and require additional therapies. In addition, patients are at increased risk of frequent infections, bone problems, reduced kidney function and anemia.

About Regeneron in Hematology
At Regeneron, we’re translating more than 3 decades of biology expertise with our proprietary VelociSuite technologies to develop potentially paradigm-changing medicines for patients with diverse blood cancers and rare blood disorders.

Our blood cancer research is focused on bispecific antibodies that are being assessed both as monotherapies and in combination with each other and emerging therapeutic modalities. Together, they provide us with unique combinatorial flexibility to develop customized and potentially synergistic cancer treatments.

Our research and collaborations to develop potential treatments for rare blood disorders include explorations in antibody medicine, gene editing using CRISPR and gene-knockout technologies, as well as investigational RNA-approaches that are being investigated for their ability to deplete abnormal proteins or block disease-causing cellular signaling.

For more information, visit View Source

About Regeneron’s VelocImmune Technology
Regeneron’s VelocImmune technology utilizes a proprietary genetically engineered mouse platform endowed with a genetically humanized immune system to produce optimized fully human antibodies. When Regeneron’s President and Chief Scientific Officer George D. Yancopoulos was a graduate student with his mentor Frederick W. Alt in 1985, they were the first to envision making such a genetically humanized mouse, and Regeneron has spent decades inventing and developing VelocImmune and related VelociSuite technologies. Dr. Yancopoulos and his team have used VelocImmune technology to create approximately a quarter of all original, FDA-approved or authorized fully human monoclonal antibodies currently available. This includes Dupixent (dupilumab), REGEN-COV (casirivimab and imdevimab), Libtayo (cemiplimab-rwlc), Praluent (alirocumab), Kevzara (sarilumab), Evkeeza (evinacumab-dgnb) and Inmazeb (atoltivimab, maftivimab, and odesivimab-ebgn).