Discovery of STRO-002, a Novel Homogeneous ADC Targeting Folate Receptor Alpha, for the Treatment of Ovarian and Endometrial Cancers.

STRO-002 is a novel homogeneous folate receptor alpha (FolRα) targeting antibody-drug conjugate (ADC) currently being investigated in the clinic as a treatment for ovarian and endometrial cancers. Here, we describe the discovery, optimization, and antitumor properties of STRO-002. STRO-002 was generated by conjugation of a novel cleavable 3-aminophenyl hemiasterlin linker-warhead (SC239) to the nonnatural amino acid para-azidomethyl-L-phenylalanine incorporated at specific positions within a high affinity anti-FolRα antibody using Sutro's XpressCF+, which resulted in a homogeneous ADC with a drug-antibody ratio (DAR) of 4.

Hydrogen sulfide concentration in the milieu of the hydrated alanine dipeptide determines its polyproline II-beta propensity: Main chain contribution to the energetic origin of the formation of amyloid.

In view of the observation that the concentration of hydrogen sulfide in brains with Alzheimer's disease (AD) is lower than that in normal brains and in line with our previous studies indicating that additional content in the aqueous environment (milieu) of a peptide can change its local energetic preference from a polyproline II (P) to a β conformation (and therefore its tendency to form the β-chain structures that lead to the amyloid plaques associated with the disease), we have studied the effect of H S concentration on such propensity in a simple model peptide, the alanine dipeptide (ADP). The two concentration states are represented by ADP(H O) (H S) and ADP(H O) (H S) . Ab initio calculations of these structures show that the lowest energy of the former is a β conformation while that of the latter is a P, mirroring the observed AD results and strengthening our proposal that amyloid diseases are better viewed in the context of a protein milieu-folding paradigm.

Targeting CD74 in multiple myeloma with the novel, site-specific antibody-drug conjugate STRO-001.

STRO-001 is a site-specific, predominantly single-species, fully human, aglycosylated anti-CD74 antibody-drug conjugate incorporating a non-cleavable linker-maytansinoid warhead with a drug-antibody ratio of 2 which was produced by a novel cell-free antibody synthesis platform. We examined the potential pharmacodynamics and anti-tumor effects of STRO-001 in multiple myeloma (MM). CD74 expression was assessed in MM cell lines and primary bone marrow (BM) MM biopsies.

Milieu-Initiated Inversion of the Aqueous Polyproline II/β Propensity in the Alanine Tripeptide: Aggregation Origin of the Onset of Amyloid Formation.

Extending our earlier analogous study of the alanine dipeptide (ADP), we have now analyzed the effect of the external environment on the polyproline II (P) and β relative energies, the P/β propensity, of the alanine tripeptide (ATP). Ab initio calculations of ATP(HO) and ATP(HO)(HCl) exhibit the same propensity inversion as in ADP: in the pure water case the PP conformation is favored while the addition of the HCl molecule results in the ββ conformation being of lower energy. A comparison, following an intermediate insertion and departure of an HCl molecule, shows that the energy of a hydrogen-bonded (HO)βATP::βATP(HO) structure is lower than that of the sum of two separate PP systems, i.

Modulation of P2X3 and P2X2/3 Receptors by Monoclonal Antibodies.

Purinergic homomeric P2X3 and heteromeric P2X2/3 receptors are ligand-gated cation channels activated by ATP. Both receptors are predominantly expressed in nociceptive sensory neurons, and an increase in extracellular ATP concentration under pathological conditions, such as tissue damage or visceral distension, induces channel opening, membrane depolarization, and initiation of pain signaling. Hence, these receptors are considered important therapeutic targets for pain management, and development of selective antagonists is currently progressing.