Preclinical studies of BB-1701, a HER2-targeting eribulin-containing ADC with potent bystander effect and ICD activity.

Background: Several HER2-targeting antibody-drug conjugates (ADC) have gained market approval for the treatment of HER2-expressing metastasis. Promising responses have been reported with the new generation of ADCs in patients who do not respond well to other HER2-targeting therapeutics. However, these ADCs still face challenges of resistance and/or severe adverse effects associated with their particular payload toxins.

Antibody-drug conjugate MORAb-202 exhibits long-lasting antitumor efficacy in TNBC PDx models.

The antibody-drug conjugate (ADC) MORAb-202, consisting of farletuzumab paired with a cathepsin B-cleavable linker and eribulin, targets folate receptor alpha (FRA), which is frequently overexpressed in various tumor types. MORAb-202 was highly cytotoxic to FRA-positive cells in vitro, with limited off-target killing of FRA-negative cells. Furthermore, MORAb-202 showed a clear in vitro bystander cytotoxic effect in coculture with FRA-positive/negative cells.

MORAb-202, an Antibody-Drug Conjugate Utilizing Humanized Anti-human FRα Farletuzumab and the Microtubule-targeting Agent Eribulin, has Potent Antitumor Activity.

Microtubule-targeting agents (MTA) have been investigated for many years as payloads for antibody-drug conjugates (ADC). In many cases, these ADCs have shown limited benefits due to lack of efficacy or significant toxicity, which has spurred continued investigation into novel MTA payloads for next-generation ADCs. In this study, we have developed ADCs using the MTA eribulin, a derivative of the macrocyclic polyether natural product halichondrin B, as a payload.

Tumor antigen CA125 suppresses antibody-dependent cellular cytotoxicity (ADCC) via direct antibody binding and suppressed Fc-γ receptor engagement.

Cancers employ a number of mechanisms to evade host immune responses. Here we report the effects of tumor-shed antigen CA125/MUC16 on suppressing IgG1-mediated antibody-dependent cellular cytotoxicity (ADCC). This evidence stems from prespecified subgroup analysis of a Phase 3 clinical trial testing farletuzumab, a monoclonal antibody to folate receptor alpha, plus standard-of-care carboplatin-taxane chemotherapy in patients with recurrent platinum-sensitive ovarian cancer.

Improved Intraoperative Detection of Ovarian Cancer by Folate Receptor Alpha Targeted Dual-Modality Imaging.

Complete resection of tumor lesions in advanced stage ovarian cancer patients is of utmost importance, since the extent of residual disease after surgery strongly affects survival. Intraoperative imaging may be useful to improve surgery in these patients. Farletuzumab is a humanized IgG1 antibody that specifically recognizes the folate receptor alpha (FRα).

Targeting endosialin/CD248 through antibody-mediated internalization results in impaired pericyte maturation and dysfunctional tumor microvasculature.

Over-expression of endosialin/CD248 (herein referred to as CD248) has been associated with increased tumor microvasculature in various tissue origins which makes it an attractive anti-angiogenic target. In an effort to target CD248, we have generated a human CD248 knock-in mouse line and MORAb-004, the humanized version of the mouse anti-human CD248 antibody Fb5. Here, we report that MORAb-004 treatment significantly impacted syngeneic tumor growth and tumor metastasis in the human CD248 knock-in mice.

The antitumor activity of the human FOLR1-specific monoclonal antibody, farletuzumab, in an ovarian cancer mouse model is mediated by antibody-dependent cellular cytotoxicity.

Because of its high mortality rate, ovarian cancer is a leading cause of death among women and a highly unmet medical need. New therapeutic agents that are effective and well tolerated are needed and cancer antigen-specific monoclonal antibodies that have direct pharmacologic effects or can stimulate immunological responses represent a promising class of agents for the treatment of this disease. The human folate receptor α (FOLR1), which is overexpressed in ovarian cancer but largely absent in normal tissues, appears to play a role in the transformed phenotype in ovarian cancer, cisplatin sensitivity, and growth in depleted folate conditions and therefore has potential as a target for passive immunotherapy.

Endosialin/TEM-1/CD248 regulates pericyte proliferation through PDGF receptor signaling.

Recent reports have described several cellular phenotypes that appear to be mediated by Endosialin/TEM-1/CD248 (TEM-1), including tubule formation on matrigel, migration and proliferation. It has been shown that siRNA knock-down of TEM-1 in primary human fibroblasts resulted in reduced proliferation. However, the downstream signaling events that mediate TEM-1 function(s) currently remain unknown.

A natural human IgM antibody that neutralizes botulinum neurotoxin in vivo.

Affinity-matured human antibodies have demonstrated efficacy as countermeasures for exposure to botulinum neurotoxin (BoNT), which is the cause of the disease botulism category A select bioterror agent. Little is known, however, about the potential role of natural (un-mutated) antibodies in the protective immune response to BoNT. Here we describe the cloning of two human IgM antibodies that bind serotype A BoNT.

Interaction of endosialin/TEM1 with extracellular matrix proteins mediates cell adhesion and migration.

Endosialin/TEM1 was originally discovered as a human embryonic fibroblast-specific antigen and was later found to be differentially expressed in tumor stroma and endothelium. Endosialin/TEM1 overexpression has been observed in many cancers of various tissue origin, including colon, breast, pancreatic, and lung. The knockout (KO) mouse model showed the absence of endosialin/TEM1 expression reduced growth, invasion, and metastasis of human tumor xenografts.

Alterations in vasodilator-stimulated phosphoprotein (VASP) phosphorylation: associations with asthmatic phenotype, airway inflammation and beta2-agonist use.

Background: Vasodilator-stimulated phosphoprotein (VASP) mediates focal adhesion, actin filament binding and polymerization in a variety of cells, thereby inhibiting cell movement. Phosphorylation of VASP via cAMP and cGMP dependent protein kinases releases this "brake" on cell motility. Thus, phosphorylation of VASP may be necessary for epithelial cell repair of damage from allergen-induced inflammation.

[About changes in the structure of surgically treated goiter].

On the base of our own goiter material treated surgically between 1974-1996, we compared incidence of various types of goiter and thyroid carcinoma in years 1974-1985 and 1986-1996. We stated statistically significant decrease of operated Basedow goiter and significant incidence increase of thyroid cancer. In given years frequency of incidence of differentiated and anaplastic thyroid carcinoma have been changed.

Cancer in hyperthyroidism.

The aim of the study was to determine the incidence of thyroid cancer in toxic goitre. Based on the material from 14,500 goitre surgeries, including 3,466 patients with toxic goitre, incidence of thyroid cancer, in relation to age and sex of the patients were determined. In 14,500 goitre surgeries, 12,887 women and 1,613 men (F:M 7.

[Lymphadenectomy in thyroid gland carcinoma--staging and therapy].

The aim of our study was to evaluate elective lymphadenectomy in surgical management of thyroid cancer. Since 1990 we have performed thyroidectomy with modified lymphadenectomy in 265 patients operated because of thyroid cancer. In 33 cases (14.

[Strumectomy in children and adolescents--personal studies with 12,000 operations].

At the Surgery Clinic of the Endocrinology Institute in Lódź we operated 12 344 patients between 1974 and 1992 because of various types of goitre. Among these there were 295 children and adolescents, 2.4%- aged between 9-18 years: 268 girls (90.

[Thyroid neoplasms in children and adolescents--personal experience].

Between 1974-1992 we operated 12,344 patients at the Clinic of Surgery of the Institute of Endocrinology of the Lódź Medical Academy for various forms of goiter. Of these, 295 patients were between the ages of 9-18 years, including 268 (90.8%) girls and 27 (9.

Gastrin and somatostatin levels in patients with gastric cancer.

Gastrin and somatostatin-like immunoreactivity (SLI) levels were studied by means of radioimmunoassay in peripheral venous blood of healthy volunteers and patients suffering from gastric adenocarcinoma or duodenal and gastric ulcers. Gastrin and SLI levels were also evaluated in patients in blood drawn from gastric veins during surgery. The elevations of gastrin and SLI levels were found in patients with gastric cancer as compared with healthy people and patients suffering from ulcers.

Cyclic AMP in non-toxic nodular goiter.

Cyclic AMP concentrations in a non-toxic nodular goiter were measured by means of the radiocompetitive protein-binding assay. It has been shown that cold thyroid nodules contain a higher concentration of cAMP than the macroscopically normal, extra-nodular thyroid tissue.

[Experimental allo-paratopic heart transplantation in dogs as a biological bypass of the left ventricle].

1. The authors' model of paratopic cardiac replacement by means of a branched Dacron prosthesis is considered a simple method for left-heart replacement. 2.