Published September 21, 2016
| Version v1
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Targeting CD47 in cancer with bispecific antibodies
Description
CD47 is a ubiquitous immune checkpoint receptor overexpressed in cancer. Upregulation of CD47 plays a key role in immune evasion and correlates with poor clinical prognosis. CD47 interacts with SIRP-alpha on macrophages and other myeloid cells conveying a 'don't eat me' signal which inhibits phagocytosis of tumor cells. While monoclonal antibodies (mAbs) inhibiting CD47 boost tumor destruction by enhancing the killing potential of macrophages, the widespread tissue distribution of CD47 makes their clinical development challenging.
To circumvent tolerability and antigen sink problems arising from ubiquitous expression of CD47, we generated dual-targeting bispecific antibodies (biAbs) allowing selective blockade of CD47 on malignant cells expressing a tumor-associated antigen (TAA), CD19 or mesothelin. These bispecific kappa-lambda bodies pair a high affinity anti-TAA arm with a CD47 targeting arm and are structurally identical to human IgG1. As such, they combine efficient tumor cell targeting and selective CD47 blockage with immune activating mechanisms mediated by IgG1 constant Fc portion. We show that these biAbs are able to selectively kill cancer cells through ADCP (antibody-dependent cellular phagocytosis) and antibody-dependent cell-mediated cytotoxicity (ADCC). Potent anti-tumor activity as either monotherapy or in combination was also demonstrated in vivo, in experiments using human cancer cell lines and patient-derived xenografts.
Dual targeting anti-CD47/TAA biAbs interact weakly with normal healthy cells expressing physiological levels of CD47. In vitro safety studies demonstrate a minimal binding to human erythrocytes, platelets or T cells, and no evidence of platelet activation at the anticipated therapeutic concentrations. Pharmacokinetic and safety studies performed with NI-1701 in non-human primates (NHP) demonstrate long half-life and no effects on hematological parameters (e.g., red blood cell and platelet counts) up to 100mg/kg, the highest dose tested. Importantly, we also demonstrate that, contrary to anti-CD47 mAbs, dual targeting CD47 neutralizing biAbs preserve their tumoricidal efficacy in the presence of bystander CD47-positive cells. As a corollary, we show that dual targeting biAbs allow an efficacious yet safe targeting of CD47 in cancer. Dual targeting bispecific antibody approach could potentially be applied to limit the extent of therapeutic neutralization of other ubiquitously expressed antibody targets.
To circumvent tolerability and antigen sink problems arising from ubiquitous expression of CD47, we generated dual-targeting bispecific antibodies (biAbs) allowing selective blockade of CD47 on malignant cells expressing a tumor-associated antigen (TAA), CD19 or mesothelin. These bispecific kappa-lambda bodies pair a high affinity anti-TAA arm with a CD47 targeting arm and are structurally identical to human IgG1. As such, they combine efficient tumor cell targeting and selective CD47 blockage with immune activating mechanisms mediated by IgG1 constant Fc portion. We show that these biAbs are able to selectively kill cancer cells through ADCP (antibody-dependent cellular phagocytosis) and antibody-dependent cell-mediated cytotoxicity (ADCC). Potent anti-tumor activity as either monotherapy or in combination was also demonstrated in vivo, in experiments using human cancer cell lines and patient-derived xenografts.
Dual targeting anti-CD47/TAA biAbs interact weakly with normal healthy cells expressing physiological levels of CD47. In vitro safety studies demonstrate a minimal binding to human erythrocytes, platelets or T cells, and no evidence of platelet activation at the anticipated therapeutic concentrations. Pharmacokinetic and safety studies performed with NI-1701 in non-human primates (NHP) demonstrate long half-life and no effects on hematological parameters (e.g., red blood cell and platelet counts) up to 100mg/kg, the highest dose tested. Importantly, we also demonstrate that, contrary to anti-CD47 mAbs, dual targeting CD47 neutralizing biAbs preserve their tumoricidal efficacy in the presence of bystander CD47-positive cells. As a corollary, we show that dual targeting biAbs allow an efficacious yet safe targeting of CD47 in cancer. Dual targeting bispecific antibody approach could potentially be applied to limit the extent of therapeutic neutralization of other ubiquitously expressed antibody targets.