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Heroin Antibody Fares Better than Earlier Therapies that Targeted its Metabolites

A monoclonal antibody against heroin (11D12) is effective in blocking the euphoric and lethal effects of this much-abused opioid. The current findings…

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A heroin-targeting monoclonal antibody (11D12) is effective in blocking the euphoric and lethal effects of this much-abused opioid, reported a study conducted on mice by scientists at the Scripps Research Institute in La Jolla, CA. The findings offer a promising new strategy for treating heroin addiction and overdose.

Kim Janda, PhD, a professor of chemistry at Scripps Research is the senior author of the study

“Our findings suggest that a monoclonal antibody-based therapy will be more effective than a vaccine and should be targeted to heroin itself rather than its psychoactive metabolites,” said Kim Janda, PhD, the Ely R. Callaway, Jr., professor of chemistry, director of the Worm Institute for Research & Medicine at Scripps Research, and the senior author of the study.

“The work from Dr. Janda and colleagues is very interesting and timely given the importance of developing new strategies to address the opioid epidemic and the dramatic increase in fatal overdoses attributable to opioids or mixtures of opioids and stimulants such as cocaine and methamphetamine,” said Marco Pravetoni, PhD, professor at the department of psychiatry and behavioral medicine at the University of Washington School of Medicine, whose own team is developing vaccines and monoclonal antibody (mAb) against heroin, oxycodone, fentanyl, and fentanyl analogs. “The findings show target selection is critical to advance an effective therapy.” Pravetoni was not involved in the current study. “

“This work provides compelling data that challenges our current understanding of heroin pharmacodynamics. It continues to show the utility of high-affinity antibodies, not only as biological tools, but as viable therapeutics to fight the ongoing opioid crisis,” said Nicholas Jacob, PhD, senior research scientist at Cessation Therapeutics. Jacob was not involved in the current study.

Political leaders and scientists around the globe have been trying to quash the exponentially growing opioid epidemic for decades. However, current medications and behavioral interventions have failed to abate this public health crisis. Instead, opioid abuse and overdose cases have escalated to unprecedented levels since the start of the COVID-19 pandemic.

FDA-approved small molecule medications for opioid use disorders (OUDs)—methadone, buprenorphine, naltrexone, and naloxone—are limited by adverse side effects, short half-lives, limited availability, high cost, lack of adherence to medication regimen, potential for abuse, and relapse to addiction once the medication is discontinued. Immunopharmacotherapy provides a viable alternative. This treatment approach uses antibodies to block the action of illicit substances, retaining the compounds in peripheral circulation.

Decades of studies have attributed heroine’s psychoactive and lethal effects to its metabolites: 6-monoacetylmorphine (6-AM) and morphine. Therefore, earlier immunopharmacotherapeutics have used active and passive vaccines to target heroin’s metabolites instead of heroin itself. “Passive vaccines” often involve injection of monoclonal antibodies (mAbs) against the target or its metabolites, while active vaccines use immune-stimulating proteins that mimic the target or its metabolites to trigger the patient’s own immune system. However, these therapies have had limited success, underscoring the need to reassess the selection of therapeutic targets.

That the heroin vaccines Janda’s team and others were developing did not meet with success in clinical trials, prompted Janda to take a step back and evaluate perceptions and misperceptions in the drug addiction field.

“Most researchers viewed heroin to be simply a ‘prodrug’ that crosses the blood-brain barrier very quickly and that its ‘prodrug’ ability was simply to transport the main mu-opioid receptor drugs, 6-acetylmorphine and ultimately morphine, into the brain,” said Janda. “Based upon this reasoning, targeting heroin was an afterthought.”

When the earlier heroin vaccines failed to counter the effects of a heroin dose as was anticipated, poor adjuvants in the vaccine cocktail were singled out as the culprit.

Janda said, “In reality, the overall formulation of the vaccines was correct but the targeting of 6-acetylmorphine and morphine with the antigen was misguided.”

Departing from earlier efforts in developing an effective immunopharmacotherapeutic to treat heroin abuse, the current study analyzed four unique mAbs that target either heroin, 6-AM, or morphine, or both heroin and 6-AM. The development of these mAbs using a deutero-heroin hapten with broad-spectrum affinity for heroin and its metabolites, was reported in an earlier study by the same group. The researchers profiled the binding affinities of these mAbs using surface plasmon resonance (SPR), enabling them to select four distinct antibody clones with superior abilities in binding heroin or one of the metabolites.

“By using these antibodies, we were able to dissect, which of these three drugs was important to target for vaccine (antibody) development,” said Janda.

The researchers then conducted pharmacokinetic assays, overdose assays, and hot plate and tail flick assays for pain perception, to identify the targets that would effectively blunt the behavioral, toxic, and lethal effects of heroin. These in vitro and in vivo tests showed that the heroin-targeting mAb 11D12 was, unexpectedly, the optimal therapeutic to suppress the effects of heroin, over the other mAbs that targeted its two major metabolites.

This study reveals that monoclonal antibody 11D12 blunts heroin’s psychoactive and lethal effects in mice. [Adapted from Lee et al., ACS Central Science]

The authors showed that 11D12 blocks heroin’s analgesic effects and prevents heroin from slowing breathing and heart rates—the direct causes underlying heroin’s lethality. The mAb 11D12 accomplished these at a high degree of potency needed for human clinical trials.

Pravetoni said, “Lee et al., provide evidence that mAb can be used in reversal of opioid overdose and to reduce lethality post exposure. These results are consistent with our work on anti-opioid mAbs (Baehr et al., JPET 2020Baehr et al., JPET 2022Hicks et al., HVI 2022), and support the notion that vaccine and mAb warrant clinical investigation.”

Moreover, the investigators found that 11D12 remained active in circulation for weeks, unlike earlier therapies that were cleared from circulation within hours. This is a key advantage against poor patient compliance in adhering to treatment regimens, which is common among patients with addiction.

The efficacy of 11D12 in countering the effects of heroin took Janda and his team by surprise, since unlike the other three antibodies tested, it targets heroin with the highest binding affinity and not its metabolites. Since esterase enzymes in the blood rapidly convert heroin to morphine and 6-acetylmorphine through sequential deacetylation, scientists have, until now, identified the metabolites as better targets.

“The focus on the metabolites basically misguided the field—our report will reset research in a direction where successful clinical trials should now be achievable,” said Janda. The current findings clarify the reasons underlying the failure of earlier attempts in developing therapeutics that targeted heroin’s metabolites alone.

“From work in the field, we know that targeting heroin, 6-AM, and morphine may be equally important. However, the impact of individual vaccines or mAb formulations will be ultimately assessed in human subjects through clinical trials,” said Pravetoni. “For instance, targeting heroin and 6-AM would be important to blunt the acute toxicity and reward from heroin, but it is not clear whether targeting morphine would also be necessary to counteract the chronic effects of heroin metabolites in OUD patients.”

“We are always trying to optimize the ability of opioids and other abused drugs to generate antibodies, since high levels of antibodies are needed to counteract the toxic and lethal effects of the drugs that are abused, particularly fentanyl-related opioids,” said Thomas Kosten, MD, the Waggoner professor of psychiatry, pharmacology, neuroscience, and immunology at Baylor College of Medicine. “While this work focuses on heroin and that class of opioids, similar work from this research group has contributed much to our ability to develop vaccines and monoclonals for other classes of abused drugs including the fentanyl-related opioids, which are the most lethal and resistant to our existing FDA-approved treatments of methadone, buprenorphine, and depot naltrexone. This paper provides an excellent contribution to our field of immunotherapy for addictions.” Kosten was not involved in the current study.

In future studies, the team will test a human version of the mouse monoclonal antibody 11D12, and parallel mAbs to neutralize the synthetic opioids fentanyl, carfentanil, and other related compounds.

Janda said, “Our heroin antibody could in theory hold translation value for clinical trials if humanized.”

The post Heroin Antibody Fares Better than Earlier Therapies that Targeted its Metabolites appeared first on GEN - Genetic Engineering and Biotechnology News.

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Stay Ahead of GDP: 3 Charts to Become a Smarter Trader

When concerns of a recession are front and center, investors tend to pay more attention to the Gross Domestic Product (GDP) report. The Q4 2022 GDP report…

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When concerns of a recession are front and center, investors tend to pay more attention to the Gross Domestic Product (GDP) report. The Q4 2022 GDP report showed the U.S. economy grew by 2.9% in the quarter, and Wall Street wasn't disappointed. The day the report was released, the market closed higher, with the Dow Jones Industrial Average ($DJIA) up 0.61%, the S&P 500 index ($SPX) up 1.1%, and the Nasdaq Composite ($COMPQ) up 1.76%. Consumer Discretionary, Technology, and Energy were the top-performing S&P sectors.

Add to the GDP report strong earnings from Tesla, Inc. (TSLA) and a mega announcement from Chevron Corp. (CVX)—raising dividends and a $75 billion buyback round—and you get a strong day in the stock markets.

Why is the GDP Report Important?

If a country's GDP is growing faster than expected, it could be a positive indication of economic strength. It means that consumer spending, business investment, and exports, among other factors, are going strong. But the GDP is just one indicator, and one indicator doesn't necessarily tell the whole story. It's a good idea to look at other indicators, such as the unemployment rate, inflation, and consumer sentiment, before making a conclusion.

Inflation appears to be cooling, but the labor market continues to be strong. The Fed has stated in many of its previous meetings that it'll be closely watching the labor market. So that'll be a sticky point as we get close to the next Fed meeting. Consumer spending is also strong, according to the GDP report. But that could have been because of increased auto sales and spending on services such as health care, personal care, and utilities. Retail sales released earlier in January indicated that holiday sales were lower.

There's a chance we could see retail sales slowing in Q1 2023 as some households run out of savings that were accumulated during the pandemic. This is something to keep an eye on going forward, as a slowdown in retail sales could mean increases in inventories. And this is something that could decrease economic activity.

Overall, the recent GDP report indicates the U.S. economy is strong, although some economists feel we'll probably see some downside in 2023, though not a recession. But the one drawback of the GDP report is that it's lagging. It comes out after the fact. Wouldn't it be great if you had known this ahead of time so you could position your trades to take advantage of the rally? While there's no way to know with 100% accuracy, there are ways to identify probable events.

3 Ways To Stay Ahead of the Curve

Instead of waiting for three months to get next quarter's GDP report, you can gauge the potential strength or weakness of the overall U.S. economy. Steven Sears, in his book The Indomitable Investor, suggested looking at these charts:

  • Copper prices
  • High-yield corporate bonds
  • Small-cap stocks

Copper: An Economic Indicator

You may not hear much about copper, but it's used in the manufacture of several goods and in construction. Given that manufacturing and construction make up a big chunk of economic activity, the red metal is more important than you may have thought. If you look at the chart of copper futures ($COPPER) you'll see that, in October 2022, the price of copper was trading sideways, but, in November, its price rose and trended quite a bit higher. This would have been an indication of a strengthening economy.

CHART 1: COPPER CONTINUOUS FUTURES CONTRACTS. Copper prices have been rising since November 2022. Chart source: StockCharts.com. For illustrative purposes only.

High-Yield Bonds: Risk On Indicator

The higher the risk, the higher the yield. That's the premise behind high-yield bonds. In short, companies that are leveraged, smaller, or just starting to grow may not have the solid balance sheets that more established companies are likely to have. If the economy slows down, investors are likely to sell the high-yield bonds and pick up the safer U.S. Treasury bonds.

Why the flight to safety? It's because when the economy is sluggish, the companies that issue the high-yield bonds tend to find it difficult to service their debts. When the economy is expanding, the opposite happens—they tend to perform better.

The chart below of the Dow Jones Corporate Bond Index ($DJCB) shows that, since the end of October 2022, the index trended higher. Similar to copper prices, high-yield corporate bond activity was also indicating economic expansion. You'll see similar action in charts of high-yield bond exchange-traded funds (ETFs) such as iShares iBoxx $ High Yield Corporate Bond ETF (HYG) and SPDR Barclays High Yield Bond ETF (JNK).

CHART 2: HIGH-YIELD BONDS TRENDING HIGHER. The Dow Jones Corporate Bond Index ($DJCB) has been trending higher since end of October 2022.Chart source: StockCharts.com. For illustrative purposes only.

Small-Cap Stocks: They're Sensitive

Pull up a chart of the iShares Russell 2000 ETF (IWM) and you'll see similar price action (see chart 3). Since mid-October, small-cap stocks (the Russell 2000 index is made up of 2000 small companies) have been moving higher.

CHART 3: SMALL-CAP STOCKS TRENDING HIGHER. When the economy is expanding, small-cap stocks trend higher.Chart source: StockCharts.com. For illustrative purposes only.

Three's Company

If all three of these indicators are showing strength, you can expect the GDP number to be strong. There are times when the GDP number may not impact the markets, but, when inflation is a problem and the Fed is trying to curb it by raising interest rates, the GDP number tends to impact the markets.

This scenario is likely to play out in 2023, so it would be worth your while to set up a GDP Tracker ChartList. Want a live link to the charts used in this article? They're all right here.


Jayanthi Gopalakrishnan

Director, Site Content

StockCharts.com

 

Disclaimer: This blog is for educational purposes only and should not be construed as financial advice. The ideas and strategies should never be used without first assessing your own personal and financial situation, or without consulting a financial professional.

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Hotels: Occupancy Rate Down 6.2% Compared to Same Week in 2019

From CoStar: STR: MLK Day Leads to Slightly Lower US Weekly Hotel PerformanceWith the Martin Luther King Jr. holiday, U.S. hotel performance came in slightly lower than the previous week, according to STR‘s latest data through Jan. 21.Jan. 15-21, 2023 …

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With the Martin Luther King Jr. holiday, U.S. hotel performance came in slightly lower than the previous week, according to STR‘s latest data through Jan. 21.

Jan. 15-21, 2023 (percentage change from comparable week in 2019*):

Occupancy: 54.2% (-6.2%)
• Average daily rate (ADR): $140.16 (+11.3%)
• evenue per available room (RevPAR): $75.97 (+4.4%)

*Due to the pandemic impact, STR is measuring recovery against comparable time periods from 2019. Year-over-year comparisons will once again become standard after Q1.
emphasis added
The following graph shows the seasonal pattern for the hotel occupancy rate using the four-week average.

Click on graph for larger image.

The red line is for 2023, black is 2020, blue is the median, and dashed light blue is for 2022.  Dashed purple is 2019 (STR is comparing to a strong year for hotels).

The 4-week average of the occupancy rate is below the median rate for the previous 20 years (Blue), but this is the slow season - and some of the early year weakness might be related to the timing of the report.

Note: Y-axis doesn't start at zero to better show the seasonal change.

The 4-week average of the occupancy rate will increase seasonally over the next few months.

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American Express Numbers Show What Still Gets People to Spend Money

American Express stock jumped nearly 12% since earnings dropped.

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American Express stock jumped nearly 12% since earnings dropped.

Even though American Express  (AXP) - Get Free Report earnings announced Friday afternoon fell somewhat short of expectations for the quarter, shares still soared to highs unseen for many months due to a number of strong metrics -- quarterly revenue growth of 17%, plans to raise its dividend by 15% from 52 to 60 cents and an annual revenue that surpassed $50 billion for the first time ever.

At $52.9 billion, the latter is driven primarily by an increase in quarterly member spending. Last year, that number was at $42.4 billion. 

According to American Express Chairman and CEO Stephen J. Squeri, the increase can be attributed to higher numbers of millennials gaining in earning power and using their AmEx above other cards to tap into rewards as many approach milestones like marriage, career advancement, and homeownership.

"Millennial and Gen Z customers continue to be the largest drivers of our growth, representing over 60% of proprietary consumer card acquisitions in the quarter and for the full year," Squeri said in an earnings call discussing the results.

People Are Using Their AmEx Cards a Lot

The $52.9 billion number is up 25% from what was seen last quarter and reflects a number of different factors also having to do with post-pandemic spending.

"We ended 2022 with record revenues, which grew 25% from a year earlier, and earnings per share of $9.85, both well above the guidance that we provided when we introduced our long-term growth plan at the start of last year, despite a mixed economic environment," Squeri said.

AmEx further reported that 12.5 million new members signed up for cards in 2022 while existing members used their cards frequently. Fourth-quarter sales at AmEx's U.S. consumer services and commercial segments rose by a respective 23% and 15%.

But higher expenses also led to falling below analyst expectations. The fourth-quarter income of $1.57 billion, or $2.07 a share, is down from $1.72 billion ($2.18 a share) in the fourth quarter of 2021. FactSet analysts had predicted $2.23 a share.

"I'm not sure what that's really a function of right now -- whether it's a function of the economy or of confusion on where to advertise right now," Squeri told Yahoo Finance in reference to lower spending on the part of small business and digital advertisers. "We're going to watch that, but the consumer is really strong, travel bookings are up over 50% vs pre-pandemic."

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It's a Good Time to Be Tracking Credit Card Companies

Immediately after the earnings dropped, AmEx stock started soaring and was up nearly 12% at $175.24 on Friday afternoon. This is a high unseen in months -- the last peak occurred when, on September 12, shares were at $162.45. 

Whether due to or despite analyst threats of a looming recession, people have been using their credit cards very actively throughout the end of 2022.

When it posted its earnings earlier this week, Mastercard  (MA) - Get Free Report surpassed Wall Street expectations of $5.8 billion and $2.65 per share in fourth-quarter earnings. Visa  (V) - Get Free Report also saw revenue rise 11.8% to $7.94 billion in the same quarter. The numbers also reflect higher numbers of people traveling and using their credit cards in different countries.

"Visa's performance in the first quarter of 2023 reflects stable domestic volumes and transactions and a continued recovery of cross-border travel," outgoing CEO Al Kelly said of the results during a call with financial analysts.

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