Earlier this month the United States Patent and Trademark Office awarded U.S. Patent 9,458,242 to Immunomedics for additional claims under the patent family “Dosages of immunoconjugates of antibodies and SN-38 for improved efficacy and decreased toxicity.” This new patent, which will expire in July 2033, covers the use of labetuzumab govitecan, also known as IMMU-130. Labetuzumab govitecan is Immunomedics’ second investigational antibody-drug conjugate or ADC for the treatment of solid cancers.
Using Immunomedics’ advanced proprietary technologies researchers have created humanized antibodies that can be used either alone in unlabeled or “naked” form, or conjugated with radioactive isotopes, chemotherapeutics, cytokines or toxins. With this technology Immunomedics has built a pipeline of eight clinical-stage product candidates, including antibody-drug conjugates that are designed to deliver a specific payload of a chemotherapeutic directly to the tumor while reducing overall toxic effects that are usually found with conventional administration of these chemotherapeutic agents.
Immunomedics’ most advanced antibody-drug conjugate is sacituzumab govitecan, also known as IMMU-132. This investigational drug has received Breakthrough Therapy Designation from the U.S. Food and Drug Administration (FDA) for the treatment of patients with triple-negative breast cancer who have failed at least two prior therapies for metastatic disease.
Active metabolite of irinotecan
Labetuzumab govitecan is composed of SN-38, the active metabolite of irinotecan a , an FDA approved chemotherapy for colorectal cancer, linked to labetuzumab, the Immunomedics’s humanized antibody that targets the carcinoembryonic antigen (CEACAM5), which is expressed on colorectal and other solid cancers. This antibody-drug conjugate, at the 10 mg/kg dose level, has been active in the therapy of patients with metastatic colorectal cancer who had failed multiple prior therapies, including irinotecan.
Potent antitumor agents
Camptothecin and its derivatives are a class of potent antitumor agents. Irinotecan and topotecan are analogs of camptothecin that are approved cancer therapeutics. [1] This class of drug act by inhibiting topoisomerase I enzyme by stabilizing topoisomerase I-DNA complex [2]
Camptothecin present specific issues in the preparation of drug-conjugates. One issue is the insolubility of most camptothecin derivatives in aqueous buffers.[3]
In the antibody-camptothecin conjugates the solubility of the drug is enhanced by placing a defined polyethyleneglycol (PEG) moiety (i.e., a PEG containing a defined number of monomeric units) between the drug and the antibody, wherein the defined PEG is a low molecular weight PEG containing 1-12 monomeric units.[3]
Camptothecins also provide specific challenges for structural modification for conjugating to macromolecules. For instance, camptothecin itself contains only a tertiary hydroxyl group in ring-E. The hydroxyl functional group in the case of camptothecin must be coupled to a linker suitable for subsequent protein conjugation. In potent camptothecin derivatives such as SN-38, the active metabolite irinotecan, and other C-10-hydroxyl-containing derivatives such as topotecan and 10-hydroxy-camptothecin, the presence of a phenolic hydroxyl at the C-10 position complicates the necessary C-20-hydroxyl derivatization.[3]
Furthermore, the lability under physiological conditions of the δ-lactone moiety of the E-ring of camptothecins results in greatly reduced antitumor potency. Hence, conjugation is carried out at a pH of 7 or lower to avoid the lactone ring opening. But conjugation of a bifunctional camptothecin possessing an amine-reactive group such as an active ester would typically require a pH of 8 or greater. Finally, an intracellularly-cleavable moiety preferably is incorporated in the linker + spacer connecting camptothecin and the antibodies or other binding moieties.[3]
Researchers at Immunomedics have developed a more effective methods of preparing and administering antibody-camptothecin conjugates, such the investigational antibody-SN-38 conjugates. An important aspect of their work is developing methods designed to optimized dosing and administration schedules that maximize efficacy and minimize toxicity of the antibody-camptothecin conjugates for therapeutic use in human patients.
Clinical development
“We are very encouraged by the results with IMMU-130 from an open-label Phase II study, which has completed patient enrollment with patient follow-up continuing,” commented Cynthia L. Sullivan, Immunomedics’ President and Chief Executive Officer.
“We have had an end-of-Phase II discussion with the FDA for a future registration pathway for this ADC. One Phase 3 study design under consideration includes evaluating IMMU-130 in patients with metastatic colorectal cancer who have received two or more prior therapies,” Sullivan further added.
Additional patent
Also issued was U.S. Patent 9,457,072 to IBC Pharmaceuticals, Immunomedics’ majority-owned subsidiary, for additional claims under the patent family “Dock-and-Lock® (DNL®) vaccines for cancer therapy.”
This new patent, which will expire in March 2026, concerns methods and compositions for creating anti-cancer vaccine complexes using Immunomedics’ proprietary DNL® protein conjugation platform technology. These DNL® complexes have the ability to simultaneously bind to dendritic cells on one arm and to tumor markers on cancer cells using the other arm. In so doing, these anti-cancer vaccine DNL® complexes are designed to induce an immune response against their targeted cancer cells, which could inhibit the growth of, or eliminate, the cancer cells.
a Irinotecan, also known as CPT-11, is an analog of camptothecin.
