Celebration Thread TrueBinding Galectin-3

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J11
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Celebration Thread TrueBinding Galectin-3

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LB15- RESULTS FROM A CLINICAL STUDY OF AN ANTIGALECTIN-
3 MONOCLONAL ANTIBODY IN PATIENTS

Background: Galectin-3 has been reported to be highly
expressed in Alzheimer’s disease (AD) brain tissues. Our
studies elucidated its intrinsic ability of acting as glue to
promote oligomerization of Abeta, pTAU and other amyloid
proteins in vitro. It’s antagonist monoclonal antibodies showed
dramatic cognition improvement and plaque reduction in AD
mice after only two-week treatment Inhibition of Galectin-3
is a novel approach to the treatment of AD. The hypothesis
is disease reversal, not halting disease progression. Gal-3
is a ubiquitous endogenous protein involved the pathology
of certain neurodegenerative, metabolic, and immunologic
disorders. TB006 is a humanized IgG4 type monoclonal
antibody with high affinity and selectivity for Gal-3.
Preclinical studies in Tg mice demonstrated dramatic cognitive
improvement and plaque reduction with only two weeks of
treatment. In a SAD study in healthy volunteers, doses of up
5000 mg (~70 mg/kg) were safe and well tolerated. Dosing
of the clinical lead antibody TB006 in a single ascending dose
(SAD) study in healthy volunteers up to 5000mg (70mg/
kg) was safe and well tolerated. This phase 1b/2a study was
conducted in moderate to severe AD patients to assess the
safety, tolerability, PK and efficacy of five weekly TB006 doses.
Methods: This was a seamless Ph 1b/2a double-blinded,
placebo controlled, multicenter study. AD patients with a
screening MMSE <24 and without confounding neurologic or
psychiatric disease were eligible. In Ph 1b, 3 groups (140 mg,
420 mg, 1000 mg) of 8 patients in sequential ascending fashion
received either weekly TB006 (6) or placebo (2) infusions for 5
doses. In Ph 2a, 1 participants16 were to be randomized (1:1)
to receive either TB006 (1000mgthe highest safe and tolerated
dose from Part 1) or placebo weekly for 5 doses. Ph 2a used
the clinical dementia rating -sum of boxes (CDR-SB) score as
the primary endpoint. Other endpoints were the mini-mental
state examination (MMSE), neuropsychiatric inventory (NPI),
CDR battery and plasma and imaging (MRI/PET) biomarkers.
Cognition testing was done at baseline and on Days 15, 364,
64, and 104. Safety assessments were conducted at each
visit. The sample size provided 80% power to detect a mean
difference between TB006 and placebo of 0.25 point at Day 104
on the CDR-SB. Results: 157 patients, including 24 in Part 1,
were randomized at 15 US sites. ; Nine9 subjects prematurely
discontinued. TB006 was safe and well tolerated at all dose
levels. There were 9 severe adverse events (SAEs), including 1
death. None were related to TB006 treatment. Most other AEs
were mild, sporadic and self-limiting. Patients in Group 3 (1000
mg), as well as all placebo patients in Ph 1a were included in
the efficacy analysis. The primary endpoint was met. Patients

receiving TB006 showed a dramatic 0.9 point reduction on the
CDR-SB score
compared with placebo (p<0.015). Secondary
efficacy endpoints were equally robust. Mean efficacy endpoint
scores in the placebo group remained consistent throughout the
observation period. Conclusion: TB006 demonstrated evidence
of AD reversal in this short-term treatment study. TB006 was
safe and well tolerated.
Last edited by J11 on Tue Mar 21, 2023 6:11 pm, edited 3 times in total.
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Re: Celebration Thread TrueBinding Galectin-3

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NEW THERAPIES AND CLINICAL TRIALS
P24- POTENTIAL REVERSAL OF ALZHEIMER’S DISEASE.


Background: Alzheimer’s disease (AD) is a chronic
progressive neurodegenerative disorder caused by multiple
pathogenic factors including Amyloid-β (Aβ), phospho-Tau
(pTau), a-synuclein, and ApoE4, etc. It is widely accepted that
intermediate oligomeric forms, rather than monomers or mature
fibrils, are more neurotoxic. Galectin-3 (Gal-3) was reported to
be involved in Aβ oligomerization. Here, we show that Gal-3
promotes oligomerization of Aβ and other pathogenic factors,
and TB006, a monoclonal antibody targeting Gal-3, acts as a
possible treatment for AD by degrading neurotoxic oligomers
and reducing inflammation. Pre-clinical studies show that
TB006 is an efficacious therapeutic entity through preventing
formation of toxic oligomers and blocking or even reversing
AD progression. Objectives: Gal-3 expression is increased in
brains from AD patients, particularly in microglia associated
with amyloid plaques. Our objectives were to examine the role
of Gal-3 in Aβ aggregation (conformational oligomer formation)
and to investigate the therapeutic efficacy of our novel Gal-3
antibody for treatment of AD. Methods: We used two anti-
Gal-3 antibodies, our clinical lead TB006 and a mouse crossreactive
surrogate, mTB001, to establish the benefits of Gal-3
neutralization in AD in vitro and in vivo. The effects of mTB001
were tested in three AD mouse models (two transgenic mouse
models (APPSwe, 5xFAD) and an Aβ42-injected mouse model).
After a two-week treatment, a spatial memory function test was

conducted, followed by biochemical and immunohistochemical
characterizations. Results: Amyloid aggregation is a hallmark of
several neurodegenerative diseases (including AD, Parkinson’s
disease and amyotrophic lateral sclerosis) affecting the brain or
peripheral tissues, whose intermediates (oligomers, protofibrils)
and final mature fibrils display different toxicity. In vitro, Gal-3
intrinsically and selectively promoted, while mTB001 and TB006
degraded, oligomerization of only pathogenic protein forms
like Ab42/40, a-synuclein, pTau and ApoE4, but not of nonpathogenic
normal Tau and ApoE2/3. Gal-3 enhanced, while
mTB001 blocked, Ab42-induced lysosomal dysfunction and proinflammatory
activation in BV2 microglial cells. Additionally,
Ab42 and Gal-3 synergistically induced, while mTB001
reversed, neuronal death. In vivo, in three mouse models of
AD, cognitive deficits were strongly attenuated after just two
weeks of mTB001 treatment. Mechanistically, Gal-3 antibody
blocked the initiating events in AD (Aβ aggregates), reduced
inflammation and rescued neuronal damage. Furthermore,
microhemorrhages, a potential safety liability seen in clinical
stage drugs, were reduced. Conclusion: Pre-clinical studies
show that TB006 is an efficacious therapeutic entity through
preventing formation of toxic oligomers and blocking or even
reversing AD progression. Clinically, TB006 has shown a
superior safety profile without any drug-related adverse events
in a nearly finished healthy volunteer trial. Promising efficacy
data are expected in Q2/2022 from the ongoing phase I/II AD
trial.
P25-
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Re: Celebration Thread TrueBinding Galectin-3

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Wow! The above was from CTAD 2022 abstracts. I read the program and glanced over the reference to galectin-3 though I did not explore this any further. However, today I re-encountered TrueBinding the company behind a mab for Gal-3 and looked into it more. Wow!

The post directly above has the title of Potential Reversal of AD- that should always capture one's attention. The first post also captured my attention because it mentioned that the study included moderate to severe AD patients-- not many trials try to treat severe AD. This is very interesting!

I am not clear where the 0.9 point reduction on CDR-sb in patients receiving TB006 is sourced from.The figure seems to only show a 0.44 benefit.
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Re: Celecbration Thread TrueBinding Galectin-3

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True 1 Galectin 3.PNG
True 1 Galectin 2.PNG
True 1 Galectin 1.PNG
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Re: Celebration Thread TrueBinding Galectin-3

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What's it all about? The above figures run through the clinical results. They got down to 5 MMSE and only~30% of the treated patients were plaque positive. I am not sure why they would not insist on a positive amyloid scan for inclusion. Even though the galectin-3 mab does not specifically target amyloid plaque it did in fact reduce plaques as seen in the PET scans. I suppose that this would count as another confirmation of the amyloid hypothesis.

Bottom figure shows that there was a cognitive benefit within 30 days of starting treatment which lasted 1 month. This 1 month of treatment continued to have benefit of 0.44 CDR-sb even out to 106 days. That is quite impressive.
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Re: Celebration Thread TrueBinding Galectin-3

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True 1 Galectin 5a.PNG
True 1 Galectin 5.PNG
True 1 Galectin 4.PNG
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Re: Celebration Thread TrueBinding Galectin-3

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The above slides investigate the biology involved. In the first figure we see how gal-3 is over-expressed in the AD brain and how this protein can latch onto various other proteins such as beta-amyloid, tau, APOE e4 etc.. I am not sure whether they reported the CDR-sb outcome by e4 genotype; it might be of interest if they were to. One might wonder what effect agglomerations of e4 coordinated by gal-3 might have in the brain. On the right we see that gal-3 knock out mice had much less beta amyloid in their brains and they also had much less cognitive impairment.

Middle set of figures show how gal-3 promotes beta-amyloid, tau and APOE e4 accumulations. Bottom slide shows how gal-3 acts to grab various proteins such as beta-amyloid with its 5 arms and then forms dimers, trimers and toxic oligomers. TN006 the anti-Gal-3 antibody dissolves the amyloid etc. aggregates and reverses the progression of AD.

Of interest is that by not directly attacking beta-amyloid plaques there would be no side effects related to ARIA. The phase 2 single dose trial confirmed this and found no evidence of ARIA.
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Re: Celebration Thread TrueBinding Galectin-3

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This is very exciting! It appears that there is a way of disrupting beta-amyloid plaques indirectly by blocking gal-3 which acts as a chaperone protein to form the plaques. When gal-3 is blocked with mabs, the existing plaques apparently will then spontaneously dissolve. The research also speaks about how microglial when in the untreated beta-amyloid environment release cytokines, but this is prevented when gal-3 mabs are given. Further research speaks of how gal-3 inhibition can upregulated NEP and other beta-amyloid degrading enzymes, TL4 and inflammation and how reducing concentration of beta-amyloid near the synapse can help restore neurons to proper functioning.

The research keeps getting better and better!
Instead of thinking directly about the beta-amyloid plaques one can move somewhat away from them and apparently still have powerful anti-dementing effects.
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Re: Celebration Thread TrueBinding Galectin-3

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SNP 1.PNG
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Re: Celebration Thread TrueBinding Galectin-3

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With many of these AD treatments I have wondered how they could have possibly figured it out. There are thousands and thousands of proteins. How do you pull galectin-3 out of the hat and produce an anti-dementing effect?

This is where GWAS would be of considerable benefit. All you would need to do is look at the genome and see what genetic variants protect or enhance AD risk. In the above table we see a number of SNPs in the gal-3 protein which is actually in the LGALS3 gene. So for instance rs4652 was found to enhance AD risk by 11%. This gives you a starting point to rationally investigate LGALS3 further. Clearly this then can be an extremely powerful drug development platform. Go through all of the AD GWAS hits and see what happens when you knock out the gene etc.. This is actually very comforting! The entire AD proteome is now being unraveled. The complete system of AD biology is revealed through the genetic variants and then the full list of treatment approaches is largely transparently clear for all to observe.
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