Engineering Multispecific T-Cell Engaging Antibodies for High-Risk Leukemias in Children and Adolescents

Technology Overview

Dr. Mignon Loh

Leukemia is the most common type of cancer in children and most childhood leukemias are acute. Acute leukemias are fast growing, and thus they need to be treated quickly. Standard treatment for acute leukemias in children is chemotherapy. A major issue with chemotherapy is toxicity, which can have long-term effects on the patient and is of particular concern in children.

Pediatric hematologist-oncologist Mignon Lee-Cheun Loh, MD, has focused her career on understanding how genetic changes in leukemias can be harnessed to improve survival outcomes in children. Her current translational research combines immunology with genomics to create better therapeutics that are effective and less toxic for children, adolescents and young adults with leukemia. One subtype of acute leukemia is B-myeloid mixed-phenotype acute leukemia (MPAL). This type of leukemia displays some features consistent with B-cell acute lymphoblastic leukemia (B-ALL) and some features of acute myeloid leukemia (AML). Although MPAL is not common, cure rates for children and adolescents diagnosed with this subtype remain lower (60%-85%) than for almost all other subtypes of acute lymphoblastic leukemia (ALL), which now have overall survival rates ranging from 75%-80%.

Developing multispecific T-cell engagers to target B-myeloid MPAL

To improve therapies for MPAL, Dr. Loh and colleagues took advantage of the fact that blast cells in MPAL frequently express both CD33 (myeloid) and CD19 (lymphoid) antigens — but importantly, no healthy cells express both of these antigens. This feature presents an opportunity to selectively kill leukemia cells with minimal toxicity to normal cells. This approach is an advance over other targeted immunotherapies that recognize only one antigen and thus kill healthy cells along with the MPAL cells.

To achieve this selective targeting of tumor cells, Dr. Loh and team, in collaboration with protein engineer Jason Price, PhD, and pediatric neuro-oncologist James Olson, MD, PhD, have engineered multispecific T-cell engagers (MTEs) that bind CD19 and CD33 on MPAL cells and CD3 on healthy T cells. (CD3 is a T-cell coreceptor involved in activating cytotoxic T cells and T helper cells.) Healthy T cells are critical weapons that are employed to help kill the leukemia cells once the MTE recognizes the MPAL cell.

These MTEs have been affinity tuned so that they bind poorly to normal cells that express only CD19 or only CD33 but bind tightly to MPAL cells that express both CD19 and CD33. The researchers screened more than 60 novel affinity-tuned MTEs, and 30 that showed lower cytotoxicity were advanced to in vivo mouse studies. The MTEs, which showed successful control of disease in the mice at treatment doses that were well tolerated, also spared healthy B cells and myeloid cells. Furthermore, the selected MTEs contain basic sequences that are already components of FDA-approved therapeutics and have gone through human clinical trials or have been extensively studied for any immunogenicity concerns.

Historically, MPAL patients respond poorly to traditional chemotherapy. This novel approach of co-targeting antigens, though, could be available for treatment of any leukemia that presents with expression of antigens from both myeloid and lymphoid lineages. Thus, potential applications more broadly include B-lymphoblastic leukemias because they all express CD19, and many also express low levels of CD33. Furthermore, these MTEs could be used as a way to induce deep remissions and improve outcomes in concert with chemotherapy, and they have the potential to serve as a bridge therapy until patients can receive curative hematopoietic cell transplantation.

Dr. Loh, who is Director of the Ben Towne Center for Childhood Cancer and Blood Disorders Research at Seattle Children’s Research Institute, is a clinician and translational researcher with extensive expertise in pediatric leukemias, and she has published more than 230 peer-reviewed papers. For nine years, she led the Acute Lymphoblastic Leukemia Committee of the Children’s Oncology Group and designed and supervised the pivotal trial published in 2024 that demonstrated the efficacy of blinatumomab, a CD19 T-cell engager for the treatment of children with standard-risk ALL. This therapy, when added to traditional chemotherapy, has now become standard of care for this patient population.

Dr. Loh is interested in partnering to further develop and test the MTEs as highly specific novel immunotherapies with minimal cytotoxicity against normal cells to treat leukemia when cells express both myeloid and lymphoid antigens, as well as other antigens that could be targeted for protein design.

Stage of Development

• Preclinical in vitro
• Preclinical in vivo

Partnering Opportunities

• Collaborative research and development
• Sponsored research agreement
• Consultation agreement
• Licensing
• Clinical trial collaboration
• Investigator-initiated clinical trials
• Data access

Publications

Jamet S, Zhang H , Ditzler S, … Olson JM, Price J, Loh ML. Affinity-tuned T-cell engager for dual targeting of B-myeloid mixed-phenotype acute leukemia (B-MPAL). Blood. 2024;144(Suppl. 1):90-90.

Simonin M, Boissel N, Petit A, Loh M, et al. Prognostic impact of the PredicT-ALL classifier in the AALL0434 trial: a model combining NGS, MRD and WBC at diagnosis. Blood Adv. 2025;9(20);5323-5326.

Learn More

• Mignon Loh, MD
• Loh Lab
• Improving Outcomes for Philadelphia-Positive and Philadelphia-Like Acute Lymphoblastic Leukemia