Anti-cancer antibody-drug conjugates (ADCs) are trying to expand the therapeutic index of traditional chemotherapy by utilizing the targeting specificity of monoclonal antibodies (mAbs) to increase the efficiency of the delivery of potent cytotoxic agents (chemotherapy) directly to tumor cells. In the past three years, the number of ADCs approved by the FDA has tripled to 13. Although several ADCs have demonstrated sufficient efficacy and safety to warrant FDA approval, the clinical use of all ADCs leads to substantial toxicity in treated patients, and many ADCs have failed during clinical development due to their unacceptable toxicity profiles. Analysis of the clinical data has demonstrated that dose-limiting toxicities (DLTs) are often shared by different ADCs that deliver the same cytotoxic payload, independent of the antigen that is targeted and/or the type of cancer that is treated. DLTs are commonly associated with cells and tissues that do not express the targeted antigen (i.e., off-target toxicity), and often limit ADC dosage to levels below those required for optimal anti-cancer effects. At f5 Therapeutics, we are hoping to replace 1/3 of the ADC (MaB, linker, warhead) with a targeted protein degrader.  Advantages of this approach include:​

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• High Specificity of MOA (not a general cytotoxic agent)

• Less “off-target” action (decreased toxicity if f5 molecules are prematurely released)

• Lower concentrations required (more potent anti-tumor activity versus Nexavar)

• Wider therapeutic window (Lower development of resistance by having novel MOA versus current chemotherapy treatments)

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 We have an amazing opportunity to advance ADC treatments for patients and providers.