尊龙凯时·(中国区)人生就是搏!

GB261 (CD20/CD3, BsAb) is the first T-cell engager with low affinity to bind CD3 and has Fc functions (ADCC and CDC). GB261 (CD20/CD3, BsAb) significantly inhibits rituximabresistant cancer cell proliferation in both in vitro assays and in vivo models; meanwhile with T-cell activation, GB261 (CD20/CD3, BsAb) induces less cytokine release compared with compound in the same class. Thus, GB261 (CD20/CD3, BsAb) is a highly potent bispecific therapeutic antibody for B cell malignancies. It has potential to be a better and safer T-cell engager with competitive advantages over other CD3/CD20 agents.

More than a dozen of GB261 (CD20/CD3, BsAb) clinical centers have been established in Australia and China. We obtained the preliminary clinical Proof of Concept (“POC”) data in the first-in-human (“FIH”) clinical trial of GB261 in Australia in the process of a dose escalation up to 3mg, which were consistent with the molecular design mechanism of GB261 (CD20/CD3, BsAb), indicating a good safety, pharmacokinetic profile and clinical antitumor activities.

As at 30 June 2023, the low-medium dose group escalations of the phase I/II GB261 (CD20/ CD3, BsAb) clinical trial were completed. The high dose groups are currently in dose escalation. Preliminary data showed that GB261 (CD20/CD3, BsAb) has demonstrated promising efficacy, while initial efficacy has also been seen in patients who have failed prior CD20/CD3 bi-specific antibodies (mosunetuzumab), CAR-T, and CD3/CD19 bi-specific antibodies therapies.

Preliminary clinical data showed favourable tolerability, which was favourable for combination therapy. Cytokine release syndrome (CRS) was mild, transient and less frequent compared with other CD20/CD3 bi-specific antibodies products (low incidence: 12.8% (Grade 1: 8.5%; Grade 2: 4.3%); no Grade 3; no anti-IL6 used; no interruption of treatment. No immune effector cellassociated neurotoxicity syndrome (ICANS) was observed.

In respect of pharmacokinetics (PK), the half-life of GB261 (CD20/CD3, BsAb) was long and supported tri-weekly dosing.

GB261 (CD20/CD3, BsAb) is scheduled for dose escalations in the second half of 2023.

Genor Biopharma participated at the 65^th American Society of Hematology (ASH) 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).

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.

Click here to download the full content of the poster.

GB263T (EGFR/cMET/cMET, TsAb) was the first tri-specific antibody of EGFR/cMET/cMET in the world, targeting EGFR and two different cMET epitopes, so designed to enhance its safety and efficacy. With highly differentiated design, GB263T (EGFR/cMET/cMET, TsAb) exhibits multiple mechanisms of action to inhibit primary and secondary EGFR mutations and cMET signaling pathway simultaneously.

In pre-clinical studies, GB263T (EGFR/cMET/cMET, TsAb) effectively thwarted ligand-induced phosphorylation of EGFR and c-MET compared to its Amivantamab (JNJ-372) analogue, and demonstrated better dual inhibition of EGFR and cMET signaling pathways. Meanwhile, GB263T (EGFR/cMET/cMET, TsAb) effectively induced the endocytosis of EGFR and cMET, and significantly reduced the protein expression levels of EGFR and cMET. GB263T (EGFR/cMET/ cMET, TsAb) played a significant dosage-dependent role in tumor suppression in several different tumor models including EGFR exon 20 insertions, EGFR exon 19 deletions, C797S mutations and various cMET expression abnormalities. In toxicology studies in cynomolgus monkeys, no significant toxic side effects were observed after 4 weeks of observation, even in the highly-dosed group.

The 2024 Annual Meeting of the European Society of Medical Oncology (ESMO) has be held in Barcelona, Spain, from 13 to 17 September. As one of the largest, most academic and authoritative clinical oncology conferences in the world, the latest results of many important studies will be presented at the conference. Among them, the latest clinical trial data of GB263T GB263T (EGFR/cMET/cMET, TsAb) under Genor Biopharma was released in the form of a poster on September 14.

1272P - Updated results from a first-in-human, phase I/II study of GB263T, a novel EGFR/cMET/cMET tri-specific antibody, in patients with advanced EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC)

Background

GB263T, a novel trispecific antibody directed against EGFR and cMET, adopts the design of two humanized VHH antibodies that recognize two different cMET epitopes. Here, we report updated phase I study results of GB263T in patients with advanced EGFRm NSCLC (NCT05332574).

Methods

This multicenter, phase I/II study was conducted to characterize the safety, tolerability, pharmacokinetics and preliminary efficacy of GB263T and establish the recommended Phase 2 dose (RP2D). The phase I portion includes dose escalation and dose expansion. Patients with EGFRm NSCLC with prior EGFR TKI and platinum-based chemotherapy were enrolled. GB263T was given at 140-1680 mg IV weekly for the first two 28-day cycles and biweekly thereafter until disease progression or intolerable toxicity.

Results

As of December 31, 2023, 15 patients were treated. All patients had previously received third-generation EGFR-TKI and platinum-based chemotherapy. The most common treatment-related adverse events (TRAEs) were rash (60.0%), fatigue (40.0%), paronychia (40.0%), and infusion related reaction (33.3%), and all are mild (grade 1/2). Only one patient developed ≥grade 3 TRAE (grade 3 oral mucositis, the only DLT reported at 1680mg, which resolved after symptomatic treatment). AE leading to treatment discontinuation occurred in 1 patient (grade 1 interstitial lung disease (ILD)), who had prior HER3-ADC therapy and already exhibited ILD-like minor image change). No AE leading to death occurred. Among 14 response-evaluable patients, two PRs and 6 SDs were observed. For the patient subset with EGFR sensitive mutations and progressed after third-generation EGFR-TKI treatment, at therapeutic efficacious doses of 1260/1680mg (N=7), confirmed ORR was 28.6% (2/7). Three patients with cMET alterations after third-generation EGFR-TKI demonstrated clear clinical benefit (2 PRs and 1 durable SD), with the longest treatment duration over 12 months (840mg) at data cutoff.

Conclusions

GB263T showed a favorable safety profile with promising efficacy at the therapeutic dose (1260-1680mg) in previously heavily treated patients with EGFRm NSCLC.

Presenter/Authors

Q. Du, Y. Lv, J. Xu, F. Peng, H. Cao, X. Yang, Z. Qian, X. Li, Y. Cao, Q. Ding, Y. Tan, S. Han;
Genor Biopharma Co. Ltd., Shanghai, China

Disclosures 

Q. Du, None..
Y. Lv, None..
J. Xu, None..
F. Peng, None..
H. Cao, None..
X. Yang, None..
Z. Qian, None..
X. Li, None..
Y. Cao, None..
Q. Ding, None..
Y. Tan, None..
S. Han, None.

Abstract

Background: Immunotherapy using immune checkpoint modulators such as anti-PD1/PD-L1 have been widely used in cancer therapy. Combination of checkpoint inhibition using anti-PD1 and anti-CTLA4 has improved therapeutic efficacy but is also accompanied by severe immune related adverse events (irAEs) which limited their clinical use. Bi-specific antibody targeting PD-1/CTLA-4 such as cadonilimab has shown improved clinical benefits with reduced irAEs in cervical cancer. Vascular endothelial growth factor (VEGF) is overexpressed in various solid tumors and anti-VEGF agents inhibit neovascularization and shrink tumor with time. Combined application of bevacizumab and PD-1/PD-L1 blockade displays durable and improved anti-tumor effects. We have recently developed a novel tri-specific antibody GB268, specifically targeting PD-1, CTLA-4 and VEGF with fine-tuned activity & potency for each arm to simultaneously block PD-1/CTLA-4 mediated immune-suppression and VEGF mediated tumor angiogenesis.

Methods: GB268 is a hexavalent antibody with symmetrical structure, composed of anti-PD-1 VHH antibody, anti-CTLA-4 VHH antibody, and anti-VEGF conventional antibody. The Fc part is silenced by introducing L234A/L235A mutations. Comprehensive in vitro and in vivo characterization of GB268 have been carried out. Along with in vivo efficacy studies, toxicity has also been evaluated with a murine arthritis model in hPD1/hCTLA4 double-KI mice to assess immune related AEs.

Results: GB268 specifically bound to PD-1, VEGF, and CTLA-4 with high affinity and completely blocked PD-1 and VEGF pathways in reporter systems. To reduce the CTLA4 inhibition-induced AEs, the CTLA-4 arm was intentionally designed to only partially block the interaction of CTLA4 to its ligands CD80/CD86, and furthermore, the blockade of CTLA-4 was highly dependent on PD-1 expression. GB268 displayed robust anti-tumor efficacy with attenuated toxicity in murine models. In multiple PBMC-humanized models including A375 melanoma model, HT29 colorectal cancer model, and NCI-H460 NSCLC model, etc., GB268 exhibited significantly better anti-tumor efficacy, compared to PD-1/CTLA-4 bsAb and PD-1/VEGF bsAb, or in the combination of monoclonal antibodies to PD-1, CTLA-4 or VEGF. In arthritis induction model using hPD1/hCTLA4 double KI mice, GB268 had improved tolerance than cadonilimab and at least 20-fold better safety profile than ipilimumab combined with nivolumab.

Conclusions: GB268 is a first-in-class anti-PD-1/CTLA-4/VEGF tri-specific antibody with innovative design. Preclinical data demonstrated GB268 is very effective in provoking anti-tumor responses. At the meantime, immune-related AEs is alleviated. Thus, GB268 may emerge as a promising novel therapeutics for cancer treatment.

Presenter/Authors

Y. Tan, X. Li, F. Yu, J. Xu, Z. Qian, Y. Cao, X. Yang, Q. Du, F. Peng, S. Han, Q. Ding;
Genor Biopharma Co. Ltd., Shanghai, ChinaDisclosures Y. Tan, None..
X. Li, None..
F. Yu, None..
J. Xu, None..
Z. Qian, None..
Y. Cao, None..
X. Yang, None..
Q. Du, None..
F. Peng, None..
S. Han, None..
Q. Ding, None.

Abstract

Introduction: Multiple myeloma (MM) accounts for 10% of all hematologic cancers. Recent advances in MM therapy have greatly increased the overall response and survival rate. However, almost all patients eventually relapse. The prognosis still remains poor. BCMA and GPRC5D are overexpressed in myeloma cells. Although CAR-T and T cell engager (TCE) targeting BCMA or GPRC5D have been efficacious in MM patients, resistance does occur. Since the expression of BCMA and GPRC5D in MM are heterogeneous, to further improve the overall response and survival, we have recently generated a novel tri-specific T-cell engager, GBD218, targeting both BCMA and GPRC5D. GBD218 has demonstrated potent in vitro and in vivo activity against myeloma cells.

Methods:Anti-BCMA and GPRC5D nanobodies were screened from alpaca immune libraries, and anti-CD3 antibody was engineered from mouse hybridoma clone. The tri-specific antibodies were constructed in a “1+1+1” format through “knob into hole” technology fused with silenced IgG1 Fc. The format of the tri-specific antibodies was optimized by multiple rounds of in vitro activity and druggability evaluation. The in vivo tumor growth inhibition effects were evaluated in PBMC-humanized xenograft mouse models.

Results: GBD218 has been designed to potently bind hBCMA (KD=0.4nM) and hGPRC5D (cell binding EC50 ~ 2nM). To reduce CRS and other potential AEs associated with TCEs, a low affinity of anti-CD3 Fab was used. In cell-based functional assays, GBD218 showed efficient cytotoxicity against single and double positive MM cell lines with various expression levels of BCMA and GPRC5D. T cell activation and cytokine release induced by GBD218, in the presence or absence of MM cancer cells, is nicely balanced for great killing efficacy and the low risk of CRS. Importantly, the results showed that GBD218 exhibited superior in vitro killing activity compared to benchmarks, including teclistamab, talquetamab, the combination of teclistamab and talquetamab, suggesting a synergistic effect of GBD218 by targeting BCMA and GPRC5D. In xenograft models, GBD218 showed excellent anti-tumor activity, indicating great potential for GBD218 as a promising therapeutics for MM.

Conclusion: GBD218 is a novel tri-specific antibody that showed potent in vitro and in vivo anti-tumor activity. GBD218 efficiently kills both BCMA and/or GPRC5D expressing MM cells, which may hold promise to increase response rate and improve survival in MM patients in clinic.

Genor Biopharma Co. Ltd participated at the 38th Annual Meeting of The Society for Immunotherapy of Cancer, 2023, in San Diego, shared posters for programs:

Generation of an innovative BsAb targeting CCR8/CTLA-4

BACKGROUD: CTLA-4-expressing regulatory T cells (Tregs) are abundantly present in tumor tissues and suppress anti-tumor responses. Currently approved CTLA-4 inhibitors, such as ipilimumab, induce severe irAEs, which limited their use. Therefore, next-generation of CTLA-4 inhibitors with reduced toxicity and increased efficacy is highly demanded, given the fact that CTLA-4 inhibition has showed unique advantages in inducing immune memory response and prolonging anti-tumor activity.

SIGNIFICANCE: CCR8 is recently found to be predominantly expressed on intra-tumor Tregs but little on peripheral Tregs or activated Tconv. Anti-CCR8 antibodies have been shown significant anti-tumor activity in pre-clinical studies. We have hypothesized that a strong anti-CCR8 arm may provide preferential inhibition of CTLA-4 on CCR8+CTLA-4+ intra-tumor Tregs and have synergistic effects on Tregs in TME. Therefore, we have developed a novel BsAb, GBD201, targeting CCR8/CTLA-4. The innovative bsAb exhibited potent depletion of intra-tumor Tregs but spared peripheral Tregs and Tconv. In hCCR8/hCTLA-4 mice, GBD201 showed better efficacy and safety profile compared to ipilimumab.

Genor Biopharma Co. Ltd participated at the 38th Annual Meeting of The Society for Immunotherapy of Cancer, 2023, in San Diego, shared posters for programs:

• Development of a tri-specific antibody targeting PD-1/CTLA-4/TIGIT.

BACKGROUD: Immune checkpoint inhibitors (ICIs) such as anti-PD-1/PD-L1 and anti-CTLA-4 antibodies have achieved enormous success in cancer treatment. However, only a subset of patients shows clinical responses. The combination of CTLA-4 and PD-1 blockers have increased response rates in patients, but severe immune related adverse events (irAEs) have limited their use. TIGIT is another inhibitory receptor, and often co-expressed with PD-1 on tumor-infiltrating CD8+ cytotoxic T cells, which may also provide important negative signals. Several anti-TIGIT blocking antibodies have shown encouraging anti-tumor activity in clinical studies when combined with PD-1/PD-L1 blockers. We have recently generated a tri-specific antibody, GBD209, targeting PD-1/CTLA-4/TIGIT and by fine tuning and balancing the potency of each arm.

SIGNIFICANCE: GBD209 has excellent anti-tumor efficacy by synergistically blocking PD-1, TIGIT, and CTLA4 pathways on T cells. To reduce the potential toxicity caused by CTLA4 inhibition, GBD209 was designed to only partially block the interactions of CTLA4 with it’s ligands CD80/CD86, and the blockade was highly dependent on the expression PD-1, reducing peripheral toxicity. GBD209 exhibited better efficacy than PD-1/CTLA-4 bsAb as well as the combination therapy of anti-PD-1, CTLA-4, and TIGIT antibodies in animal model. In vivo arthritis model in hPD-1/hPD-L1/hCTLA-4/hTIGIT KI mice showed GBD209 had at least 15-fold better tolerance compared to Ipilimumab. Thus, GBD209 may represent a next generation of check point inhibitor with good safety profile for cancer treatment.

GB226 is an investigational, humanized, IgG4 mAb targeting the programmed cell death-1 receptor (PD-1) on immune cells. It selectively blocks dual ligands (PD-L1 and PD-L2), and restores the ability of the immune system to recognize and kill tumor cells.

We will continue to explore approval for geptanolimab (GB226) in other indications as well as novel combination therapy potential, including combination therapy with our STING agonist (GB492), to benefit more patients in China with unmet medical needs.

In January 2022, Gxplore-008, a phase II pivotal clinical study evaluating GB226 in recurrent or metastatic cervical cancer patients with PD-L1 positive status having failed in platinum-based chemotherapy, completed the last subject enrollment.

GB492 (IMSA101, STimulator of interferon genes, STING) is the major mediator of innate immune sensing of cancerous cells, which the Group exclusively licensed from ImmuneSensor Therapeutic in June 2020.

STING agonist, as an immune stimulatory therapy, may further increase the response of immune checkpoint inhibitors for patients. Multiple studies have shown that STING agonists can activate the cGAS-STING signaling and significantly enhance the efficacy of cancer immunity cycle when using in combo with other immune checkpoint inhibitors (ICI), which may become a potential first-in-class therapy.

In Phase I/II clinical trials of GB492 (IMSA101)  as a monotherapy or in combination with GB226 (Aibining^®艾比寧^®, Geptanolimab) in patients with advanced/treatment-refractory malignancies, monotherapy clinical trials were finished and a dose escalation up to 400ug was completed in January 2022.

In January 2022, approval was obtained from the CDE to directly conduct a dose-escalating study of GB492 (IMSA101) in combination with PD-1 in patients with advanced malignancy, based on the available data on the 400ug dose group in the monotherapy study in China and all data of the monotherapy dose-escalation study in the United States. In this clinical trial, an innovative FIH trial design was employed to combine the dose escalations when GB492 (IMSA101) was administered alone and when it was administered with GB226 (Aibining^®艾比寧^®, Geptanolimab). It is the first STING agonist combination therapy that has obtained clinical trial approval in China.