POLYMER DRUG CONJUGATES TO CREATE NEW TREATMENT OPTIONS

CIS Pharma develops novel antibody-drug- conjugates (ADCs) based on our proprietary polymer carrier platform. Our polymers serve as carriers that are loaded with cytotoxic drugs, radioisotopes or other active entities. The carrier together with its cargo is conjugated to a target-specific antibody using site-directed linker chemistry, different from the linker chemistry used to attach the payload. As a result, our polymer drug conjugates (PDC) offer a higher number of binding sites compared to conventional ADCs.

ADC’s combine target-specificity of an antibody to a tumor antigen with a potent cytotoxic drug. In comparison to the administration of a cytotoxic drug alone, side effects are significantly reduced as normal cells remain unimpaired during treatment. Conventional ADCs use linkers to load cytotoxic drugs onto the antibody directly, limiting the number of drug cargo that is delivered to the tumor cells.

CIS Pharma’s PDCs and applied linker chemistry are designed to be resistant to degradation, thereby offering higher plasma stability and shelf life in comparison to other ADCs. After drug release, the degradation products of our conjugates are eliminated by renal excretion. In cell toxicity studies, both monomers as well as polymers show excellent toxicity profiles. 

Our carriers will increase the solubility of hydrophobic drugs that suffer from low bioavailability and are expected to extend half-life of conjugates. They allow conjugation of different classes of cytotoxic drugs and combinations thereof. Our ADC platform also include binding sites for radioisotopes. Our conjugation technology is compatible with an array of target-specific agents such as antibodies, antibody fragments, aptamers and smaller homing agents.

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EARLY CANCER DETECTION BY DIAGNOSTIC POLYMER CONJUGATES

In tumor therapy, precise diagnostic instruments to identify early lesions or metastases remain a medical need unmet. In lung cancer with more than 1.6 million deaths per year, the large cohort of non-small-cell lung cancer (NSCLC) suffers from bad prognosis when detected in later stage. The 5-year survival rates for NSCLC patients diagnosed at later stage drop from 57% in stage I to 5% in stage III. However, only 20 % of the patients are diagnosed in stage I.

At CIS Pharma we are developing diagnostic polymer conjugates comprising binding sites for radioisotopes. Our polymer carriers are loaded with a higher number of radioactive tracers compared to conventional conjugation technologies, improving the signal to noise ratio in positron emission tomography scans (PET scans). As a result, smaller tumor nodules may be detected and an efficient therapy may be initiated early on. Our technology allows switching from diagnostic to therapeutic radioisotopes without further modification of carrier needed. CIS Pharma has partnered with Paul Scherrer Institute of ETH to conjugate radioisotopes to CIS Pharma’s drug carrier. 

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MODE OF ACTION

1 The antibody-polymer-drug-conjugate (APDC) binds to a tumor specific antigen, e.g. an overexpressed cell surface receptor. 2 The APDC/receptor complex is internalized into the cell (membrane). 3 Membrane vesicles are formed around the APDC/receptor complex and the vesicles are transported to specific cell organelles. 4 The membrane vesicles containing the APDC/receptor complex are fused with a lysosome. 5 The low pH and high content of proteolytic enzymes in the lysosome leads to the degradation of the antibody/receptor complex as well as the linkers which bind the cytotoxic drug to the polymeric backbone. 6 The cytotoxic drug is released from the lysosome. 7 The released cytotoxic payload leads to the death of the cancer cell, e.g. by inhibition of DNA replication.

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