Engineering Human CD64 Chimeric Receptors for Immune Therapy

Heterologous High Affinity IgG Fc Receptor Expressed by Recombinant Immune Cells

Recombinant immune cells are genetically modified to express a heterologous high affinity IgG Fc receptor. The IgG Fc receptor is a chimeric construct. One iteration is referred to as hCD64/16a, created by cloning cDNAs of CD16a and CD64 from human peripheral blood leukocytes and fusing components of these two FcγR cDNAs to create a chimeric receptor. It consists of the extracellular region of CD64 and the transmembrane and cytoplasmic regions of CD16a. The CD64 in the extracellular domain binds with high affinity to the Fc region of IgG antibodies, and the CD16a transmembrane and cytoplasmic domains then initiate potent cell signaling. The recombinant immune cells provide a sustained cytotoxic immune response against a target (i.e., tumor cells) in the presence of therapeutic antibodies. Moreover, it is possible to attach therapeutic antibodies to cells expressing hCD64/16a prior to administering them into patients, thus providing two potential clinical benefits: 1) reducing the amount of therapeutic antibody normally administered to the patient, and 2) directing hCD64/16a-expressing cells to sites of cancer, using the attached antibody as an interchangeable targeting element.

FcγR Interactions may Improve Therapeutic Antibody Efficacy

Monoclonal antibodies (mAbs) for therapeutic purposes (i.e., infectious diseases, chronic diseases, and cancer) has become one of the fastest growing classes of drugs, but their efficacy is limited by intrinsic low affinity IgG Fc receptors in patients and non-responsiveness of some malignancies/diseases to antibody therapies. Augmenting Fcγ receptor interactions with therapeutic antibodies may improve therapeutic antibody efficacy. This new hCD64/16a construct is expected to bind therapeutic mAbs with high affinity and deliver a potent intracellular signal. In addition, therapeutic hematopoietic cell lines (e.g., NK92 cells), human induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) can be differentiated into effector leukocytes, and primary leukocytes can be engineered to express hCD64/16a to be used for cellular adoptive transfer therapy.

BENEFITS AND FEATURES:

• Functional heterologous IgG Fc receptor
• Cloned cDNAs of CD16a and CD64 from human peripheral blood leukocytes
• Contains extracellular region of CD64 and transmembrane and cytoplasmic regions of CD16a
• Sustained cytotoxic immune response against a target (i.e., tumor cells)
• Binds therapeutic mAbs with high affinity, delivers a potent intracellular signal
• Fcγ receptor interactions may improve therapeutic antibody efficacy and reduce the amount of antibody for treatment
• Potential to attach different therapeutic antibodies to engineered effector cells for targeting multiple tumor antigens and malignancies
• Effector leukocytes could be produced from therapeutic hematopoietic cell lines, iPSCs, ESCs, and primary leukocytes for cellular adoptive transfer therapy

APPLICATIONS:

• Cancer treatment
• Immunotherapy

Phase of Development - In Vitro assessments completed; ready for In Vivo testing