PD-L1x4-1BB: A Novel Immune Checkpoint Strategy

ABL BIO Secures Key Patents for Novel Cancer Therapy, Advances Promising Clinical Pipeline

SEOUL, South Korea – [Date] – ABL BIO, a clinical-stage biopharmaceutical company, has announced a important milestone with the granting of patents in the United States and Canada for its PD-L1x4-1BB bispecific antibody, Ragistomig (ABL503). This material patent, initially filed internationally in February 2019, now boasts a global coverage including Colombia, China, Malaysia, Indonesia, Eurasia, Japan, Chile, South africa, and New Zealand, securing rights through 2039.

Ragistomig is currently undergoing Phase 1 clinical trials for patients with PD-L1 positive solid tumors. Building on encouraging safety and tolerability data from its monotherapy administration, ABL BIO is actively exploring combination strategies to enhance efficacy.

The innovative Ragistomig leverages ABL BIO’s proprietary ‘Grabody-T’ bispecific antibody platform. This platform is designed to specifically activate T cells via 4-1BB within the tumor microenvironment, aiming to mitigate the dose-limiting toxicities often associated with conventional 4-1BB single-agent antibodies.

the Grabody-T platform’s potential is further exemplified by its lead program, CLDN18.2 x 4-1BB bispecific antibody, Zibastomig (ABL111). Recent data presented at the European Society of Oncology (ESMO GI 2025) demonstrated a remarkable overall response rate (OR) of 71% (12/17) and a disease control rate (DCR) of 100% when Zibastomig was combined with the PD-1 inhibitor Obdibo and chemotherapy in patients. Furthermore, in an expansion cohort, the 8mg/kg and 12mg/kg dose groups showed an extraordinary 83% (10/12) response rate.

Looking ahead, ABL BIO is poised to advance its next clinical candidate, the B7-H4 x 4-1BB bispecific antibody ABL103. Phase 1b/2 clinical trials involving ABL103 in combination with PD-1 inhibitor Keytruda are on the horizon.

“The positive clinical data emerging from the combination therapy trials of Zibastomig, our fastest-developing Grabody-T based bispecific antibody, further validates the immense potential of our Grabody-T Platform,” stated Lee Sang-hoon, CEO of ABL BIO. “We are also actively pursuing partnerships for our cerebrovascular barrier (BBB) shuttle platform, Grabody-B, and are pleased with the progress of ABL301, our parkinson’s disease candidate, in collaboration with Sanofi.”

evergreen Insights:

The patent protection secured by ABL BIO for Ragistomig highlights the critical importance of intellectual property in the biopharmaceutical industry. Strong patent portfolios not only safeguard a company’s investments in research and development but also provide a competitive edge and attract potential partnerships and investments.

The advancement of bispecific antibodies like Ragistomig and Zibastomig represents a significant trend in oncology drug development. By engaging multiple targets together, these novel modalities aim to achieve enhanced efficacy, overcome resistance mechanisms, and potentially offer improved safety profiles compared to monotherapies. The success of the Grabody-T platform, as evidenced by the data from Zibastomig, underscores the power of innovative antibody engineering to unlock new therapeutic possibilities.

The company’s strategic diversification across its pipeline, with programs targeting different tumor types and utilizing distinct platform technologies (Grabody-T and Grabody-B), demonstrates a forward-thinking approach to maximizing its therapeutic impact. The ongoing clinical evaluation and strategic partnerships reflect a commitment to translating scientific innovation into tangible patient benefits.

What are the potential benefits of combining PD-L1 blockade and 4-1BB agonism into a single bispecific antibody like PD-L1x4-1BB?

Understanding the Landscape of Immune checkpoint Inhibitors

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, offering durable responses in previously intractable malignancies. However, a significant portion of patients don’t respond to existing therapies like anti-PD-1 or anti-CTLA-4. This resistance fuels the search for novel strategies to enhance anti-tumor immunity. One promising avenue is targeting multiple immune checkpoints simultaneously, and the PD-L1x4-1BB approach represents a cutting-edge progress in this field. Keywords: immune checkpoint inhibitors, cancer immunotherapy, PD-1, CTLA-4, tumor microenvironment.

What is PD-L1x4-1BB?

PD-L1x4-1BB is a bispecific antibody designed to simultaneously block the PD-L1 checkpoint and activate the 4-1BB (CD137) costimulatory receptor. Let’s break down each component:

PD-L1 (Programmed Death-Ligand 1): Expressed on tumor cells and antigen-presenting cells, PD-L1 binds to PD-1 on T cells, suppressing their activity and allowing tumors to evade immune destruction.Blocking this interaction restores T cell function. Keywords: PD-L1 blockade, tumor evasion, T cell exhaustion.

4-1BB (CD137): A costimulatory receptor found on activated T cells. agonizing 4-1BB enhances T cell proliferation, survival, and effector function. Keywords: 4-1BB agonism, T cell activation, costimulatory signals.

The “x” in PD-L1x4-1BB signifies the bispecific nature of the antibody – it can bind to both PD-L1 and 4-1BB simultaneously. This dual action is the core of its innovative strategy.

The Rationale Behind Combining PD-L1 Blockade and 4-1BB Agonism

Conventional ICIs like anti-PD-1/PD-L1 release the brakes on T cells, but often, these T cells are still functionally impaired. They may lack sufficient activation signals to mount a robust anti-tumor response. 4-1BB agonism provides that crucial “gas pedal,” amplifying T cell activity.

Here’s why this combination is particularly attractive:

1. Synergistic Effect: Blocking PD-L1 prevents T cell suppression, while 4-1BB agonism boosts T cell activation, creating a synergistic effect.
2. Overcoming Resistance: Patients resistant to single-agent PD-1/PD-L1 blockade may benefit from the added costimulation provided by 4-1BB.
3. Enhanced T Cell Persistence: 4-1BB signaling promotes the survival and long-term persistence of anti-tumor T cells, potentially leading to more durable responses. Keywords: synergistic immunotherapy, overcoming resistance, T cell persistence.

Preclinical and Clinical Data: What Does the Research Show?

Early preclinical studies with PD-L1x4-1BB have demonstrated promising results in various mouse models of cancer.These studies showed:

Increased T Cell Infiltration: Greater numbers of T cells where observed within tumors treated with the bispecific antibody.

Enhanced Anti-Tumor Activity: Significant tumor regression and improved survival rates were observed compared to either PD-L1 blockade or 4-1BB agonism alone.

Reduced tumor Growth: PD-L1x4-1BB effectively slowed down tumor progression.

clinical trials are currently underway to evaluate the safety and efficacy of PD-L1x4-1BB in patients with advanced solid tumors. Initial Phase 1 data presented at major oncology conferences (ASCO, ESMO) have shown:

Manageable Safety Profile: The antibody appears to be generally well-tolerated, with adverse events consistent with those observed with other ICIs and 4-1BB agonists.

Evidence of Anti-Tumor Activity: Some patients have experienced tumor shrinkage or stable disease, suggesting clinical benefit.

Biomarker Identification: Researchers are actively investigating biomarkers that may predict response to PD-L1x4-1BB, such as PD-L1 expression levels and T cell infiltration patterns. Keywords: clinical trials, Phase 1 data, biomarker discovery, safety profile.

Potential Applications and Cancer Types

While still under inquiry, PD-L1x4-1BB holds promise across a broad range of cancer types, including:

* Non-Small Cell Lung Cancer (NSCLC): A significant unmet need exists for new therapies for NSCLC, particularly in patients who have progressed on first-line ICIs