Legend Bio announces the latest progress in solid tumors and allogeneic CAR-T therapy

Today, Legend Bio introduced the latest layout and developments of the company's cell therapy development at the R&D Day event
.

The CAR-T therapy cilta-cel, which targets B cell maturation antigen (BCMA), developed by Legend Bio and Janssen, has shown certain anti-cancer activity in clinical trials for the treatment of multiple myeloma

At today’s R&D Day event, the executives of Legend Bio not only introduced the latest R&D layout of cilta-cel, but also detailed the company’s key R&D projects in the treatment of solid tumors, as well as the construction of innovative allogeneic CAR-T Breakthrough in therapy technology platform
.

Overcome the obstacles of CAR-T therapy in the treatment of solid tumors

Overcome the obstacles of CAR-T therapy in the treatment of solid tumors

Although CAR-T therapy has made significant progress in the treatment of hematological malignancies, it has not yet achieved the same curative effect in the treatment of solid tumors
.

This is because there are a variety of immunosuppressive cells and cytokines that inhibit T cell activity in the tumor microenvironment of solid tumors, and it is not easy to find antigens that are specifically expressed in solid tumors but not expressed in healthy tissues

▲CAR-T therapy needs to overcome multiple challenges in the treatment of solid tumors (Image source: Legend Biology official website)

CAR-T therapy for gastric cancer and pancreatic cancer

CAR-T therapy for gastric cancer and pancreatic cancer

Legendary Bio's LB1908 is a CAR-T therapy targeting Claudin 18.
2 (CLDN 18.
2)
.

CLDN18.

▲Tissue expression of CLDN18.
2 and CLDN18.
1 (Image source: Legendary Biology official website)

The VHH antibody platform developed by Legend Biology utilizes Nanobodies that contain only heavy chains produced in alpaca animals
.

Because this antibody does not have a traditional light chain, it is smaller than the antibody produced by the human body, but it can bind to the antigen tightly like a traditional antibody

▲The benefits of VHH antibody platform to CAR-T design (Image source: Legend Biology official website)

LB1908 uses the VHH antibody design to ensure that it has a high degree of specificity for CLDN18.
2
.

In preclinical animal models of gastric cancer and pancreatic cancer, it has shown strong anti-cancer activity

▲Introduction to LB1908 (picture source: Legendary Bio's official website)

At present, this CAR-T therapy under development has entered a phase 1 clinical trial of dose escalation
.

In the first patient treated with the lowest dose of LB1908, it showed good safety and preliminary anticancer activity

▲Patients treated with the lowest dose of LB1908 showed signs of clinical remission (Image source: Legend Biotech official website)

Legend Bio plans to further expand clinical trials in China, and is preparing to submit an IND application for this therapy to the US FDA
.

"Armed" CAR-T Therapy Overcoming the Obstacles of Tumor Microenvironment

"Armed" CAR-T Therapy Overcoming the Obstacles of Tumor Microenvironment

In order to overcome the impact of immunosuppressive factors in the tumor microenvironment on the activity of CAR-T, Legend Bio’s unique technology platform screens large-scale intracellular targets that allow CAR-T cells to resist immunosuppressive signals, and uses them to improve therapy in the tumor microenvironment.
Persistence and liveliness in the media
.

Image source: Legendary Bio's official website

The company's LB2101 is an "armored" CAR-T therapy targeting GPC-3
.

In addition to the chimeric antigen receptor (CAR) that targets GPC-3, it also expresses a transmembrane protein that is activated by signals in the tumor microenvironment

▲Introduction of LB2101 (picture source: Legendary Biology official website)

In animal experiments, this therapy showed higher anti-cancer activity compared with the unarmed CAR-T therapy, and the cell expansion in the animal body was greater
.

▲LB2101 (purple) significantly improves the function of CAR-T therapy (Image source: Legendary Biology official website)

CAR-T therapy for small cell lung cancer

CAR-T therapy for small cell lung cancer

LB2102 is a CAR-T therapy targeting DLL3
.

DLL3 is a potential target widely expressed in small cell lung cancer (SCLC) and certain neuroendocrine tumors

▲Introduction to LB2102 (picture source: Legendary Bio's official website)

Pre-clinical in vivo studies have shown that this therapy is more effective in shrinking tumors than traditional CAR-T therapy, and the number of CAR-T cells in the peripheral blood and CAR-T cells infiltrating the tumor are significantly increased
.

▲ LB2102 (red) in vivo animal experiment results (picture source: official website of Legend Biology)

An allogeneic CAR-T technology platform that does not use gene editing

An allogeneic CAR-T technology platform that does not use gene editing

An important obstacle that needs to be overcome in allogeneic CAR-T cell therapy is that T cells transplanted into the patient's body attack the host's tissues and the host's immune rejection of foreign cells
.
Currently, most allogeneic CAR-T therapies use gene editing to knock out the endogenous T cell receptor (TCR) in T cells and other proteins that may trigger host immune rejection
.
Although this therapy can use a variety of gene editing tools to permanently knock out proteins that trigger immune rejection, it also has some potential risks, including off-target effects of gene editing tools and potential risks of chromosomal abnormalities
.
The risk of chromosomal abnormalities also led to the suspension of a recent clinical trial of allogeneic CAR-T therapy by the FDA
.

▲The advantages and limitations of using gene editing to develop allogeneic CAR-T therapies (picture source: Legendary Biology official website)

Legendary Bio's development strategy is to develop proteins that bind to TCR subunits in cells.
After they bind to the α and β subunits of TCR, they hinder the formation of normal TCR complexes, thereby blocking the transmission of endogenous TCR signals
.
This strategy does not require gene editing of cells, and proteins that block endogenous TCR signals can be simultaneously expressed by viral vectors carrying CAR transgenes, reducing the production steps of CAR-T therapy
.

▲Allogeneic CAR-T technology platform that does not rely on gene editing to block TCR signals (Image source: Legendary Biology official website)

The CAR-T therapy LUCAR-20S developed using this platform has entered phase 1 clinical trials
.
At present, 5 patients with relapsed/refractory non-Hodgkin's lymphoma have received the drug
.
Among them, 3 patients (60%) achieved partial remission, and no dose-limiting toxicity was found
.
In one of the patients, 30 days after receiving treatment, radiological imaging tests showed that all the lesions had almost completely disappeared, and the bone marrow biopsy was still positive, so it was judged to be a partial remission
.

▲Case report of receiving LUCAR-20S treatment (Image source: Legendary Biology official website)

Cilta-cel's future research and development plan

Cilta-cel's future research and development plan

The cilta-cel targeting BCMA has shown excellent efficacy in multiple myeloma patients who have received a variety of pre-treatments
.
On the R&D day, Legend Bio introduced the further clinical development plan of cilta-cel
.
The company, in cooperation with Janssen, has launched a phase 2 clinical trial to evaluate the efficacy of cilta-cel in patients with multiple myeloma who have received 1-3 pre-treatment treatments
.
At the same time, two key phase 3 clinical trials have been launched to evaluate the potential of cilta-cel as a first-line therapy and a second-line therapy for patients with multiple myeloma
.

▲Cilta-cel's future research and development plan (picture source: Legendary Bio's official website)

Reference materials:

[1] Legend Biotech R&D Day.
Retrieved October 18, 2021, from https://investors.
legendbiotech.
com/static-files/3cb06824-4ee5-4610-951c-8a3bd8e9ec3b

[2] US Food and Drug Administration Grants BCMA CAR-T Cilta-cel Priority Review for the Treatment for Relapsed/Refractory Multiple Myeloma.
Retrieved October 18, 2021, from https://investors.
legendbiotech.
com/news-releases/news -release-details/us-food-and-drug-administration-grants-bcma-car-t-cilta-cel