Hu8F4 / UT MD Anderson Cancer Center - LARVOL DELTA

Development of a novel LRP1 antibody that identifies upregulation of membrane LRP1 on activated and chimeric antigen receptor T cells (ASH 2025) - "Using a CAR-T cell developed within our group named Hu8F4-CAR, which uses the scFv of the Hu8F4 mAb targeting the leukemia-associated PR1/HLA-A2 complex on AML, we profiled the expression of LRP1 on these CAR-T cells (Ma et al...Furthermore, because LRP1 is coexpressed with PD-1 on activated CAR-T cells, their surface expression my be coordinately regulated. Overall, we report the development of a novel LRP1 monoclonal antibody, 2A7, which readily identifies upregulation of LRP1 preferentially on the surface of effector memory, central memory, activated CD4 and CD8 T cells, and a subset of CAR-T cells that maintain an activated state."

CAR T-Cell Therapy • IO biomarker • Dyslipidemia • Hematological Malignancies • Leukemia • Metabolic Disorders • CD14 • CD8 • LRP1 • PD-1

A phase I study of the T-cell receptor-like antibody Hu8F4 in pts with advanced myeloid neoplasms (ASH 2025) - "The novel T-cell receptor-like antibody, Hu8F4 was well tolerated with no dose-limiting toxicities observedat the maximum planned dose. While there were no objective responses, rapid peripheral blastreduction temporally related to each infusion suggested antileukemic activity. Real-time pK data onstudy indicate a possible sink effect mediated by high circulating disease burden that may be overcomeby a more frequent dosing strategy."

Clinical • IO biomarker • Metastases • P1 data • Chronic Myelomonocytic Leukemia • Febrile Neutropenia • Graft versus Host Disease • Hematological Malignancies • Hypotension • Infectious Disease • Leukemia • Respiratory Diseases • Septic Shock • ASXL1 • DNMT3A • TET2 • TP53

Mechanistic approach exploring combination agents to potentiate anti-leukemia activity of Hu8F4, a clinical stage T cell receptor mimic antibody (ASH 2025) - "Wealso tested recombinant SIRPα-Fc (TTI-621), another agent in clinical development designed to blockCD47. In pilot experiments anti-LRP1 antibodies improved ADCP effect of Hu8F4 byup to 80% (p<0.0001) in the presence of NSG BMDM, however the mechanism and in vivo activity of a-LRP1 antibodies are under investigation.In summary, we tested both well-known and novel regulators of ADCP, such as SIRPα, TREM2 and LRP1 incombination with Hu8F4. Understanding the mechanisms and potential contribution of these agents hasimplications not only for Hu8F4, but for other TCR-mimics and other antibodies that work through ADCPas well."

Clinical • IO biomarker • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Dyslipidemia • Hematological Malignancies • Leukemia • Solid Tumor • GLI2 • LRP1 • SIRPA • TREM2

CD47 Blockade Enhances Phagocytic Activity of the TCR-Mimic Antibody Hu8F4 Against HLA-A2+ AML (ASH 2023) - "We incubated fluorescently labeled human Mφ with CFSE-labelled target cells (U937-A2 or THP1), that had been pre-treated with Hu8F4 or isotype control antibody (Herceptin), at E:T=10, with or without anti-CD47 F(ab')2. Importantly, combining Hu8F4 with CD47 blockade significantly increased the Hu8F4 activity and together eliminated AML. The role of other phagocytosis checkpoints, such as SIRPα and LILRB-1 also warrant further investigation."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD14 • CD47 • GLI2 • SIRPA

Phase I Study of the T-Cell Receptor-like Antibody, Hu8F4 in Patients with Relapsed and Refractory Myeloid Malignancies (ASH 2023) - "Hu8F4, a first-in-class TCR mimic antibody, was well tolerated with expansion planned at more frequent dose intervals. On-target peripheral blast reduction temporally related to infusion suggests biological activity. Real-time pharmacokinetic data indicate a possible sink effect that may be overcome by a more frequent dosing strategy that is planned."

Clinical • IO biomarker • P1 data • Chronic Myelomonocytic Leukemia • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Hypotension • Infectious Disease • Leukemia • Oncology • Pneumonia • Respiratory Diseases • Thrombocytopenia • TP53

Hu8F4-CAR T cells with mutated Fc spacer segment improve target specificity and mediate anti-leukemia activity in vivo. (PubMed, Cytotherapy) - "Herein, we demonstrate that modification of the IgG1-based spacer can eliminate Fc receptor binding-induced adverse effects and Hu8F4-CAR(PQ)-T cells can kill leukemia in vivo."

CAR T-Cell Therapy • IO biomarker • Journal • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

P-TRP-2447-14: Hu8F4 in Treating Patients With Advanced Hematologic Malignancies (clinicaltrials.gov) - P1 | N=72 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Jan 2024 ➔ Jan 2026 | Trial primary completion date: Jan 2024 ➔ Jan 2026

Metastases • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Chronic Myeloid Leukemia • Chronic Myelomonocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Myelofibrosis • Oncology

A novel, codon-based method to modulate off-tumor toxicity of chimeric antigen receptor (CAR) T cells (AACR 2024) - "In CAR-T cells, we aim to use this novel, codon-based approach to fine tune and modulate CAR-T cell expression and function to elicit full on-tumor activity while lessening off-tumor toxicity.In our approach, we replaced specific endogenous codons within the non-antigen binding domains of Hu8F4-CAR, a TCR-like 2nd generation CAR developed by our group which targets the leukemia-associated antigen PR1/HLA-A2 (Ma et al...Importantly, in addition to reduced off-tumor activity against healthy myeloid cells, rare codon-modified variants preserve their activity against on-tumor target cells, including the U937-A2+ cell line and primary acute myeloid leukemia. Altogether, these results suggest that our approach can modulate CAR expression and functionality creating a novel methodology to reduce the likelihood of off-tumor adverse effects typically associated with CAR therapies."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Hu8F4 in Treating Patients With Advanced Hematologic Malignancies (clinicaltrials.gov) - P1 | N=72 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Recruiting ➔ Active, not recruiting

Enrollment closed • Metastases • Acute Myelogenous Leukemia • Chronic Myeloid Leukemia • Chronic Myelomonocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Myelofibrosis • Oncology

Phase I study of the T-cell receptor-like antibody Hu8F4 in patients with advanced hematologic malignancies (AACR 2023) - "Hu8F4 was well tolerated with no dose-limiting toxicities observed at the maximum planned dose. On-target peripheral blast reduction temporally related to infusion suggests biological activity. Real-time pharmacokinetic data on study indicate a possible sink effect that may be overcome by a more frequent dosing strategy."

Clinical • IO biomarker • Metastases • P1 data • Acute Myelogenous Leukemia • Chronic Myeloid Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • TP53