Combinatorial Drug Therapy for Increased Tumor Targeting and Reduced Toxicity
Invention Summary
Combining 2 agents with the same cancer target but differing bio-distributions and/or pharmacokinetics results in additive tumor targeting, dosage and efficacy while also reducing toxicity.
Technology Overview
Anti-cancer drugs are limited by their maximum tolerated dose (MTD). This is the dose, beyond which, greater efficacy could be achieved, but the risks associated with this increase often outweigh the benefits.
The inventor has disclosed a method to overcome this problem by combining 2 drugs, each of which is directed towards the same molecular target but where each agent has a different bio-distribution and/or pharmacokinetics resulting in non- or minimally overlapping toxicities. This results in an additive accumulation and enhanced activity of these agents at the desired target site while also maintaining toxicity levels within acceptable limits.
The inventor has used this technology to successfully attack prostate cancer cells. He used 2 agents, a monoclonal antibody (mAb J591) and a small molecule ligand, both of which target the prostate-specific membrane antigen (PSMA), to deliver a payload of a beta particle 177Lu. J591-177Lu results in bone marrow toxicity because of the inherent sensitivity of the bone marrow to radiation, and the long half-life of the antibody which persists in the blood circulation and bone marrow. On the other hand, the small molecule ligand is rapidly excreted via the urinary tract, resulting in potential delayed renal toxicity because the kidneys receive a significant radiation dose. Similarly, the small molecule ligand rapidly penetrates normal tissues such as the salivary glands resulting in radiation toxicity. These sites are not affected with the mAb therapy. Hence, these 2 drugs have the same target (PSMA) but differing and mutually exclusive sites of toxicity. Co-administering these agents, for example at 75% MTD each, results in the delivery of a greater overall dose of 177Lu to the tumor than either agent alone at 100% MTD. This results in greater treatment efficacy, while the toxicity would be lower than that of either agent alone at 100% MTD. These 2 agents also bind to different and non-competing sites on PSMA, and therefore do not interfere with each other’s activities.
Similar results were observed when mice xenografts were used to perform in vivo animal experiments. The best anti-tumor effects were observed with the monoclonal antibody at or close to its MTD. However, similar results were obtained with the simultaneous administration of sub-MTD levels of both the monoclonal antibody and the small molecule inhibitor.
Potential Applications
Optimal treatment regimens can be devised for patients that are amenable to treatment with different drugs, without having to deal with enhanced toxicity issues.
Advantages
Enhanced dosage, efficacy and activity of anti-cancer agents without the adverse side effect of increased toxicities.
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