CB307: A Dual Targeting Costimulatory Humabody VH Therapeutic for Treating PSMA-Positive Tumors.

PURPOSE: CD137 is a T- and NK-cell costimulatory receptor involved in consolidating immunologic responses. The potent CD137 agonist urelumab has shown clinical promise as a cancer immunotherapeutic but development has been hampered by on-target off-tumor toxicities. A CD137 agonist targeted to the prostate-specific membrane antigen (PSMA), frequently and highly expressed on castration-resistant metastatic prostate cancer (mCRPC) tumor cells, could bring effective immunotherapy to this immunologically challenging to address disease. EXPERIMENTAL DESIGN: We designed and manufactured CB307, a novel half-life extended bispecific costimulatory Humabody VH therapeutic to elicit CD137 agonism exclusively in a PSMA-high tumor microenvironment (TME). The functional activity of CB307 was assessed in cell-based assays and in syngeneic mouse antitumor pharmacology studies. Nonclinical toxicology and toxicokinetic properties of CB307 were assessed in a good laboratory practice (GLP) compliant study in cynomolgus macaques. RESULTS: CB307 provides effective CD137 agonism in a PSMA-dependent manner, with antitumor activity both in vitro and in vivo, and additional activity when combined with checkpoint inhibitors. A validated novel PSMA/CD137 IHC assay demonstrated a higher prevalence of CD137-positive cells in the PSMA-expressing human mCRPC TME with respect to primary lesions. CB307 did not show substantial toxicity in nonhuman primates and exhibited a plasma half-life supporting weekly clinical administration. CONCLUSIONS: CB307 is a first-in-class immunotherapeutic that triggers potent PSMA-dependent T-cell activation, thereby alleviating toxicologic concerns against unrestricted CD137 agonism.

Evaluation of NTP42, a novel thromboxane receptor antagonist, in a first-in-human phase I clinical trial.

Background: The thromboxane receptor (TP) antagonist NTP42 is in clinical development for treatment of cardiopulmonary diseases, such as pulmonary arterial hypertension. In this randomized, placebo-controlled Phase I clinical trial, NTP42, administered as the oral formulation NTP42:KVA4, was evaluated for safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) in healthy males. Methods: The first-in-human trial had three Parts: A, single ascending dose (SAD) study with seven groups given 0.25-243 mg NTP42:KVA4 or placebo; B, food effect study where one SAD group (9 mg) was also given NTP42:KVA4 or placebo after a high-fat breakfast; C, multiple ascending dose study with three groups given 15-135 mg NTP42:KVA4 or placebo once-daily for 7 days. Results: Seventy-nine volunteers participated. No serious adverse events occurred, where any drug- or placebo-related adverse events were mild to moderate, with no correlation to NTP42:KVA4 dose. NTP42 was rapidly absorbed, yielding dose proportional increases in exposure after single and repeat dosing. PK confirmed that, with a clearance (T1/2) of 18.7 h, NTP42:KVA4 is suited to once-daily dosing, can be taken with or without food, and does not accumulate on repeat dosing. At doses ≥1 mg, NTP42 led to complete and sustained inhibition of thromboxane-, but not ADP-, induced platelet aggregation ex vivo, with direct correlation between NTP42 exposure and duration of PD effects. Conclusion: Orally administered NTP42:KVA4 was well tolerated, with favorable PK/PD profiles and evidence of specific TP target engagement. These findings support continued clinical development of NTP42:KVA4 for cardiopulmonary or other relevant diseases with unmet needs. Clinical Trial Registration: clinicaltrials.gov, identifier NCT04919863.

Caffeine induces a profound and persistent tachycardia in response to MDMA ("Ecstasy") administration.

Caffeine promotes hyperthermia and lethality when co-administered with the recreational drug 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") to rats. In the present study, co-administration of caffeine (10 mg/kg, s.c.) with MDMA (10 mg/kg, s.c.) induced a profound tachycardic response compared to rats treated with either drug alone. However, neither caffeine (30 microM) nor MDMA (1-30 microM), alone or in combination, affected the electrocardiogram of the isolated heart suggesting that central and sympathomimetic actions, rather than direct actions of these drugs on the heart, are responsible for the tachycardia observed in vivo. This is a serious drug interaction, which could have important health consequences for recreational drug users.

Adenosine A1 receptor blockade mimics caffeine's attenuation of ethanol-induced motor incoordination.

The effects of co-administration of caffeine and ethanol were assessed on the motor coordination of rats on the accelerating rotarod (accelerod). Ethanol (2.5 g/kg, orally) decreased motor performance on the accelerod. Co-administration of caffeine (5 and 20 mg/kg, orally) dose-dependently attenuated this ethanol-induced deficit. Caffeine (20 mg/kg, orally) alone did not affect motor performance in the test. As caffeine is a non-selective adenosine receptor antagonist the ability of adenosine A(1) and A(2A) receptor blockade to attenuate ethanol-induced motor incoordination was determined. Pre-treatment with the adenosine A(1) receptor antagonist DPCPX (5 mg/kg, intraperitoneally) attenuated ethanol (2.5 g/kg, orally)-induced motor incoordination. By contrast, prior administration of the adenosine A(2A) selective antagonist SCH 58261 (10 mg/kg intraperitoneally) had no effect on the ethanol-induced motor deficit. These data demonstrate that adenosine A(1) receptor blockade mimics the inhibitory action of caffeine on ethanol-induced motor incorordination, and may contribute to the ability of caffeine to offset the acute intoxicating actions of ethanol.