Twiv 815 30

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30:01 right so because after all again as we
30:04 mentioned that the segment that binds is
30:06 short like an antigen but it is part of
30:08 the protein so these antibodies block uh
30:11 the super antigenic properties right
30:14 that is that's what uh betina then uh
30:17 reported the original phrase from in
30:20 this
30:21 2014 paper have they been used
30:23 therapeutically
30:26 so apparently
30:27 i i was told pfizer was interested and
30:31 then at that time they humanized the
30:33 monoclonal antibody then a ceo change
30:36 and the project was dropped
30:39 okay
30:41 so when we look closer
30:43 the way
30:44 63 that particular antibody interacts
30:47 with
30:48 sip we see that it is interacting with
30:52 those uh
30:54 acidity
30:55 basic amino acids lots of lysines here
30:58 lysines that are sequentially homologous
31:02 to the arginines in this uh secretogenic
31:06 region
31:07 of the spike
31:08 and then of course we tried we we
31:11 verified if you wish that 63 this
31:14 antibody also bites our spike and indeed
31:18 we've seen the same amino acid acetic
31:20 acid amino acid
31:22 of the uh
31:24 antibody interacting with the basic
31:27 amino acids of the spike exactly at this
31:30 region where the cleavage takes place
31:34 so now okay binding does it really it
31:37 doesn't uh imply uh you know
31:40 a functional impact of course but then
31:43 moshe's
31:44 uh his collaborators they also did the
31:47 experiments to show that there is indeed
31:50 in
31:51 a you know
31:52 a decrease in effectivity in a 63 the
31:55 fab those dependent manner
31:57 so that are this has been now published
32:00 in a
32:01 uh
32:02 sort structure
32:04 and
32:04 then uh we started to think even deeper
32:07 should i go on or just wait okay
32:11 so i think it would be great just to
32:12 reiterate this finding so you have this
32:16 monoclonal antibody that was known to
32:19 bind to the seb
32:21 molecule another superantigen and then
32:24 you showed that it could block
32:26 infectivity for sars cov2 in
32:30 two which shares a
32:32 segment common with scd right so there
32:35 is you know the binding epitope on
32:38 starscope to glycoprotein is almost
32:40 identical to that on seb not only
32:43 sequentially but also structurally right
32:45 so evidently something that binds one of
32:48 them would bind the other
32:49 so binding was fine but it was also
32:52 we also showed that it reduced
32:53 effectivity yeah so this must have been
32:55 a really exciting finding
32:58 of course
32:59 okay
33:01 it was particularly exciting because the
33:03 existing monoclonals you know
33:06 that that we use in patients
33:09 we were told that
33:10 you have to use them very early because
33:12 it only works to block uh
33:15 viral uh product you know like
33:17 reproduction and entry but it's it
33:20 doesn't really work in the later stages
33:22 of
33:22 anti-inflammatory stage this this
33:25 potentially theoretically would affect
33:27 both both parts both
33:30 you know blocking viral viral infection
33:33 as well as if the super antigen tcr
33:36 is shown to be functional and playing a
33:38 role it may block that as well so
33:41 what you're thinking is that maybe the
33:44 inflammatory disease not mis but other
33:49 inflammatory diseases in covid might be
33:51 in a a reflection of some super
33:54 antigenic uh interaction right yes and
33:56 that you know for example adults that go
33:59 into you know some of them
34:02 akiko's work with yale for example have
34:04 shown at some some uh patients have
34:07 prolonged a cytokine storm you know that
34:10 goes on and and is it possible that this
34:13 is playing a role yeah you know scb is
34:15 very interesting uh uh of course this is
34:18 all theoretical and and
34:20 and it needs to be proven but
34:23 by age
34:25 you know 16 you know or 60 80 of the
34:29 population have anti-scb antibodies uh
34:32 but but 20 of the population cannot make
34:36 anti-cb antibodies and then you lose
34:38 your anti-acb antibodies these are known
34:41 from toxic shock syndrome studies so is
34:44 it possible that after 70 or 80 years of
34:47 age apparently people use their anti-scb
34:50 antibodies is it perhaps why
34:54 it's more
34:55 severe disease at that age so these this
34:58 this is a one possibility the other was
35:01 was very intriguing is the ivig has been
35:04 used
35:05 in both missy and also in some studies
35:08 for adult severe covet
35:11 and there are some trials still going on
35:13 ivig is full of anti-scb this is why
35:17 toxic shock syndrome's therapy is ivig
35:20 plus steroids you know um
35:23 so this is another theoretical thing
35:25 that we're working on you know uh so
35:28 that's that's why this is this was
35:29 important so some of this discussion
35:31 gets me wondering about the uh kinetics
35:34 uh of this
35:36 uh disease because
35:38 uh misc i think you said uh can show up
35:42 pretty late after infection in children
35:45 and likewise the
35:47 inflammatory the severe inflammatory
35:50 syndrome shows up pretty late
35:52 in uh
35:54 adults and i have thought of this as
35:57 uh pretty much after the most acute part
36:00 of the infections are over so the
36:02 question arises in my mind
36:04 uh
36:05 is the super antigen effect
36:08 sort of a hit and run long term thing or
36:10 do you need to have super antigen
36:13 present in
36:15 you know something like a stoichiometric
36:17 uh amount
36:18 at the time that the disease is induced
36:21 what are the kinetics all right so so
36:23 this is this is the question i get all
36:25 the time you know uh
36:27 and and and and so so the kinetics is
36:30 that you know we're working these are
36:33 observations right now and hypotheses
36:36 that need to be completely completely
36:38 understood better i mean
36:41 i mean i feel like we're building we're
36:44 building a ship
36:46 while we're sailing
36:49 you know that's how that's how the whole
36:51 disease has been and and miss c is the
36:53 same you know
36:54 we found as we go so but
36:57 but the way
36:58 i can envision is that the super
37:01 antigenic motif
37:03 particularly when s1 is shed and
37:05 particularly when
37:07 you know david waltz uh uh uh uh
37:10 you know from brigham has shown that
37:12 circulating s1 levels directly correlate
37:16 with disease severity in adults like who
37:18 goes to the icu and stuff so so one
37:21 aspect is that perhaps these super
37:24 antigens that are shed in the s1 that
37:27 have become more more ex you know
37:31 exposed are playing a role in cytokine
37:34 release acute that's one part
37:36 then
37:38 kids would miss c
37:40 how do you explain that they're coming
37:42 back four weeks six weeks later if this
37:44 is an acute disease and their acute
37:46 disease is just very mild sometimes even
37:49 just like a
37:51 exposure and nothing but then they come
37:53 with hyperinflammatory syndrome
37:55 as an autoimmune kind of like a
37:57 mechanism almost right like like kind of
38:00 like group a strap and then four weeks
38:02 later you develop rheumatic fever kind
38:05 of thing right and there i think the
38:07 hypothesis has to be
38:09 either a
38:11 autoimmune
38:13 interaction that the superantigen is
38:15 inducing not only the t cells that are
38:18 going crazy but also polyclonal b cell
38:20 activation that eventually turns against
38:23 itself and and may explain all this auto
38:26 antibodies that us and many other people
38:29 have reported now in missy this is one
38:32 thing the other thing is that in misty
38:34 patients there is another paper that we
38:36 published with alessandro fasano from uh
38:39 and laurel juncker at jci that shows
38:42 that these kids continue to have virus
38:45 in their stool
38:46 up to four weeks six weeks and they have
38:49 increased gut permeability and they're
38:52 leaking perhaps some of these s-ones
38:54 indeed they measured s1 level in the
38:57 miss c patients and it correlates with
39:00 disease severity even at four six weeks
39:03 later because of gut permeability so
39:06 while super antigen may cause a acute
39:09 cytokine release in some patients adults
39:12 or others
39:13 it may also cause this late onset
39:16 autoimmune kind of things that we're
39:18 seeing perhaps even
39:20 even in long covet in addition to to
39:23 miss c but these are all theories that
39:25 that needs to be proven
39:28 so another question that i had was about
39:32 uh potential predisposing factors and
39:36 why it's only a fraction
39:38 of
39:39 people who show up with this i know
39:41 you've done some work on this but i've
39:43 raised the question and i noticed in
39:45 particular a sentence from your pnas
39:48 paper
39:49 saying that uh
39:51 speaking of
39:52 misc
39:54 uh and this was i forget exactly one but
39:57 no such cases have been reported in
39:59 china japan or south korea that made me
40:01 wonder whether there was
40:03 a genetic component or something like
40:05 that absolutely and maybe
40:07 maybe yvette can show the slide about
40:09 the hla hla finding that uh event if you
40:13 have that
40:14 that slide you know so i don't think i
40:16 have it uh
40:18 no it's the four slides i send you uh uh
40:20 but you may you know maybe you didn't
40:22 include them but uh so
40:25 so this is the tcr uh 11 2 skewing and
40:28 then the hla skewing but anyway so what
40:31 we have published uh in in in a jci
40:35 paper
40:36 is that um
40:39 there is obviously a t cell receptor
40:41 skewing so you can say okay you found
40:44 this super antigen and of course the
40:46 reviewers said the same thing right
40:48 well how do you know it's doing anything
40:50 you know i mean is it really causing any
40:52 functional like does it was it there
40:54 just like for for structure or is it
40:56 doing a uh
40:59 how do you know it's playing a role in
41:00 the disease um or super antigenic role
41:03 even so we had to come in the pns paper
41:06 in the adults that have
41:08 hyperinflammatory syndrome and show that
41:10 they do indeed have t-cell receptors
41:13 skewing 24
41:15 1 or some other a couple of them
41:18 and that was in that paper
41:20 in in a subsequent paper in jci we
41:23 showed that in kids with miss c there is
41:26 specifically t cell v beta uh 12-2 that
41:30 is that is uh skewed or blooming you
41:34 know so that is a signature in a way of
41:37 a super antigenic immune signature that
41:39 t cells specific t cell receptors are
41:42 are skewing
41:43 yale group has shown the same thing and
41:45 a french group has shown the same thing
41:47 so this is now repeated in three cohorts
41:49 that t cell receptor 11 2 is skewed
41:53 in that paper we start the paper by just
41:56 saying
41:56 hla associated t cell receptor skewing
42:00 so we had
42:01 i think five or eight kids with missy
42:05 and among those with severe missy
42:08 to our surprise all of them
42:11 had
42:12 a unique trio of hla uh a finding you
42:16 know i think you know um
42:18 um
42:19 so it was a2 uh uh b35 and and
42:24 c404 i think it's in the paper so so
42:27 this three alleles you know of hla one
42:33 is somehow helping the superantigenic
42:37 motif to be presented to do to the tcr
42:41 and this is the first clue in my opinion
42:44 that there is some genetic
42:45 predisposition this is why 60 70 percent
42:48 of cases are either hispanic or
42:51 african-american in this country and
42:53 then african-american african origin in
42:56 europe now
42:58 i was very happy to see a
43:01 med archive paper from nih that just was
43:06 came out two days ago
43:08 and it's in the abstract as well that
43:11 the same three alleles are shown in more
43:14 than half of their misc patients so so
43:17 this is a clue that
43:20 why this is such a rare disease you know
43:22 so so would you expect then
43:25 that this superantigenic region of spike
43:29 might bind better
43:31 to
43:32 that particular tcr can you can you
43:35 approach this structurally yes actually
43:38 that's what we've done also and you know
43:41 we first the first the data we got from
43:44 our collaborators in germany was
43:47 that the you know this subset of tcr's
43:51 that are observed to be overexpressed in
43:54 adults with severe coveted
43:57 19
43:59 and then we checked whether you know
44:01 those tcrs would be binding and the pns
44:03 paper already contains that later on
44:07 then a similar type of study for tcr
44:10 skewing was done with
44:12 the children
44:13 the one published in journal of clinical
44:15 investigation
44:17 and that's where you know the
44:19 particular tcr v beta chain 11-2
44:24 was found to be distinctly overexpressed
44:28 and then we have also shown how the
44:30 interaction you know we have all those
44:32 results in those papers how the
44:34 interactions with the superantigenic
44:37 region
44:38 and
44:39 this particular vibra chain
44:42 are very strong
44:44 now there is one more thing though i
44:46 would like to add
44:47 uh
44:48 there you know we a very interesting
44:50 study caught our attention last year
44:54 uh where uh
44:56 it was published in science
44:58 by matthias at all

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