On December 12, 2023 AbelZeta Pharma, Inc. ("AbelZeta" or the "Company"), a global clinical-stage biopharmaceutical company focused on discovery and development of innovative and proprietary cell-based therapeutic products, reported clinical data for both C-CAR039 for the treatment of patients with relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL), and C-CAR066, for the treatment of patients with r/r large B-cell lymphoma (LBCL) who failed prior CD19 CAR-T therapy at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, AbelZeta, DEC 12, 2023, View Source [SID1234638480]).

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"We are thrilled to share the long-term follow-up results from our clinical studies of C-CAR039 and C-CAR066 at the Annual Meeting of ASH (Free ASH Whitepaper), said Tony (Bizuo) Liu, Chairman and CEO of the Company. "The positive outcomes underscore the potential of these novel therapies in advancing the treatment landscape for patients with r/r B-NHL. The observed response rates, durability, and manageable safety profile demonstrated in both studies reinforce our commitment to pioneering innovative and effective solutions in immuno-oncology for patients suffering from serious hematological malignancies."

"We are proud of our collaboration and license agreement with Janssen to facilitate the global development and accessibility of C-CAR039 and C-CAR066. This strategic partnership aligns with our mission to bring innovative and life-changing therapies to patients worldwide."

In May 2023, AbelZeta Pharma (formerly CBMG) entered into a global collaboration and license agreement with Janssen Biotech, Inc. (Janssen), a Johnson & Johnson company, for C-CAR039, an anti-CD19 & CD20 bi-specific CAR-T therapy, and C-CAR066, an anti-CD20 CAR-T.

Study Conclusions
At a longer median follow-up of 30.0 months, C-CAR039 demonstrated a favorable safety profile with deep and durable response in patients with r/r B-NHL, especially in LBCL patients.
Longer term follow-up demonstrated that C-CAR066 can produce a deep and durable response with a favorable safety profile in patients with r/r LBCL who failed prior CD19 CAR-T therapy.
About the C-CAR039 Study
C-CAR039 has been developed as a novel 2nd generation 4-1BB bi-specific CAR-T targeting both CD19 and CD20 antigens with an optimized bi-specific antigen binding domain. C-CAR039 has consistently shown ability to eradicate CD19/CD20 single or double positive tumor cells in vitro and in vivo. GMP manufacturing of C-CAR039 was carried out in a serum free and fully closed semi-automatic system.

In the Phase I clinical trials in China (NCT04317885, NCT04655677, NCT04696432, NCT04693676), dose escalation and expansion studies were conducted to evaluate the safety and efficacy of C-CAR039 in r/r B-NHL patients. C-CAR039 was administered as a single intravenous dose after a 3-day cyclophosphamide (300mg/m2x3d) plus fludarabine (30mg/m2x3d) conditioning regimen.

Key Results of C-CAR039
Between November 5, 2019, and January 11, 2022, 48 patients received C-CAR039 at the dose ranges of 1.0 x 106 to 5.0×106 CAR-T cells/kg. Of the 48 patients, 44 (91.7%) patients had large B-cell lymphoma (LBCL) (DLBCL, n=37; PMBCL, n=3; tFL, n=4), 3 patients had FL and 1 patient had MCL. The median age was 55 (range, 25-71) years, and 11 (22.9%) patients were ≥ 65 years. Thirty-six (75%) patients were in Ann Arbor Stage III/IV with 3 median prior lines of therapy, 32 (66.7%) patients were refractory to their last treatment, and 22 (45.8%) patients never achieved CR to their prior therapies.

As of September 25, 2023, 45 patients (93.8%) experienced CRS, only 1 (2.1%) were grade 3. Three patients had grade 1 or 2 ICANS at a dose of 5.0×106 CAR-T cells/kg. Grade 3 or higher cytopenia not resolved by Day 30 following C-CAR039 infusion included neutropenia (54.2%), thrombocytopenia (20.8%), and anemia (20.8%). At cutoff date, 66.7% patients had infections with 25% grade 3 or higher. Second primary malignancy after C-CAR039 infusion was observed in 3 patients and none were related to C-CAR039. Fifteen deaths occurred, 11 due to disease progression.

Of the 48 patients, 47 patients were evaluable for efficacy. The median follow-up time was 30.0 months. The ORR and CR rate among evaluable patients were 91.5% and 85.1% respectively. Of the 43 LBCL patients, the ORR was 90.7%, with 86.0% CR. Median duration of response (DOR) was not reached. 23/47 (48.9%) patients remain in CR, 10 of them for more than 36 months. Median PFS has not been reached. KM estimates of 24-m PFS rate were 62.6% (all patients) and 64.1% (LBCL). Median OS has not been reached. KM estimates of 24-m OS rate were 76.5% (all patients) and 79.0% (LBCL).

The complete text of the abstract can be found
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About the C-CAR066 Study
C-CAR066 is a novel second generation CAR-T therapy targeting the CD20 antigen. Preclinical studies suggest that C-CAR066 has superior anti-tumor activity compared to anti-CD20 CAR-Ts derived from scFVs of Leu16, Rituximab and Obinutuzumab, and to anti-CD19 CAR-Ts derived from scFV FMC63.

The Phase I clinical trials (NCT04036019, NCT04316624) were conducted in Shanghai Tongji Hospital and Institute of Hematology & Blood Diseases Hospital in Tianjin, China, to evaluate the safety and efficacy of C-CAR066 in subjects with r/r B-NHL who were previously treated with and failed after an anti-CD19 CAR-T therapy. C-CAR066 was administered as a single intravenous dose after a 3-day cyclophosphamide (300mg/m2x3d) plus fludarabine (30mg/m2x3d) conditioning regimen.

Key Results of C-CAR066
Between October 16, 2019, and August 17, 2021, a total of 14 patients received C-CAR066 at doses of 2.0×106 CAR-T cells/kg and 3.0×106 CAR-T cells/kg. Eleven patients (78.6%) were DLBCL, 3 patients (21.4%) were tFL. The median age was 54.5 years (range, 37-67). Twelve patients (85.7%) were in Ann Arbor Stage III/IV. The median number of prior lines of therapy was 5 (range, 2-7). All patients had prior CD19 CAR-T therapy.

As of October 10, 2023, 12/14 patients (85.7%) experienced CRS, all were grade 1/2, except for 1 patient who experienced a grade 4 CRS. No patients experienced ICANS. Grade 3 or higher cytopenia not resolved by Day 30 following C-CAR066 infusion occurred in 28.6% patients and included neutropenia (21.4%), thrombocytopenia (14.3%), and anemia (14.3%). At cutoff date, 8 patients experienced infections, only 2 were grade 3. Seven deaths occurred and all due to disease progression. No SPM and new safety signals were observed with longer follow-up.

The investigator assessed ORR was 92.9%, with 57.1% CR. With the median follow-up of 27.7 months, median PFS and DOR were 9.4 months and 8.3 months, respectively. Four patients had remained in CR for more than 30 months. The Kaplan-Meier estimate of median OS was 34.8 months (11.4 – NA).

The complete text of the abstract can be found
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On December 12, 2023 Bristol Myers Squibb (NYSE: BMY) and 2seventy bio, Inc. (Nasdaq: TSVT) reported results from the preplanned final progression-free survival (PFS) analysis of KarMMa-3, the pivotal Phase 3, open-label, global, randomized controlled study evaluating Abecma (idecabtagene vicleucel) compared with standard combination regimens in adults with relapsed and refractory multiple myeloma after two to four prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody (triple-class exposed), who were refractory to their last regimen (Press release, 2seventy bio, DEC 12, 2023, View Source [SID1234638479]). At a median follow-up of 30.9 months (range: 12.7-47.8), representing the longest follow-up for a randomized Phase 3 CAR T cell therapy trial in this patient population, significantly improved PFS was maintained with Abecma compared to standard regimens (95% CI: 13.8 months vs. 4.4 months), with a 51% reduction in the risk of disease progression or death (HR: 0.49; 95% CI: 0.38-0.63). These data are being presented today in an oral presentation at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (Oral Presentation #1028).

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With extended follow-up, treatment with Abecma (n=254) continued to demonstrate higher overall response rates (ORR) and a deepening of responses versus standard regimens. The ORR with Abecma was 71% (95% CI: 66-77) with a complete response (CR) rate of 44% (95% CI: 38-50), which increased by 5% from the interim analysis. In comparison, the ORR for standard regimens was 41% (95% CI: 34-51), with a CR rate of 5% (95% CI: 2-9), which remained unchanged from the time of interim analysis. The PFS, ORR and CR rates observed in the KarMMa-3 trial in the standard regimens arm are consistent with those that have historically been observed in this heavily pre-treated triple-class exposed patient population, in which PFS is approximately four months and deep and durable responses are limited. With these data, Abecma is the first and only anti-BCMA CAR T cell therapy to demonstrate superiority over standard regimens in a randomized, controlled Phase 3 trial designed to evaluate patients with triple-class exposed relapsed and refractory multiple myeloma.

"With longer follow-up from the KarMMa-3 study, we continue to see the significant clinical benefit that Abecma delivers for triple-class exposed multiple myeloma, illustrating the potential of using Abecma for long-term disease control and remission when used earlier in the treatment paradigm," said Paula Rodriguez-Otero, M.D., Ph.D., Department of Hematology, Clinica Universidad de Navarra, Pamplona, Spain. "As the CAR T therapy with the longest real-world experience in later lines of therapy, and with these latest data which demonstrate clinically meaningful benefit and awell-established and generally predictable safety profile, Abecma has the potential to be a transformative treatment option across lines of therapy for triple-class exposed relapsed and refractory multiple myeloma."

"As the first-in-class anti-BCMA CAR T cell therapy, we have long believed in the clinical value Abecma can deliver across the treatment paradigm for multiple myeloma, transforming outcomes for patients with a relentless disease and continued unmet need," said Anne Kerber, senior vice president, Head of Late Clinical Development, Hematology, Oncology, and Cell Therapy, Bristol Myers Squibb. "These longer-term results from the KarMMa-3 trial clearly demonstrate the potential of Abecma to be an important treatment option to provide improved progression-free survival and durable responses in patients with relapsed and refractory multiple myeloma after being treated with the three main classes of therapy. We are proud to share these data which further advance the use of cell therapies as a new standard of care for more patients in earlier lines of therapy for difficult-to-treat blood cancers."
In the study, which included a patient-centric design that allowed for crossover from standard regimens to Abecma upon confirmed disease progression, overall survival (OS) was a key secondary endpoint. Due to the median PFS observed with standard regimens, more than half (56%) of patients in the standard regimens arm crossed over to receive Abecma as a subsequent therapy. The median OS was 41.4 months with Abecma (95% CI: 30.9-NR) and 37.9 months with standard regimens (95% CI: 23.4-NR) (95% CI: 0.73-1.40; HR: 1.01). However, the prespecified sensitivity analyses adjusting for crossover showed a median OS of 41.4 months for Abecma (95% CI: 30.9-NR) and 23.4 months (95% CI: 17.9-NR) for standard regimens (95% CI: 0.45-1.09; HR: 0.69), suggesting a positive trend in OS benefit for Abecma compared with standard regimens. Historically, based on real-world evidence, median OS for patients with triple-class exposed relapsed and refractory multiple myeloma is approximately 13 months.

"With the adjustments for crossover in the KarMMa-3 study, we clearly see the consistent trend in survival benefit that this anti-BCMA CAR T cell therapy delivers, introducing the potential for Abecma to be an important treatment option for these patients," said Sergio Giralt, M.D., Division of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center. "These results show remarkable and significantly improved durable outcomes for relapsing triple-class exposed multiple myeloma patients, which is a population that has had poor overall and progression-free survival and no established standard treatment approach that provides durable responses."
"It’s important to bear in mind that management of relapsed refractory multiple myeloma remains challenging; patients are becoming triple-class

exposed earlier in their treatment course and then developing disease that is resistant to existing therapies," said Steve Bernstein, M.D., chief medical officer, 2seventy bio. "We are excited that these positive results from the KarMMa-3 study demonstrate a significant clinical benefit of Abecma across lines of care in triple-class exposed multiple myeloma and look forward to the potential of expanding the benefits of Abecma to these patients earlier in their treatment course."

In the KarMMa-3 study, Abecma continued to exhibit a well-established and generally predictable safety profile, including no new safety signals, with mostly low-grade occurrences of cytokine release syndrome (CRS) and neurotoxicity. In patients treated with Abecma with extended follow-up, occurrences of CRS and neurologic toxicities remained consistent with the interim analysis with 88% of patients experiencing any grade CRS, and Grade 3/4 CRS events occurring in 4% of patients. Two patients (1%) experienced a Grade 5 CRS event. Any grade neurotoxicity occurred in 15% of patients, with Grade 3/4 neurotoxicity occurring in 3% of patients, and no Grade 5 events reported.

Abecma was recently approved in Japan for patients with relapsed or refractory multiple myeloma who have received at least two prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody based on the KarMMa-3 study, making it the first CAR T to receive regulatory approval for use in earlier lines of therapy for patients with relapsed or refractory multiple myeloma. A supplemental Biologics License Application for Abecma based on the KarMMa-3 results is currently under review with the U.S. Food and Drug Administration (FDA), and an Oncologic Drugs Advisory Committee meeting will be held to discuss the data. Regulatory applications for Abecma in earlier lines of therapy for triple-class exposed relapsed and refractory multiple myeloma are also under review with the European Medicines Agency and Swissmedic.

Results from Extended Follow-up for Cohort 2c of the KarMMa-2 Study

Results from extended follow-up for Cohort 2c of the multicohort, Phase 2, multicenter KarMMa-2 study, evaluating Abecma in patients with multiple myeloma who had an inadequate response to frontline therapy with autologous stem cell transplantation (ASCT) are also being presented in a poster presentation (Poster Presentation #2101) at the meeting. At data cutoff with a median follow-up of 39.4 months, the ORR in patients treated with Abecma (n=31) was 87.1% (95% CI: 70.2-96.4), with a CR rate of 77.4% (95% CI: 58.9-90.4). Median duration of response, median PFS and median OS were not reached, and all patients who received Abecma (n=31) remained alive at follow-up. Safety results were generally consistent with the well-established known safety profile of Abecma, with any grade CRS occurring in 58.1% of patients and no reports of Grade >3 CRS.
Abecma is the first-in-class B-cell maturation antigen (BCMA)-directed CAR T cell immunotherapy approved by the FDA for the treatment of adult patients with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. Please see the Important Safety Information section below, including Boxed WARNINGS for Abecma regarding CRS, neurologic toxicities, Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome and Prolonged Cytopenia. Abecma is also approved in the European Union, Switzerland, Canada, the United Kingdom and Israel for adult patients with triple-class exposed relapsed or refractory multiple myeloma after three to four or more prior lines of therapy.

Memorial Sloan Kettering Cancer Center disclosures: Dr. Giralt and Memorial Sloan Kettering Cancer Center have financial interests associated with the research described in this release.

About KarMMa-3

KarMMa-3 (NCT03651128) is a pivotal, Phase 3, open-label, global, randomized, controlled trial evaluating Abecma compared to standard regimens in patients with relapsed and refractory multiple myeloma who have received two to four prior lines of treatment, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody, and were refractory to the last treatment regimen. Patients were randomized to receive Abecma or standard regimens that consisted of combinations that included daratumumab, pomalidomide, and dexamethasone (DPd), daratumumab, bortezomib, and dexamethasone (DVd), ixazomib, lenalidomide, and dexamethasone (IRd), carfilzomib and dexamethasone (Kd) or elotuzumab, pomalidomide and dexamethasone (EPd) chosen based on their most recent treatment regimen and investigator discretion. The primary endpoint evaluated in this study is progression-free survival (PFS), defined as time from randomization to the first documentation of progressive disease or death due to any cause, whichever occurs first. Key secondary endpoints include overall response rate (ORR) and overall survival (OS).

About KarMMa-2

KarMMa-2 (NCT03601078) is a Phase 2, open-label, multicohort, multicenter study evaluating the efficacy and safety of Abecma in patients with relapsed and refractory multiple myeloma (Cohort 1), patients with multiple myeloma that has progressed within 18 months of initial treatment including autologous stem cell transplantation (ASCT) (Cohort 2a), or without ASCT (Cohort 2b) or, in patients with inadequate response post-ASCT during initial treatment (Cohort 2c), and patients with newly diagnosed multiple myeloma with suboptimal response to ASCT (Cohort 3). The primary endpoints evaluated in this study are ORR in Cohort 1 and complete response (CR) rate in Cohorts 2a, b, c and Cohort 3. Key secondary endpoints include CR rate in Cohort 1, ORR in Cohorts 2a, b, c and Cohort 3, duration of response, PFS and OS.

About Abecma

Abecma recognizes and binds to BCMA on the surface of multiple myeloma cells leading to CAR T cell proliferation, cytokine secretion, and subsequent cytolytic killing of BCMA-expressing cells. Abecma is being jointly developed and commercialized in the U.S. as part of a
Co-Development, Co-Promotion, and Profit Share Agreement between Bristol Myers Squibb and 2seventy bio.
The companies’ broad clinical development program for Abecma includes clinical studies (KarMMa-2, KarMMa-3, KarMMa-9) in earlier lines of treatment for patients with multiple myeloma. For more information visit clinicaltrials.gov.
Important Safety Information

BOXED WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES, HLH/MAS, AND PROLONGED CYTOPENIA

•Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients following treatment with ABECMA. Do not administer ABECMA to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
•Neurologic Toxicities, which may be severe or life-threatening, occurred following treatment with ABECMA, including concurrently with CRS, after CRS resolution, or in the absence of CRS. Monitor for neurologic events after treatment with ABECMA. Provide supportive care and/or corticosteroids as needed.
•Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS) including fatal and life-threatening reactions, occurred in patients following treatment with ABECMA. HLH/MAS can occur with CRS or neurologic toxicities.
•Prolonged Cytopenia with bleeding and infection, including fatal outcomes following stem cell transplantation for hematopoietic recovery, occurred following treatment with ABECMA. ABECMA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ABECMA REMS.

On December 12, 2023 Imugene Ltd ("Imugene") (ASX: IMU), a clinical stage immuno-oncology company, and NeoImmuneTech, Inc. ("NIT"), (KOSDAQ: 950220) a clinical-stage T-cell-focused biopharmaceutical company, reported a strategic collaboration to evaluate Imugene’s allogeneic CAR T, azer-cel, in combination with NIT’s proprietary immune T cell amplifier "Fc-fused recombinant human interleukin-7", NT-I7, for the treatment of cancer (Press release, NeoImmuneTech, DEC 12, 2023, https://mcusercontent.com/e38c43331936a9627acb6427c/files/6a6df5ec-bcfd-bb50-bb42-3b1d0e5e3600/Imugene_and_NeoImmuneTech_to_Improve_Cancer_Treatments.pdf [SID1234638448]).

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Azer-cel is an allogeneic CD19 CAR T cell therapy program with extensive clinical data and a potentially fast-to-market development strategy. Azer-cel has demonstrated clinically meaningful activity with an acceptable safety profile in blood cancers such as lymphoma and leukemia.

NT-I7 (efineptakin alfa) is the only long-acting human IL-7 cytokine in clinical stage development. NT-I7 plays a key role in T cell development and survival, boosts cancer fighting T cell numbers, their health, and functionality to enhance immune function and potentially provides improved cancer fighting benefits to patients. NT-I7 exhibits favorable stability, activity and safety profiles on patient dosing compared with naturally occurring IL-7, making it an ideal combination partner for cell therapy drugs like azer-cel.

"We are delighted to be working with NIT on the potential to enhance azer-cel activity as part of this research collaboration," said Leslie Chong, Managing Director & Chief Executive Officer of Imugene.

Dr. Se Hwan Yang, Ph.D., President and Chief Executive Officer of NeoImmuneTech said: "NT-I7 has already shown encouraging results in multiple indications in immuno-oncology and infectious diseases, both as a monotherapy or in combination. The research collaboration with Imugene, an industry leader in allogeneic cell therapy, could greatly expand the potential of our asset and accelerate its path to commercialization, as we did in acute radiation syndrome."

The strategic collaboration is effective immediately and will continue for two years whilst there are relevant research activities being performed under the research plan. Such research activities will be performed exclusively in the United States. The strategic collaboration may be terminated upon completion of the research activities, by agreement, or according to common commercial termination provisions. Imugene will fund its component of the strategic collaboration by its existing planned research activities. No additional or new funding is required for the initial activities by Imugene for the strategic collaboration. The funding of Imugene research activities is material and is allowed for in the Company’s existing research budget.

Each party has full intellectual property (IP) rights (patents) to their individual background technology. In the event new IP is generated from the strategic collaboration (each a "Joint Collaboration Technology"), the parties shall discuss in good faith the filing, prosecution, maintenance, enforcement, defense of any patent applications relating thereto, as well as each party’s right to use, such Joint Collaboration Technology.

On December 11, 2023 Alphamab Oncology (stock code: 9966.HK) reported that the independently developed global first subcutaneous injection HER2 bispecific antibody-conjugated drug (JSKN033) has received approval from the Australian Bellberry Clinical Research Ethics Committee to conduct clinical studies (JSKN033-101) for the treatment of HER2-expressing advanced or metastatic solid tumors.

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JSKN033-101 is an open-label, muticenter, phase I/II clinical study. The study consists of dose escalation and dose expansion phases: The Phase I dose escalation stage aims to assess the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of JSKN033 in patients with advanced or metastatic HER2-expressing solid tumors, determining the maximum tolerated dose (MTD) and/or Phase II recommended dose (RP2D); the Phase II dose expansion stage will evaluate the efficacy and safety of JSKN033 in HER2-expressing gastrointestinal tumors at the RP2D dose.

JSKN033 is a subcutaneous injection compound consisting of JSKN003 and envafolimab, independently developed by Alphamab. JSKN033 is expected to provide effective innovative therapy for patients and doctors through IO and ADC combo and have better safety profile and convenience due to the nature of SubC injectables.

About JSKN033

JSKN033 is the global first subcutaneous injection HER2 bispecific antibody-conjugated drug developed by Alphamab, which is composed of JSKN003 and envafolimab. JSKN003 is a HER2 dual-epitope-targeting antibody-conjugated drug composed of three parts: bispecific antibodies targeting two non-overlapping epitopes of the HER2 extracellular domain, a cleavable linker, and a topoisomerase I inhibitor. Envafolimab is a Fc fusion protein consisting of humanized anti-PD-L1 single domain antibody and human IgG1 Fc fragment, which has been approved by China NMPA as the global first subcutaneously administered PD-L1 inhibitor and marketed in China.

(Press release, Alphamab, DEC 11, 2023, View Source [SID1234657029])

On December 11, 2023 Genor Biopharma (Stock code: 6998.HK) reported the company participated at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting held in San Diego, USA on December 9-12, 2023, and shared the poster of the preliminary clinical safety and efficacy results of the phase I/II study of GB261(CD20/CD3) (Press release, Genor Biopharma, DEC 11, 2023, View Source [SID1234656303]).

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GB261, an Fc-Function Enabled and CD3 Affinity De-Tuned CD20/CD3 Bispecifc Antibody, Demonstrated a Highly Advantageous Safety/Efficacy Balance in an Ongoing First-in-Human Dose-Escalation Study in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma (Poster Number: 1719)

Introduction:
GB261 is a novel and highly differentiated CD20/CD3 bispecific T cell engager antibody computationally designed to maintain Fc effector function, i.e., antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC) to broaden the mechanisms of action (MOA) for tumor cell killing. Furthermore, the "imbalanced" design of GB261 integrates de-tuned CD3 binding to reduce CRS incidence and improve safety features of the Fc effector function. Extensive pre-clinical studies have shown that GB261 has a highly advantageous safety/efficacy balance. Here, we present the preliminary clinical safety and efficacy results of an ongoing phase I/II study for GB261 (NCT04923048).

Methods:
This is an open-label, multicenter (China and Australia), dose escalation/expansion phase 1/2 study of GB261 to evaluate the safety, tolerability and efficacy in patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma(B-NHL) and Chronic Lymphocytic Leukemia (CLL). Adult patients were eligible when they have CD20+ r/r B-NHL or CLL with no available standard of care treatments, adequate organ function, and no CNS involvement or other CNS disease, infections or other active/serious medical issues that may affect compliance or interpretation of results. GB261 was administered in 21-day cycles, weekly (QW) for the first 6 doses followed by every 3 weeks (Q3W) until disease progression, or other situation defined in protocol. Response assessment was based on Lugano 2014 and LYRIC 2016 criteria.

Results:
As of June 17, 2023, 47 r/r B-NHL patients (DLBCL:76.6%; FL:23.4%) were enrolled at flat or step-up doses of GB261 ranging from 1mg to 300mg. Median age was 60.0 years (range: 28, 81), 55.3% of patients were male. Median prior lines of therapy were 3 (range: 1, 10). 78.7% of patients were refractory to any anti-CD20 therapy, 70.2% refractory to their last systemic therapy. Median time since last prior therapy to first study treatment was 1.9 months.

In efficacy evaluable patients (n=22) from 3mg to 100mg, with at least 75% dose exposure before the first radiographic assessment, the median duration of study follow-up was 4.5 months (95%CI: 4.0, 7.4). The overall response rate (ORR) was 73% (16/22), and complete response rate (CRR) was 45.5% (10/22). ORR and CRR were 100% and 100% in 3mg, 56% and 22% in 10mg, 67% and 33% in 30mg. At 100mg dose, there were 5 evaluable patients, with ORR 100% (5/5), CRR 80% (4/5) and PR (20%, 1/5; mosunetuzumab-refractory rrDLBCL patient). Median time to response (TTR) was 1.3 months (95%CI: 1.2, 1.5), the same as median time to CR. Median duration of response (DOR) was not reached.

In safety evaluable patients (n=47), the median duration of study follow-up was 4.1 months (95%CI: 2.9, 5.3). Treatment-emergent adverse events (TEAEs) were 95.7%, treatment-related adverse events were 85.1%. The most common TEAEs were COVID-19 infection (40.4%; grade 1 or 2: 27.6%; grade >=3: 12.8%) and neutropenia (31.9%; grade 1or 2: 14.9%; grade >=3: 17.0%). AE related treatment discontinuation and death were reported in 2 patients, which were all due to COVID-19 pneumonia. CRS occurred in 12.8% (6/47) patients, was mild and transient. CRS in 100mg were 14.3% (2/14). All cases of CRS were grade 1 (8.5%, 4/47) or 2 (4.3%, 2/47), no grade 3 (Lee et al., ASTCT criteria), no interruptions of treatment, and no administration of Tocilizumab. The median duration of CRS was 7 hours. No ICANS were reported.

The PK profile of GB261 appeared to be linear across dose ranges tested (1mg -100mg). Effective half-life appeared to be 2-3 weeks which supports every 3-4 weeks dosing.

Conclusion:
GB261, a novel and highly differentiated CD20/CD3 bispecific antibody, is the first clinical stage Fc+ CD20/CD3 T cell engager. In heavily pretreated B-NHL patients, GB261 showed a highly advantageous safety/efficacy balance, consistent with the MOA. The safety profile is excellent especially for the CRS which is very mild, transient and less frequent compare with other CD20/CD3 bispecific antibodies. The response after GB261 treatment was early, deep and durable. At the 100mg dose level, 80% of patients achieved CR and with favorable safety. Additionally, clinical benefit seen in other CD20/CD3 bispecific antibody failed patients provides clinical support to the unique and differentiated MOA of GB261.