Classical monoclonal antibodies produced by nature or man bind to one antigen solely. In contrast, so-called bispecific antibodies are engineered to simultaneously bind two different antigens. These two antigens can be either located on one cell type, e.g. a tumor cell, or two different cell types, e.g. on a tumor cell on the one and an immune effector cell on the other side. An example for the first case is low affinity binding to CD47 and high affinity binding to a TAA to effectively increase phagocytosis by blocking the SIRPα-CD47 “don’t eat me signal” (SIRPα, e.g. expressed on macrophages). An active constant region (Fc) of the bsAb can bind macrophages and natural killer cells and induce increased ADCP and ADCC. Direct binding to a different cell type, the second case, is frequently designed to attract and retarget T cells to kill tumor cells (TCB).
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T cell bispecific antibodies
TCBs simultaneously bind a surface target on tumor cells and an associated T cell receptor chain present on all T cells (CD3), thus replacing conventional signal 1 within the T cell activation cascade. They thereby retarget T cells to tumor cells otherwise not attacked. TCBs have shown the ability to induce a potent T cell-mediated killing of cells carrying the target. TCBs are in principle applicable to all patients whose tumor cells express the targeted antigen. In contrast to CART-cells, no patient-specific generation ex vivo is necessary.
We in LamKap Bio group develop and characterize TCBs targeting a TAA on tumor cells from patients with solid cancers.
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CD28 costimulation
CD28 is one of the most important co-stimulatory receptors leading to full T cell activation (so-called signal 2). The goal of our bispecific antibodies is to provide a specific signal 2 to T cells via the co-engagement of a tumor-associated antigen (TAA). Importantly, CD28 engagement on T cells is monovalent and is restricted by the TAA present on tumor cells. The resulting bispecific antibodies can be used to enhance anti-tumor efficacy driven by TAA x CD3 TCBs, as for example NILK-2301 or NILK-2501, or synergize e.g., with checkpoint inhibitors.
We in LamKap Bio group develop and characterize CD28 costimulatory bispecific antibodies targeting a TAA on tumor cells from patients with solid cancers.
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Targeting CD47
CD47 is ubiquitously expressed on cells of the human body and has been described to be overexpressed on malignant cells from patients with both hematological and solid tumors. It acts as a “don’t eat me signal” to phagocytes, such as macrophages. Thereby, tumor cells escape from being eaten up.
Targeting CD47 has already shown promising preclinical and early clinical activity in different tumor entities, including hematological malignancies such as lymphoma and solid tumors, for example gastric cancer. However, as most molecules in clinical testing have an inactive/silent Fc part not able to recruit either the complement system or phagocytes, they require combination treatment with compounds that deliver necessary co-stimulating, pro-phagocytic signals, e.g. “active” monoclonal antibodies.
As CD47 is expressed on all human cells, measures need to be taken to limit the immune response to tumor cells as intended target. Our partner, LightChain Bioscience – NovImmune SA, has developed a strategy using bispecific antibodies simultaneously targeting both CD47 and a tumor specific antigen to selectively block CD47 on malignant cells. Normal cells remain largely unaffected. Doing so, our molecules can be more potent: They are armed with an active Fc (human IgG1) simultaneously activating the complement system to “drill holes” and opsonize tumor cells, and binding to Fc receptors on phagocytes and natural killer cells to get tumor cells “eaten up” respectively lyzed.
We in LamKap Bio group develop and characterize bispecific antibodies simultaneously binding a tumor-associated antigen on malignant cells with high affinity and blocking with lower affinity CD47 for selective killing and phagocytosis of tumor cells in solid malignancies.
