Development of immunomodulatory dual signaling proteins for cancer immunotherapy
Development of immunomodulatory dual signaling proteins for cancer immunotherapy
Immunotherapy has greatly improved cancer treatment, with breakthrough results from immune checkpoint inhibitors. Checkpoint inhibitors block the molecular "brakes" cancer cells use to hide from the immune system. However, many patients and cancer types still cannot be effectively treated with current therapeutics. The development of new Dual Signaling Proteins (DSPs), molecules engineered to act on two immune targets at once addresses these limitations.
This thesis explores of Lisa Jacob how the DSP platform can be used to overcome resistance and expand the reach of immunotherapy. We engineered DSP107, a bispecific molecule that blocks the CD47 "don't eat me" signal while activating the co-stimulatory pathway 4-1BB, which boosts T cell activity. DSP107 showed strong anticancer activity against hematological malignancies, synergized with therapeutic antibodies, and its favorable safety profile supported its advancement into clinical trials in 2020.
We also engineered DSP216, targeting HLA-G, an immune checkpoint that, despite being discovered over 25 years ago, has not yet been successfully targeted in the clinic, in combination with CD47. Using an AND-gate strategy, DSP216 is only active on cells expressing both checkpoints together, minimizing off-target effects while maintaining potent anti-tumor activity.
Finally, we investigated TSP215, a trispecific molecule, but found its immune-activating signal fired independently of target binding, raising safety concerns and highlighting the need for careful design in multispecific therapies. This thesis underscores the potential of DSPs to enhance efficacy, precision, and safety in cancer immunotherapy.