Preclinical Evaluation of STI-8811, a Novel Antibody-Drug Conjugate Targeting BCMA for the Treatment of Multiple Myeloma.

Treatment for patients with multiple myeloma has experienced rapid development and improvement in recent years; however, patients continue to experience relapse, and multiple myeloma remains largely incurable. B-cell maturation antigen (BCMA) has been widely recognized as a promising target for treatment of multiple myeloma due to its exclusive expression in B-cell linage cells and its critical role in the growth and survival of malignant plasma cells. Here, we introduce STI-8811, a BCMA-targeting antibody-drug conjugate (ADC) linked to an auristatin-derived duostatin payload via an enzymatically cleavable peptide linker, using our proprietary C-lock technology.

Conjugation of anti-HIV gp41 monoclonal antibody to a drug capable of targeting resting lymphocytes produces an effective cytotoxic anti-HIV immunoconjugate.

HIV-infected cells persisting in the face of suppressive antiretroviral therapy are the barrier to curing infection. Cytotoxic immunoconjugates targeted to HIV antigens on the cell surface may clear these cells. We showed efficacy in mouse and macaque models using immunotoxins, but immunogenicity blunted the effect.

Author Correction: Chemically triggered drug release from an antibody-drug conjugate leads to potent antitumour activity in mice.

The original version of this Article omitted the following from the Acknowledgements: 'This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs, through the Breast Cancer Research Program under Award No. W81XWH-15-1-0692. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense'.

Chemically triggered drug release from an antibody-drug conjugate leads to potent antitumour activity in mice.

Current antibody-drug conjugates (ADCs) target internalising receptors on cancer cells leading to intracellular drug release. Typically, only a subset of patients with solid tumours has sufficient expression of such a receptor, while there are suitable non-internalising receptors and stroma targets. Here, we demonstrate potent therapy in murine tumour models using a non-internalising ADC that releases its drugs upon a click reaction with a chemical activator, which is administered in a second step.

High turnover of tissue factor enables efficient intracellular delivery of antibody-drug conjugates.

Antibody-drug conjugates (ADC) are emerging as powerful cancer treatments that combine antibody-mediated tumor targeting with the potent cytotoxic activity of toxins. We recently reported the development of a novel ADC that delivers the cytotoxic payload monomethyl auristatin E (MMAE) to tumor cells expressing tissue factor (TF). By carefully selecting a TF-specific antibody that interferes with TF:FVIIa-dependent intracellular signaling, but not with the procoagulant activity of TF, an ADC was developed (TF-011-MMAE/HuMax-TF-ADC) that efficiently kills tumor cells, with an acceptable toxicology profile.

Heterobiaryl human immunodeficiency virus entry inhibitors.

Previously disclosed HIV (human immunodeficiency virus) attachment inhibitors, exemplified by BMS 806 (formally BMS378806, 1), are characterized by a substituted indole or azaindole ring linked to a benzoylpiperazine via a ketoamide or sulfonamide group. In the present report, we describe the discovery of a novel series of potent HIV entry inhibitors in which the indole or azaindole ring of previous inhibitors is replaced by a heterobiaryl group. Several of these analogues exhibited IC(50) values of less than 5 nM in a pseudotyped antiviral assay, and compound 13k was demonstrated to exhibit potency and selectivity similar to those of 1 against a panel of clinical viral isolates.

Design and synthesis of human immunodeficiency virus entry inhibitors: sulfonamide as an isostere for the alpha-ketoamide group.

The crystal structures of many tertiary alpha-ketoamides reveal an orthogonal arrangement of the two carbonyl groups. Based on the hypothesis that the alpha-ketoamide HIV attachment inhibitor BMS 806 (formally BMS378806, 26) might bind to its gp120 target via a similar conformation, we designed and synthesized a series of analogs in which the ketoamide group is replaced by an isosteric sulfonamide group. The most potent of these analogs, 14i, demonstrated antiviral potency comparable to 26 in the M33 pseudotyped antiviral assay.

Novel asymmetric approach to proline-derived spiro-beta-lactams.

We describe a novel asymmetric approach using Staudinger chemistry to proline-derived spiro-beta-lactams. A chiral group at C-4 of the acid chloride of proline directs the stereoselectivity of Staudinger chemistry and later is sacrificed to obtain optically active 5.4-spiro-beta-lactams.

Role of pyridine hydrogen-bonding sites in recognition of basic amino acid side chains.

A series of three, new artificial receptors for guanidinium and ammonium guests has been synthesized. All three receptors have highly preorganized clefts bearing two carboxylate groups. They differ in the number of nitrogen atoms contained in their clefts, as follows: four N atoms in receptor 3, three N atoms in 4, and two nitrogens in 5.

Circular dichroism readout of sugar recognition in the cleft of a fused-pyridine receptor.

Dicarboxamide host 2 forms 1:1 complexes with n-octyl pyranosides derived from D-glucose, D-mannose, D-galactose, D-fucose, D-lyxose, and D-arabinose. Association constants (K(a)) in the range of 77-940 M(-1) were measured in chloroform by means of induced circular dichroism and fluorescence spectroscopy. Variations in K(a) values correspond qualitatively to expected differences in hydrogen-bonding abilities of guest hydroxyl groups.