monomethyl-auristatin-e and Colonic-Neoplasms

Tumor-active-targeting drugs such as antibody-drug conjugates have emerged as promising accurate therapeutic agents. However, their complex preparations risk compromising the targeting ability of the fragment antigen binding (Fab) region and promote aggregation over long-term storage. Here, we propose a tumor-active-targeting nanomedicine, aPDL1-PLG-MMAE, that effectively targets programmed death-ligand 1 (PDL1) high-expressing tumors and delivers monomethyl auristatin E (MMAE). aPDL1-PLG-MMAE consists of an anti-PDL1 monoclonal antibody (aPDL1) and poly(L-glutamic acid) (PLG) grafted Fc-III-4C peptide/Val-Cit-PAB-MMAE (Fc-PLG-MMAE). Fc-PLG-MMAE was obtained by conjugating the Fc-III-4C peptide and Val-Cit-PAB-MMAE to PLG

Topics: Cell Line, Tumor; Colonic Neoplasms; Humans; Nanomedicine; Xenograft Model Antitumor Assays

Human epidermal growth factor receptor 2 (HER2) is a protein that is overexpressed in some types of cancer, including breast and urothelial cancer. Here we found that HER2 was present in a portion of colon cancer patients, raising the possibility of using anti-HER2 therapy. RC48, a novel antibody-drug conjugate (ADC) comprising cytotoxic monomethyl auristatin E (MMAE) and an anti-HER2 antibody tethered via a linker, showed a comparable therapeutic effect in both HER2 low expressed (IHC2+/FISH- or IHC+) and high expressed urothelial cancer patients. In vitro studies using colon cancer cell lines showed that RC48 effectively impeded the proliferation of HER2-positive cells, indicating its potential as a treatment for HER2-positive colon cancer. Mechanism study showed that RC48 not only induces cell cycle arrest but also disrupts HER2-mediated restain of cGAS-STING signaling, potentially activating an immune response against the cancer cells. The administration of RC48 significantly reduced the growth of HER2-positive colon cancer and made HER2-positive colon cancer cells more susceptible to immunotherapy. The results of our study will contribute to determining the feasibility of RC48 as a therapeutic option for HER2-positive colon cancer.

Topics: Antibodies; Carcinoma, Transitional Cell; Colonic Neoplasms; Humans; Immunotherapy; Oligopeptides; Urinary Bladder Neoplasms

Antibody-drug conjugates, comprising monoclonal antibodies (MoAbs) that bind to tumor-associated antigens, display different toxicity profiles compared with radiolabeled MoAbs. Dose-limiting toxicities may include damage to the liver and myelotoxicity. The drug component is the antimitotic agent auristatin, which is 100-1000 times more potent than doxorubicin. Consequently, auristatin antibody-drug conjugates require a high selectivity in tumor targeting to display pronounced activity at well-tolerated doses. We have evaluated the possibility of increasing the therapeutic index of BR96-auristatin by combining the administration of conjugates with subsequent extracorporeal affinity adsorption treatment.. Rats were injected with biotinylated, monomethyl auristatin F (MMAF)-conjugated monoclonal antibody BR96. The conjugate was then removed from the circulation by extracorporeal affinity adsorption treatment, 24 hours postinjection using an avidin affinity column. By analyzing blood parameters for 100 days, myelotoxicity, hepatotoxicity, and nephrotoxicity were assessed. Body weight, general status, and tumor size were also recorded. The toxicity-reducing effect of extracorporeal affinity adsorption treatment was evaluated.. Extracorporeal affinity adsorption treatment removed 85%-90% of BR96-MMAF from the circulation. Early toxicity-related death was seen in nontumor-bearing animals that were given MMAF-conjugated BR96, in contrast to animals that were given a higher amount of BR96-MMAF with subsequent extracorporeal affinity adsorption treatment, in which all survived 100 days postinjection. Extracorporeal affinity adsorption treatment reduced the loss of body weight, myelotoxicity, and hepatotoxicity.. Extracorporeal affinity adsorption treatment can be used to reduce the toxicity associated with administration of BR96-MMAF conjugates, making it possible to increase the amount of conjugates administered. The combined treatment will be further optimized in future studies.

Topics: Animals; Antibodies, Monoclonal; Colonic Neoplasms; Disease Models, Animal; Extracorporeal Circulation; Feasibility Studies; Immunoconjugates; Oligopeptides; Rats; Rats, Inbred BN; Weight Loss