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>> GOOD AFTERNOON, EVERYONE.
WELCOME TO THE WEDNESDAY
AFTERNOON LECTURE FOR TODAY.
AND WELCOME ALSO TO THE PEOPLE
WHO ARE WATCHING ON THE WEB.
WE HAVE A VERY INTERESTING
PRESENTATION ABOUT A TOPIC THAT
PRESENTS A CONSIDERABLE PUBLIC
HEALTH CHALLENGE AND THAT IS THE
GROWING PRESENCE OF ANTIBIOTIC
RESISTANCE AND THAT'S TRUE FOR
PARTICULARLY BACTERIAL
INFECTIONS THAT WE USED TO HAVE
A REALLY WONDERFUL PHARMACY
WORTH OF ANTIBIOTICS THAT WOULD
WORK IN ALMOST ANY KIND OF
BACTERIAL INFECTION AND NOW AS
YOU KNOW THE INCREASED INCIDENCE
OF HIGHLY RESISTANT ORGANISMS
WHETHER IT'S MRSA, OR 1 OF THESE
REALLY NASTY GRAM NEGATIVES IS
CAUSING ANYBODY WHO'S TAKING
CARE OF SICK PATIENTS TO GROW
INCREASINGLY ALARMED ABOUT THE
PATH THAT WE'RE ON.
SO WE DESPERATELY NEED NOW
INVENTIONS AND NEW IDEAS ABOUT
THOSE HIGHLY RESISTANT
ORGANISMS.
I THINK THERE WAS SOMEBODY 50
YEARS AGO THAT WE HAD PRETTY
MUCH SOLVED INFECTIOUS DISEASE
AND WE COULD MOVE ON TO OTHER
THINGS BECAUSE WE HAD THAT UNDER
CONTROL.
WELL TIME HAS PROVED THAT TO BE
THE MISSED MARK.
WE HAVE NEWLY EMERGING VIRUSES
RIGHT AND LEFT.
LAST YEAR EBOLA THIS YEAR ZIKA
AND THE THREAT AS INFLUENZA IS
THE GREATEST OPPORTUNITY FOR A
DISASTROUS WORLD WIDE PANDEMIC
FOR WHICH WE ARE SOMEWHAT
OVERDUE.
ANOTHER 1918 EVENT CANNOT IN ANY
WAY BE CONSIDERED OUT OF THE
QUESTION, SO WE NEED NEW
THERAPEUTICS FOR INFLUENZA AS
WELL.
TODAY'S SPEAKER IS IN FACT IN
THE MIDDLE OF ALL THAT AND WE'LL
BE TALKING ABOUT THE DEVELOPMENT
OF THERAPEUTICS FOR BOTH VIRAL
AND THERAPEUTIC INFECTIONS, AND
DR. MAN-WAH TAN IS DIRECTOR AND
SENIOR SCIENTIST AT INFECTIOUS
DISEASES DEPARTMENT AT
GENENTECH.
HE MOVED TO STANFORD WHERE FOR
12 YEARS HE WAS IN THE
DEPARTMENT OF GENETICS AND
MICROBIOLOGY AND IMMUNOLOGY.
AND THEN IN 2012, MOVED TO HIS
CURRENT ROLE AT GENENTECH, WHERE
HE'S INVOLVE ED IN A NUMBER OF
PROJECTS THAT ARE USING
INNOVATIVE STRATEGIES TO GO
AFTER AND TREAT INFECTIOUS
AGENTS OF MEDICAL IMPORTANCE.
AND AS I SAID AT THE OUTSET, WE
NEED THIS MORE CONSIDERING THE
EPIDEMIOLOGY OF THESE DIRECTIONS
THAT THE INFECTIONS SEEM TO BE
GOING.
SO IT'S A GREAT PLEASURE TO HAVE
HIM HERE AS OUR SPEAKER.
PLEASE JOIN ME IN WELCOMING
DR. MAN-WAH TAN.
[ APPLAUSE ]
>> HI, GOOD AFTERNOON AND THANK
YOU FOR THE OPPORTUNITY TO COME
AND PRESENT TO YOU SOME OF THE
SCIENCE THAT HAS BEEN GOING ON
AT GENENTECH.
SO THIS SLIDE IS ALSO FOR A
DISCLAIMER, I WORK FOR
GENENTECH, WHICH IS A MEMBER OF
THE ROCHE GROUP, ALTHOUGH THE
SIGN DOESN'T CHANGE WHETHER YOU
DO IT IN THE COMPANY OR IN AN
ACADEMIC SITUATION.
SO TODAY I'M GOING TO TALK TO
YOU ABOUT OUR APPROACHES IN
USING MONOCLONAL ANTIBODIES AND
INFECT YOWS DISEASES.
I THINK MANGE OF US ARE VERY
FAMILIAR WITH THIS KIND OF A
GRAPH, SHOW WHAT,--WHAT I'M
SHOWING HERE IS MORTALITY IN
THOUSANDS PER YEAR FOR LUNG
CANCER, STOMACH CANCER,
COLORECTAL CANCER AND BREAST
CANCER AND WE ALL KNOW HOW
DEVASTATING THESE DISEASES ARE
AND THE TOLL IT TAKES ON HUMAN
CIVILIZATION, IN THE U.S., E. U.
AND INDIA, MEXICO, BRAZIL, SOUTH
CORIA AND TURKEY.
YOU NOTICE THAD INFECT YOWS
BACTERIAL INFECTIONS FOR
EXAMPLE, IT'S 1.5 MILLION PEOPLE
A YEAR.
AND WHAT'S TROUBLING TO ME WHEN
I LOOK AT A FIGURE LIKE THIS IS
THAT THERE'S ENTIRE CONTINENT
MISSING.
WE DON'T EVEN HAVE AFRICA THERE.
WE ONLY LOOKED FOR A COMPANY, IN
PARTICULAR, WE ONLY LOOK AT AREA
WHERE IS WE CAN DEVELOP DRUGS
FOR WHICH THERE IS RETURN ON
INVESTMENT, RIGHT?
SO WE NOW LOOK AT CHRONIC HBV,
AND LOOK AT INFLUENZA AND WHEN
YOU LOOK AT THESE COUNTRIES IT
IS COMPARABLE TO BREAST CANCER
AND YOU LOOK AT BACTERIAL
INFECTIONS IN THE U.S., AND YOU
WILL FIND IT IS ALSO COMPARABLE
TO BREAST CANCER FOR THESE
COUNTRIES.
AND ANOTHER TROUBLING FACT IS
THAT DESPITE THE SERIOUS HUMAN
AND ECONOM TOLL IT INFLICTS,
INFECTIOUS DISEASES ONLY MAKE UP
A FRACTION OF THE PUBLIC AND
PRIVATE FACTORS AND GENENTECH
ONLY ENTERED INTO THE INFECTIOUS
DISEASE AREA ABOUT 9 YEARS AGO.
AND SO WHAT CAN WE DO AND WHY DO
WE DO INFECTIOUS DISEASE?
IT IS BECAUSE OF THIS AS WELL
THAT DR. COLLINS TALKED ABOUT
AND I'M JUST USING BACTERIAL
INFECTIONS AS AN EXAMPLE.
SO YOU LOOK AT--THESE ARE THE
CLASSES OF ANTIBIOTICS AGAINST
BACTERIAL INFECTION.
WHAT I'VE SHOWN HERE IS THAT THE
LAST NEW CLASS OF ANTIBIOTIC
WHICH WAS INTRODUCED TO THE
CLINE NICK 2003, WAS ACTUALLY
DISCOVERED IN 87.
AND FOR EVERY SINGLE CLASS OF
ANTIBIOTIC RESISTANCE HAVE
EMERGED, USUALLY SHORTLY AFTER
THE INTRODUCTION OF THESE
ANTIBIOTIC.
AND SO, AND WHAT I'VE SHOWN HERE
ARE THE 2 OTHER IMPORTANT
POINTS.
MANY OF THE NEWER ANTIBIOTICS
ARE INTRODUCED TO THE CLINIC ARE
ACTIVE ONLY AGAINST GRAM
POSITIVE BACTERIA: POINT NUMBER
2 IS IF YOU LOOK AT THE GREEN
VERSUS BLACK, YOU WILL SEE THAT
MAJORITY OF ANTIBIOTIC ARE
ACTUALLY GIFTS FROM NATURE.
THEY ARE NATURAL PRODUCT OR
DERIVATIVES OF NATURAL PRODUCT.
HAS NATURE ONLY GIVEN US NATURAL
PRODUCTS?
WE HAVE USED IMMUNE SERUM
AGAINST TIP THERAPY ANDIA AND
TETANUS IN 1890.
SO WE THINK JUST AS WE
UNDERSTAND ABOUT OUR IMMUNE
SYSTEM, ANTIBODY IS ALSO A VERY
IMPORTANT COMPONENT OF DEFENSE
AND COULD POTENTIALLY BE
HARNESSED FOR TREATMENT OF
INFECTIOUS DISEASES.
THAT'S WHAT NATURE DOES WITH
ANTIBODY.
AND ANOTHER POINT I WANT TO
RAISE IS THAT IF YOU NOW LOOK AT
GRAM NEGATIVE INFECTION, THE
SITUATION IS EVEN MORE DIRE.
THE LAST CLASS WAS GREWSED IN
1968 AND IT WAS DISCOVERED IN
THIS 1961.
IT ONLY TOOK 7 YEARS TO DEVELOP
THE DRUG IN THE 70S AND 60S AND
NOW IT TAKES 15-20 YEARS TO
DEVELOP A NEW DRUG AGAINST NOW.
SO THERE ARE SEVERAL CHALLENGES
THAT PEOPLE WOWORK IN THE
INFEBLGHTIOUS DISEASE AREA FACE.
SO TODAY I WILL TELL YOU 2
STORIES ON HOW WHY CAN HARNESS
THE OTHER GIFTS FROM NATURE, THE
ANTIBODIES AND WE'RE TALKING
ABOUT MONOCLONAL ANTIBODIES TO
TREAT INFLUENZA A INFECTIONS AND
THEN THIS NOVEL THERAPEUTIC
PLATFORM THAT WE CALL ANTIBODY
ANTICONJUGATE AND I WILL USE
VIREMIA AS AN EXAMPLE BUT WE
THINK IT COULD BE EXTEND TO THE
S. AURUOUS AS WELL.
SO WE WANT TO ACKNOWLEDGE THE
PEOPLE WHO WORKING ON THIS
PROJECT, THEY ARE THE 1S THAT
NUCLEATED THE TEAM THAT BROUGHT
ABOUT THIS MONOCLONAL ASPECT
BODY.
SO AS DR. COLLINS TALKED ABOUT
EARLY ON, INFLUENZA INFECTION IS
AN IMPORTANT DISEASE.
HERE IS EPIDEMIOLOGY.
OVER 600,000 HOSPITALIZATIONS IN
THE U.S. AND E. U.
THIS IS THE NUMBER FOR
NONPANDEMIC SEASONINGS.
AND 25,000 DEATHS IN U.S. ALONE.
MANY OF US ARE VACCINATED WHICH
IS GREAT AND I ENCOURAGE THAT
STRONGLY BUT ONLY PARTIALLY
EFFECTIVE: AFRICA REALLY
DEPENDS ON IMMUNO COMPETENCE AS
WELL AS ANTIGEN MATCH.
SO AS I GET OLDER AND I KNOW
THAT IS AN INEVITABLE FACT I
KNOW MY IMMUNE COMPETENCY WILL
REDUCE AND VACCINATION WILL NOT
WORK AS WELL FOR ME AND MANY OF
US IN THE FUTURE.
AND IN 2014 FOR EXAMPLE, THE CDC
SHOWED THAT VACKIZATION
EFFECTIVENESS WAS ONLY 18%
AGAINST H3 N2 BECAUSE OF THE
MISMATCH.
AND THE INFLUENZA VIRUSES,
INFLUENZA A ACCOUNTS FOR 80% AND
B ACCOUNTS FOR 20% AND THIS IS
MORE DETAIL ON WHY WE FIND IT IS
AN UNMET NEED.
SO NO THERAPY DEMONSTRATED
CLINICAL BENEFITS ON PATIENTS
THAT ARE HOSPITALIZED WITH
INFLUENZA, SO THAT IS THE UNMET
NEED THAT WE'RE TRYING TO
ADDRESS.
THE STANDARD OF CARE RIGHT NOW
IS SUPPORTIVE CARE AND
NEUROINHIBITTOR.
SO THE NEXT SLIDE I WILL TALK
ABOUT A GENERAL, BRIEF
INTRODUCTIONOT LIFE CYCLE OF
INFLUENZA, SO INFLUENZA IN AN
RNA VIRUS WITH 8 SEGMENTS HERE,
IS SHOWN HERE, THERE ARE 3
IMPORTANT EXTRA CELLULAR
COMPONENTS: OR CELL ASSOCIATED
GLYCOPROTEINS, HEMOGLUTE9 AND H2
CHANNELS AND THESE ARE ALL
TARGETS OF DRUGS.
THE NEUROAMINIDACE VIRAL
RELEASE, VEHICLE NATION BINDS TO
THE HEAD REGION OF THE HEME LOW
GLUTENIN AND IT'S THE ACID
RECEPTOR.
HA ALSO MEDIATES THE FUSION
BETWEEN THE ENDOSOME AND THE
HOST MEMBRANE, THE VIRAL
MEMBRANE AND THE HOST MEMBRANE
TO RELEASE VIRAL CONTENT FOR
TRANSCRIPTION AND TRANSLATION
AND THEN THE NEUROMITT DACE
RELEASES THE BUDDING VIRUS TO
CAUSE NEW INFECTION.
SO NEUROMINIDACE INHIBITORS, AND
TAM OVIR BLOCKS THIS PROCESS AND
MANY OF THE GLOBULINS BLOCK THIS
ATTACHMENT.
HOWEVER, WHEN WE STARTED TO LOOK
AT THIS PROBLEM, WE REALIZE THAT
THE REASON WHY WE NEED TO HAVE
DIFFERENT VACCINES EVERY YEAR IS
BECAUSE THESE--THE 2 MAJOR
CIRCULATING HA VIRUS IN THE
HUMAN ARE THE H1 AND H3 AND WHEN
YOU LOOK AT HEMOGLUTENIN
SEQUENCE, THEY'RE ONLY 48%
IDENTICAL ESPECIALLY WHEN YOU
LOOK NOW AT THE HEAD REGION.
SO THIS IS A COMPILATION OF OVER
11,000 HA FROM THE 16 SUBTYPES
OF H. A. THAT EXIST IN NATURE.
SO THEY FALL INTO 2 GROUPS.
AND SO WE HAVE TO BE VACCINATED
WITH THE H. A. CORRESPONDING TO
GROUP 1 AS WELL AS GROUP 2.
THERE ARE HOWEVER, A SMALL
MINORITY OF ANTIBODIES THAT'S
BEEN PRODUCED BY SOME OF US.
THEY ARE ACTUALLY BINDING TO A
CONSERVED REGION AND WE LEARNED
OF THE EXISTENCE THAT REPORTED
THAT WHEN A CLONE OF A HELPED
THOUSAND B-CELLS THEY FOUND 1
BROADLY NEUTRALIZING ANTIBODY.
SO THERE IS THAT NEEDLE IN THE
HAY STACK THAT IS WORTH LOOKING
FOR BUT IT IS A TINY LITTLE
NEEDLE IN A VERY, VERY BIG HAY
STACK.
SO CAN WE LOOK FOR THESE BROADLY
NEUTRALIZING ANTIBODY?
WHAT WE WANT IS 1 THAT BINDS AND
TARGETS BOTH GROUP 1 AND GROUP 2
SO THAT IT WILL BE ABLE TO
NEUTRALIZE ALL OF THEM AND THAT
IT IS MORE EFFICACIOUS THAN THE
STANDARD OF CARE.
SO IT IS WITH THAT GOLDEN MIND
THAT WE DEVELOP, WE DEVELOP A
STRATEGY TO FIND THAT NEEDLE IN
AT THIS TIME B-CELL HAY STACK.
SO THE APPROACH IS AS FOLLOWS.
INITIALLY, WE GET PBMC FROM
VACCINATED DONORS AND VACCINATED
WITH HA 3, HA-1 FROM THESE 2
STRAINS AND PBMC ARE THEN
ACTIVATED INVITRO USING VERY
DIFFERENT HA SUBTYPES.
THESE PBMC ARE INJECTED INTO THE
SPLEEN OF KID MICE AND THEN
AFTER 8 DAYS, THE SPLEENIC
PLASMA BLASTS ARE BEING--THE
EFFECTS ARE SORTED USING AGAIN A
DIFFERENT SUBTYPE AND THEN THE
PROFILE OF THIS ANTIBODY IS THEN
TESTED FOR THE ABILITY TO BIND
ACROSS OTHER SUBTYPES.
SO IT IS WITH THIS WAVE OF
SELECTING FOR VIRUSES THAT WE
WERE ABLE TO CLONE 84--840 HUMAN
MAPS, 20 OF THESE BIOMULTIPLE
SUBTYPES BUT WE WERE EXCITED TO
FIND THAT 2 OF THESE ANTIBODIES
BIND AND NEUTRALIZE BOTH GROUP 1
AND GROUP 2.
H. A., 1 IS SPECIFIC TO GROUP 1
AND ANOTHER SPECIFIC TO GROUP 2.
WE THOUGHT MAYBE WE WERE LUCKY
BUT WE HAVE ACTUALLY DONE THIS
EXPERIMENT NOW AND FOUND ANOTHER
BROADLY NEUTRALIZING ANTIBODY IN
GROUP B BUT I WON'T TALK ABOUT
THAT BECAUSE THIS SCHEME IS
SIMILAR.
SO WHAT DOES THIS ANTIBODY DO?
SO WHEN WE LOOK FOR THE ABILITY
TO NEUTRALIZE HIRKS 1, 2, AND 3,
THE OTHER 1 VS BEEN SHOWN TO BE
INFECTING HUMANS AND SOME OF
THESE ARE CAUSING PANDEMIC
OUTBREAK, CAN YOU SEE THEY ARE
ABLE TO NEUTRALIZE ALL OF THESE
STRAIN AND WE HAVE ALSO TESTED
IT AGAINST OTHERS.
SO THESE ARE 1S THAT
OCCASIONALLY INFECT HUMAN LIKE
H5 OR H7 AND YOU CAN SEE THAT
THEY ALSO NEUTRALIZE H6, H7, AND
OTHERS TYPES THAT IT COULD
OCCASIONALLY INFECT HUMAN AND
POTENTIALLY BE THE NEXT PANDEMIC
AS WELL.
SO HOW DOES THIS ANTIBODY
NEUTRALIZE THE VIRUSES.
SO THE MAIN ANTIBODY, IGG 1 WE
PRODUCE THAT VAC NATION BLOCKS,
HA BY SIMPLY BINDING TO THE HA
AND PREVENTS HA FROM BINDING TO
THE ASILIC ACID ON THE BLOOD
CELLS, SO WHEN IT BINDS TO A RED
BLOOD CELL WILL CAUSE THIS
FORMATION OF LATTICE AND WILL
THEN--SO VIRUSES WILL FORM FROM
THIS LADDER AND THEN THE
ANTIBODY THAT PREVENTS THE
BINDING WILL THEN HAVE THE
HEMOGLUTENATION AS SHOWN HERE.
A HEAD ANTIBODY THAT PREVENTS
THIS BODY WHERE YOU HAVE THE
SEDIMENTATION OF THE RED BLOOD
CELL.
SO THE ANTIBODY THAT WE FOUND IN
WHICH WE CALL 4549A BECAUSE IT'S
IN CLINICAL DEVELOPMENT SO WE
GIVE IT A MORE EFICIAL NAME HAS
THIS HEMOGLUTENATION PHENOTYPE.
SO THE VIRAL BINDING BLOCKS IT
FROM THEN PREVENTS THE
HEMOGLUTENATION.
AND I TOLD YOU ANOTHER FUNCTION
IS TO ALLOW FOR FUSION BETWEEN
THE VIRAL MEMBRANE AND THE VIRAL
AND THE HOST MEMBRANE SO WE USE
THIS FUSION ASSAY WHERE H. A.
HAS BEEN EXPRESSED IN THE CELLS,
AND THEN AT THE Ph DROPS, CHAI
IS WHEN WE UNDERGO
CONFIRMATIONAL CHANGE AND WE'RE
UP FOR NEUTRALIZATION OR THE
Ph ASK WHY THAT IS BEING
FORMED.
SO IN HEAD BINDING ANTIBODY DOES
NOT PREVENT THE CONFIRMATIONAL
CHANGE AND YOU SEE THE
[INDISCERNIBLE] WHERE THE ANTIA
AND ANTIBODY PREVENTS THIS
FORMATION AND SO, MORE
IMPORTANTLY, WE FOUND THAT THIS
ANTIBODY IN FACT ALSO BINDS AND
REMAINS BOUND TO THE HA EVEN AT
ACIDIC Ph.
JUST 1 FUNCTION OF THE AGENT
BODY FROM THE FAB REGION OF
ANTIBODY BUT ANTIBODY WE KNOW
ESPECIALLY IN CONTEXT OF IGG1
WHICH IS WHAT THE ANTIBODY IS,
HAS AN SC FUNCTION.
AND 1 OF THE FUNCTIONS OF SC IS
TO RECRUIT SC GAMMA CONTAINING
CELLS AS SHOWN HERE, SO HAVE YOU
HERE--AS VIRUS INFECTED CELLS
SHOW BUDDING OF VIRUSES SO NOW
YOU HAVE THE DISPLAY OF HA OR NA
OF THE DISPLAY OF THE CELLS, SO
THE ANTIBODY WILL BYPASSED TO
THE HA IN THIS CASE AND THEN AT
THE REGION WILL RECRUIT THE FC
GAMMA RECEPTORS AND THEN THE NK
SELLS WILL PRODUCE AN INTIME
THAT WILL KILL THE INFECTED
CELLS.
SOPHISTICATEDY WE ASK THE
QUESTION WHETHER THE ANTIBODY
CELL TRIGGERS THE ANTIBODY
CELLULAR CYTOTOXICITY.
SO TO ASK THAT QUESTION WE
OBTAIN BLOOD FROM VOLUNTEER
DONORS AND NOW ASK THAT INFECTED
CELLS IN THE PRESENCE OF
INFECTED CELLS WHETHER NK CELLS
ARE ACTIVATED.
SO THIS IS OUR ANTIBODY, YOU CAN
SEE THAT THE PERCENT LAMP 1
STAINING AND THE RITUXMACK,
WHICH IS AN ANTIBODY, COME IS
ABSENT IN THE A519 CELLS DO NOT
TRIGGER THE ACTIVATION OF THE NK
CELLS AND THEN WE ASK ALSO IF IT
THE INFECTED CELLS ARE BEING
KILLED BY MEASURING THE LDH
ABSORB ANT AND YOU CAN SEE HERE
THAT THE CELLS ARE INDEED
DEAD--THE INFECTED CELLS ARE
BEING KILLED IN THE PRESENCE OF
ANTIBODY.
SO WE HAVE 2 MECHANISMS OF
ACTION, 1 BY BINDING TO THE HA,
FUSION AND THE OTHER IS TO
RECRUIT IMMUNE CELLS TO KILL
INFECTED CELLS.
SO WHERE EXACTLY DOES THE
ANTIBODY BIND?
SO WE CRYSTALLIZE THE HA, IT'S A
TRIMER WITH THE FAB OF OUR
ANTIBODY AND INDEED IT BINDS TO
THE CONSERVED REGION, THE LIGHT
CHAIN BINDING SHOWN HERE AND THE
HEAVY CHAIN SHOWN ON THE RIGHT.
AND WE HAVE ANALYZED THE AMINO
ACIDS.
THERE ARE ABOUT 32 CONTACT
POINTS BUT IT'S ANTIBODY AND
THEY'RE CONSERVED ACROSS INDEED
ALL THE HA TYPE THAT I MENTIONED
EARLIER ON.
WE WONDER THEN WHETHER
RESISTANCE COULD EMERGE VERY
EASILY AND THAT'S ALWAYS THE
QUESTION THAT BACKS AND OFTEN
TRIPS THE DISCOVERY AND
EFFECTIVENESS OF DRUGS.
SO WE'VE DONE PASSAGING OF THE
VIRUSES AND INCREASING
CONCENTRATION OF THE ANTIBODY.
OVER WEEKS.
WE WERE NOT ABLE TO FIND ANY
RESISTANT MUTE ANT, USED THE WAY
WE PASS SH1.
WE DID FIND 3 ALLELES, 1 IN THIS
RESIDUE AND ANOTHER 2 IN THE 391
RESIDUE.
SO NOW WE'RE DESCRIBING THE
RESISTANCE HERE, 387 K PREVENTS
BINDING OF THE ANTIBODY.
THESE 2 ALLELES DOES NOT PREVENT
BINDING OF THE ANTIBODY AT
NEUTRAL Ph BUT DOES IMPACT
SLIGHTLY THE BINDING ACIDIC Ph
AND ACTUALLY FUSES AT THE HIGHER
Ph THAN WILD-TYPE VIRUS.
AND WE THINK THAT ALTHOUGH WE
HAVEN'T GENERATED THE DATA IN
ANIMALS THAT WE ARE--WE SHOULD
BE ABLE TO DEAL WITH THIS
MUTATIONS BECAUSE ANTIBODY STILL
BINDS TO HA AND INFECTED CELLS
AND SHOULD RECRUIT IMMUNE CELLS
TO KILL INFECTED CELLS.
WE IN FACT HAVE THAT DATA FOR
INFLUENZA B WHICH SHOULD THAT WE
DON'T HAVE THE INFLUENZA A.
SO ANOTHER IMPORTANT FACTOR HERE
IS THAT ALL 3 ALLELES ARE LESS
FIT IN OUR INVITRO STUDIES.
SO WE DON'T KNOW THE
CONTRIBUTION OF THESE ALLELES IN
HUMAN, IN INFECTION, GIVEN THAT
THIS MOLECULE IS ALREADY IN
CLINICAL TRIAL.
THIS IS--THESE ALLELES ARE THE
1S WE ARE MONITORING IN
PATIENTS.
SO THIS IS IN A CARTOON FORM,
HOW THE ANTIBODY WORKS, SO SHOWN
HERE IT'S A HEAVY CHAIN AND
LIGHT CHAIN BOUND TO THE
CONSERVED REGION OF THE
HEMOGLUTENIN AND SO THIS IS JUST
NORMAL PART OF THE TRIMER.
YOU SEE HERE THIS IS THE FUSION
PEPTIDE, AND SO AS THE Ph
DROPS, DIFFUSION PEPTIDE AND THE
HA HERE HELIX, AV HERE THEN
FORMS A HELIX TO EXTRUDE THE
FUSION PEPTIDE SO THEN IT BINDS
TO THE WHOLE CELL AND THAT
BRINGS THE VIRAL MEMBRANE AND
HOST MEMBRANE TOGETHER TO ALLOW
FOR THE RELEASE OF VIRAL GENOME.
AND THE MHCA 549 A BINDS TO THIS
REGION AND PREVENTS THE
CONFORMATIONAL CHANGE AND THAT
THE MECHANISM THAT PREVENTS THE
VIRAL FUSION.
SO IT WORKS WELL IN VITRO, THE
QUESTION IS HOW WELL DOES IT
WORK IN VIVO.
SO WE HAVE 2 ANIMAL MODELS.
ONE IS THE MOUSE MODEL, USING
THE DDHA, 2 J STRAINS A GOAL OF
THIS PROJECT IS TO TREAT PATIENT
WHO IS ARE--WHO HAVE SEVERE
INFLUENZA.
SO THE CHALLENGE HERE IS TO
TREAT MICE LATER AFTER
INFECTION.
SO HERE WE CHOSE A TIME, 72
HOURS POST INFECTION AT OUR CUT
OFF AND ASK WHETHER THIS
ANTIBODY WORKS AND YOU CAN SEE
FOR GROUP 1 AS WELL AS IN GROUP
2, WE SEE A DOSE DEPENDENT
PROTECTION IN THIS SEVERE MODEL.
SIMILARLY IN FERRET, YOU CAN SEE
HERE THAT IF YOU INITIATE
TREATMENT 72 HOURS POST
INFECTION, ALSO TAMIVIR DOESN'T
WORK VERY WELL AND THAT SEEMS TO
ALSO SHOW AND BE TRUE IN
PATIENTS.
MHC-5 494 A IS STILL PROTECTED.
AND EVEN IN SITUATIONS WHERE
PATIENTS OR IN THIS CASE, THE
MOUSE MODEL IS BEING TREATED
WITH MHAA AT SUBEFFICACIOUS DOSE
BUT IF THEY ARE USED IN
COMBINATION, YOU SEE HERE THAT
THEY ARE ACTUALLY PROTECTIVE.
SO, THAT MAKES SENSE GIB THAT
THE MECHANISM OF ACTION OF THESE
DRUGS ARE DIFFERENT.
SO THE CLINICAL TRIAL IS REALLY
TO HAVE PATIENTS WHO ARE ALREADY
REQUIRESOX GENERATEDDATION WHO
ARE ON TAMI FLU AND ON TOP OF
THIS WE ADD MHAA 5449 A.
SO WE DON'T KNOW THE RESULT OF
THIS TRIAL BUT WHAT I HAVE TOLD
YOU TODAY IS THAT WE HAVE AN
ANTIGEN SPECIFIC IN VIVO PLASMA
BLAST.
THEY'RE EFFICIENTLY IDENTIFIED,
VERY RARE FUNCTIONAL ANTIBODY.
THIS ANTIBODY IS BROADLY
NEUTRALIZING AND IT HAS 2
MECHANISMS OF ACTION, IT'S BLOCK
M MEDIATED MEMBRANE FUSION, IT
ALSO TRIGGERS ADCC.
WE HAVE SHOWN THAT THESE
ANTIBODY NEUTRALIZES ALL
SEASONAL AND PANDEMIC STRAINS OF
INFLUENZA AND THAT THEY
SYNERGIZE WITH A TAMI FLEW
INFLUENZA TREATMENT OF INFECTION
IN THIS ANIMAL MODEL.
WE HAVE ALSO DONE A HUMAN
CHALLENGE STUDY WHERE WE SHOWED
THAT THESE ANTIBODY IS INDEED
WELL TOLERATED WITH GOOD SAFETY
PROFILES, LOW IMMUNO
GENERATEDISSITY RATE, HAS A
PSEUDOPK THAT IS CONSISTENT WITH
IGG1 WHICH IS 21 DAYS OF HALF
LIFE AND IN THE CHALLENGE STUDY
WE SHOW THAT THE INFLUENZA LOADS
AND SYMPTOM SCORES WERE SIPPING
95 CANTILY DECREASED COMPARED TO
PLACENTA SEEK SEEK O AT A DOSE
OF 3600-MILLIGRAMS.
SO HOPEFULLY IN A FEW YEARS WE
WILL BE ABLE TO SEE HOW TRULY
THIS ANTIBODY PERFORMS IN
SEVERELY ILL PATIENTS IN OUR
GLOBAL TRIAL FOR INFLUENZA.
I WILL NOW SWITCH GEARS AND TALK
ABOUT ANOTHER UTILITY OF THE
ANTIBODY AND THAT IS THE
PLATFORM USING ANTIBODY THAT IS
CONJUGATED TO AN ANTIBIOTIC
USING A CLEAVABLE LINKER AND I
WILL TELL YOU A STORY OF HOW
THAT'S BEEN DEVELOPED TO TREAT
STAFF AU REUS, ON THIS.
AND I WILL SHOW THAT WHO WORKED
ON THE PROGRAM, THE SMALL
MOLECULE AND THEN ***
VANDLEN ON LINKING THOSE 2
MOLECULES TOGETHER.
I THINK MANY OF US KNOW THAT
STAFF AUREUS IS A ORGANISM THAT
CAN CAUSE A VARIETY OF
INFECTIONS IT RANGES FROM WOUND
AND SOFT TISSUE INFECTIONS TO
LIFE THREATENING ENDOCARTITEIS
OR NECK ROUGH ATOMITIZING
PNEUMONIA AND SEPTIC SHOCK.
AND EVEN WITH WITH THE
ADVANCEMENT OF THIS NEW
ANTIBIOTIC I TALKED TO YOU
ABOUT, LINEZOLID, AND
DAPTOMYCIN,EE WE ARE SEEING
THESE ASSOCIATE WIDE THE
INFECTION AND BETWEEN 10-20,000
PATIENTS DIE OF MRSA INFECTION
EACH YEAR.
SO THE QUESTION THAT CAME TO
MIND WAS WHY DO ANTIBIOTIC
THERAPY FAIL EVEN WITH THE NEW
CLASS OF ANTIBIOTIC.
SO TO ADDRESS THAT QUESTION
ACCIDENT WE WENT AND LOOKED AT
THE INFECTION CYCLE OF STAFF
AUREUS.
SO JUST TO RECAP WHAT I TOLD YOU
HERE, DESPITE APPROPRIATE
ANTIBIOTIC TREATMENT, 40% OF
PATIENTS HAVE PERSISTENT
BACTERIAEREMMIA, IT'S MORE THAN
4 DAYS AND 70% OF THE PATIENTS
WHO HAVE PERRIST SENT DAN
DEVELOPED THE METASTATIC TREAD
AND THAT LEADS TO 20% MORTALITY.
SO WHAT MAY BE GOING ON HERE SO
TYPICALLY STAPH AUREUS IS ENTER
THROUGH AN OPEN WOUND AND WHEN
IT ENTERS THE BLOOD STREAM IT'S
RAPIDLY INTERNALIZED BY
NUTRIFILLS.
SO AND NUTRIFILLS IS FIRST LINE
OF DEFENSE.
SO WESTBOUND THESE CELLS,
STAPH AUREUS CAN SURE VIVE AND
IS NOT ONLY SURVIVES BUT IT USES
THIS SPREAD FLEW THE BLOOD
STREAM TO THE OTHER TISSUES, THE
BONE, LUNG, HARD VALVE AND THE
LUNG.
AND THEN, I WILL LYSE NUTRIFILLS
AFTER SEVERAL DAYS.
STAPH IS ALSO ENDOW WIDE A
VARIETY OF PROTEINS ON THE
SURFACE TO INNOVATE
NONPHAGOCYTIC CELLS.
SO IT USES NONBINDING PROTEIN
SUCH AS A AND B THAT BINDS TO
FIBER LECTIN AS WELL AS NMD,
DRKSA AND INSIDE THE CELLS STAPH
PROLIFERATES AT SMALL COLONY
VARIANT AND CAN PERSIST FROM
DAYS TO WEEKS.
OVER THE PROCESS OF IT BEING IN
THE CELLS, IT UNDERGOES
TRANSCRIPTIONAL CHANGE AND IT
STEADILY INCREASES THE LEVEL OF
THE BINDING PROTEIN SO THAT WHEN
IT LYSIS, THE EPITHELIAL CELLS
AND THE NONPHAGOCYTIC CELLS IT'S
TRYING TO REINVADE THE OUTER
CELLS.
SO STAPH CAN INVADE THE
PHAGOCYTIC CELLS AND CAN SO WE
ASK WHAT THE RESDENSE OF THE
THIS ON THE CELLS ON THE
EFFICACY OF THE ANTIBIOTIC.
AND SO THE QUESTION WE ASK IS
WHAT IS THE MINIMUM
RECONCENTRATION OF ANTIBIOTIC
NEEDED TO KILL STAPH AUREUS,
WHEN THEY'RE GROWING CELLULARLY
AND THIS IS THE TYPICAL MICRO
BIOLOGY ASSAY WHY DO HERE IN A
MICRO BIOLOGY LAB.
AND YOU CAN SEE IT'S 4 NANO
GRAMS PER MILL.
HOWEVER WHEN STAPH AND INSIDE
THE CELL AS SHOWN HERE THAT
THEY'RE NOW WITHIN MACROPHAGE,
UP SEE HERE THAT THE
CONCENTRATION NEEDED TO KILL THE
INTRACELLULAR BACTERIA IN FACT
SIGNIFICANTLY INCREASED HIGHER
THAN IT COULD BE ACHIEVED SO THE
C-MAX OF THE SERUM IS LOWER THAN
THE CONCENTRATION NEEDED TO KILL
EPITHELIAL RACELLULAR BACTERIA.
SO WE HYPOTHESIZE THAT
INTRACELLULAR BACTERIA ARE
REFRACTORY TO ANTIBIOTIC AND
THIS IS THE REASON FOR
THERAPEUTIC FAILURES USING
ANTIBIOTIC.
SO WE WANT TO DEVELOP A FEW
ASSAYS TO SEE IF WE CAN
RECAPITULATE THIS HYPOTHESIS.
AND SO HERE WE USE A FEW HUMAN
CELL TYPES.
A549 IS LOW CELLS, HUMAN BLOOD
AND MICRO EPITHELIAL CELLS.
YOU SEE HERE THAT STAPH AUREUS,
CAN GROW VERY WELL IN THOSE
CELLS, AND THEN PLANK TONIC
CELLS CAN BE KILLED BY SANK O
MICEIN AND HOWEVER, WHEN THIS
SEALS ARE FIRST INFECTED WITH
STAPH AUREUS, SO STAFF AUREUS IS
NOW EPITHELIAL RACELLULAR, SANK
O MICEIN IS NO LONGER ABLE TO
KILL THIS BACTERIA.
THAT'S TRUE FOR EPITHELIAL
CELLS, ENDOTHELIAL CELLS AND
OSTEOBLAST.
SO THAT'S HUMAN CELLS.
WHAT ABOUT IN THE MOUSE
INFECTION MODSLE?--MODEL?
THIS IS A TYPICAL INFECTION
MODEL WE USE TO DETERMINE THE
EFFICACY OF AN ANTIBIOTIC.
SO BACTERIA MATERIAL HAS GROWN
AS PLAN TONIC STAGE USED TO
INFECT MICE THAT'S BEEN TREATED
WITH YOUR PDF CONTROL OR
WHATEVER SOLVING CONTROL AND
THEN COMPARED TO A MOUSE THAT IS
BEING TREATED WITH SANK O
MICEIN, AND YOU CAN SEE HERE IN
THIS EXPERIMENT, SANK O MICEIN
IS VERY EFFECTIVE AT CLEARING
INFECTION.
HOWEVER, IF YOU ADD A WRINKLE TO
THIS EXPERIMENT BY FIRST RECOVER
BACTERIA SO YOU DO THIS
EXPERIMENT HERE, BUT YOU NOW
RECOVER BACTERIA THAT ARE
ALREADY INFECT THE CELL BY
TAKING PERO TON EEL LAVAGE AND
NOW USE THIS CELL TO INFECT
MOUSE IN THE PRESENCE OR ABSENCE
OF VANCO MICEIN, EVEN WITH
VANCO PRESENT, THE KIDNEY OF
THESE MICE ARE STILL--COULD BE
INFECTED AND THERE IS
PROLIFERATION.
AND SO THAT SUGGESTS TO US IS
THAT ABLATING INTRACELLULAR
STAPH AUREUS IS KEY TO CLINICAL
SUCCESS.
SO WITH THAT HYPOTHESIS IN MIND,
WE WANT TO TEST WHETHER THE
HYPOTHESIS HOLDS TRUE AND
WHETHER WE CAN DEVISE THIS
STRATEGY TO KILL THIS CELLULAR
BACTERIA.
SO THAT LED US TO THINK ABOUT
THE ANTIBODY, ANTIBIOTIC
CONJUGATE WHERE OUR IDEA HERE IS
TO OPTIMIZE, OR COAT STAPH
AUREUS, AND THEN WE HAVE A
LINKER, THAT HAS AN ANTIBIOTIC.
SO WHAT WILL HAPPEN THEN IS THAT
THIS AAC WHICH I CALL IT NOW,
WHILE TECHNICALLY IT IS A
BIOMAP, ANTIBI BODY CONJUGATE
BECAUSE WE HAVE ENGINEERED THIS
IN THE LYSEEN CHANGE SO THIS
CARRIES TOO ANTIBIOTICS PER
MOLECULE.
SO THIS IS REALLY WHAT THE
MOLECULE LOOKS LIKE.
SO HAVE YOU BACTERIAL THAT IS IN
THE BLOOD STREAM THAT WILL BE
COATED WITH THE A. A. C. AND
THEN IT'S OPTIMIZATION WILL
CAUSE THE BACTERIAL TO ENTER THE
CELLS IN MACROPHAGE, NUTRIFILLS,
OR GAMMA CONTAINING CELLS OR
KILL THE BACTERIA.
OR STAPH AUREUS, FROM THE
PHAGOCYTIC CELLS WILL VERY
QUICKLY BE CAPTURED BY THE AAC
AND DRIVE IT INTO FC CONTAINING
CELLS FOR KILLING OR FOR CELLS
THAT CONTAIN--EPITHELIAL CELLS
THAT CONTAIN THE STAPH AUREUS
CONTAINING, BECAUSE STAPH WANTS
TO IN THE ENDOTHELIAL CELLS, SO
IF THEY ARE ALREADY BEEN COATED
WITH THE AAC, AS A ENTER THE
CELLS, THEY ALSO BRING THE AAC
INTO THE INFECTED CELLS, SO
UNDER THE SUPER INFECTION
CONDITION, YOU ARE ALSO BRINGING
IN THE DRUG TO PROVIDE THIS BI
STANDARD KILLING.
SO, I WANT TO SHOW YOU WHAT
HAPPENS AND I WILL PRESENT YOU
THE DATA TO SUPPORT WHAT
HAPPENS.
SO WHAT HAPPENS HERE IS THAT
WITHIN THE PH AGOLYSOSOME, THIS
VALVE CLEAVER IS ENGINEERED BY
CLEAVE, WE ENGINEERED IT TO BE
CLEAVED BY [INDISCERNIBLE] AND
SO WE HAVE ENGINEERED A PATH
HERE THAT IS SELF-EMULATING AND
SO IT WILL THEN DESTROY ITSELF
AND NOW RELEASE THE ACCESS AND
FREE ANTIBIOTIC INSIDE THIS VERY
CONFINED ENVIRONMENT IN CLOSE
PROXIMITY TO THE BACTERIA.
AND THAT'S HOW WE ARE ABLE TO
BRING HIGH CONCENTRATION OF
ANTIBIOTIC TO THE BUG.
SO WHAT IS NEEDED IN ORDER FOR
THIS TO WORK?
SO WE NEED AN ANTIBIOTIC THAT
HAS HIGH POTENCY, ACTIVE IN LOW
Ph BECAUSE THIS IS THE
ENVIRONMENT THAT THE ACCESS OF
THE ANTIBIOTIC IS RELEASED AND
IT NEEDS TO BE CAPABLE OF
CONJUGATION.
SO WE HAVE TRIED MANY DIFFERENT
ANTIBIOTICS AND THE 1 I WILL
TALK TO YOU ABOUT IS A
DERIVATIVE OF RIFASMIN, YOU CAN
SEE THAT THE PH 5 AND 7 ARE
EQUIVALENT.
THE AAC IS COMPARABLE, MAYBE I
LITTLE LESS EFFICACIOUS, AT Ph
5 AND 7.
BOTH COULD BE RELEASED BY
CITAFSIN, HOWEVER, RIFAMPIN IS
NOT FOR THE AAC AND THE REASON
YOU CAN SHOW IN THIS GRAPH IS
THAT IT HAS A SHORT RETENTION
TIME WITHIN THE CELLS.
SO THESE CELLS ALONG WITH THE
*** O SIGNIFYITOSE HERE, AND YOU
CAN SEE HERE BY MOST OF THIS BY
RIFAMPIN IS RELEASED IS NOW
BEING FOUND INSIDE OF THE CELL
WHEREAS YOU CAN SEE HERE THE
RIFALOG CONTINUES TO BE RETAINED
IN THE CELLS.
SO 1 IMPORTANT FEATURE OF A
POTENT ANTIBI THETIC IS WE WANT
TO RELEASE AN ANTIBIOTIC INSIDE
THE CELL AND IT'S RETAINED IN
THE CELL.
SO THIS, ANOTHER VERY IMPORTANT
FEATURE OF THIS IS THAT NOW WE
CAN USE A BROAD SPECTRUM
ANTIBIOTIC AND KILLS BANTHERRIA
AND BECAUSE THIS IS ONLY
RELEASED INSIDE THE CELL.
SO BY THE TIME YOU GET OUT OF
THE CELL IT'S UNDERGONE ORDERS
THAT LEAD TO DILUTION SO NOT
ONLY DOES THE ANTIBODY PROVIDE
SPECIFICITY ON THE DRUG AND WE
CAN NOW BRING IN A BROADLY
ACTIVE ANTIBIOTIC TO KILL A BUG
AND IT'S UNLIKELY THAT THAT
CONCENTRATION AFTER DILUTION
WILL HAVE ANY IMPACT ON THE GUT
MICRO BIOTA.
SO THE QUESTION IS WHAT IS IT?
WHAT ADDITIONAL FEATURES MAKE
THIS RIFALOG MORE ACTIVE?
AND SO HERE WE WERE LUCKY.
SO IN ORDER FOR US TO LINK THIS
MOLECULE.
WE NEED MODIFICATIONS, MADE
MOLLIFICATIONSOT LEFT-HAND SIDE
AND NOW WE SEE THAT RIFA LOG
GAIN ACTIVITY THAT WAS
PREVIOUSLY ABSENT IN THE
RIFAMPIN.
SO WE DID THE ABILITY TO KILL
NONREPLICATING BACTERIA AND IT'S
STATIONARY FAITH ARE PUT IN PBS
AND YOU CAN SEE HERE OVER TIME
THAT BACTERIA DON'T SURVIVE THAT
WELL IN PBS AND THERE'S A LOG
REDUCTION, BUT CAN YOU SEE HERE
THAT RIFAMPIN IS NOT VERY
EFFECTIVE AT KILLING STATIONARY
PHASE BACTERIA BUT THE RIFA LOG
IS ABLE TO DO SO.
ANOTHER FEATURE WE BI BEGIN TO
UNDERSTAND NOW FROM THE
SCIENTIFIC COMMUNITY IS THAT
WHEN BACTERIA ARE INTRACELLULAR
THEY ENTER A STATE CALLED
PERSISTERS.
AND PERSISTERS ARE DEFINED BY
CELLS THAT WHEN THEY'RE TREATED
WITH ANTIBIOTIC ARE STILL ABLE
TO SURVIVE.
SO SAY CIPRO, YOU TREAT
ANTI--BACTERIA WITH CIPRO AND
IT'S ABLE TO KILL ABOUT 99.9% OF
THE BACTERIA AND PICTURES 1% OF
THE BACTERIA ALTHOUGH THEY ARE
RESISTANT TO CIPRO, DO NOT HAVE
GENETIC ALTERATION, THEY'RE
SIMPLY A PHENOTYPIC MANNESTATION
BECAUSE WHEN YOU RECULTURE THIS
BACTERIA AND TREAT THEM WITH
CIPRO, 99.9% OF THESE BACTERIA
WILL ALSO BE KILLED AND THE .1%
WILL SURVIVE AS PERSISTERS AND
THOSE ARE INTRACELLULARLY
DISTINCT.
SO WE ASK THE QUESTION, WHETHER
THE RIFA LOG OR RIFAMPIN HAD ANY
IMPACT ON THE PERSISTER CELL.
SO WE ADDED A SECOND ANTIBIOTIC.
SO BY ADDING RIFAMPIN IT DOESN'T
DO ANYTHING OF THE ABILITY TO
KILL THE INTERRACELLULAR
PERSISTERS HOWEVER RIFALOG CAN
ELIMINATE TO THE LIMIT OF
DETECTION THE PERSISTERS AS
WELL.
SO WE HAVE FORTUNATELY GAINED 2
M. O. A.
WE DON'T KNOW IF THEY'RE
DIRECTLY RELATED OR NOT BUT WE
KNOW IT'S ABLE TO KILL
NONREPLICATING BACTERIA AS WELL
AS NONANTIBIOTIC RESISTANCE.
SO WE HAVE THE ANTIBIOTIC
PORTION OF THIS MOLECULE.
SO NEXT WE NEED TO FIND THE
ANTIBODY.
SO INITIALLY WHEN WE WERE
WORKING ON STAPH AND LEARNING
FROM OUR INFLUENZA PROGRAM, WE
THOUGHT THAT MAYBE WE CAN FIND
NEUTRALIZING ANTIBODY THAT CAN
KILL STAFF AUREUS, WE WERE LUKEY
WITH INFLUENZA, WE LOOKED AND
LOOKED VERY, VERY HARD FOR
ANTIBODY THAT ARE ABLE TO BIND
AND KILL STAPH AUREUS AND WE
LOOKED AT OVER 40 MOAN O CLONAL
ANTIBODIES AND WE TESTED
COMBINATIONS UP TO 4 DIFFERENT
ANTIBODIES AND NONE OF THESE
WORKED.
SO ANTIBODY ALONE FOR BACTERIAL
INFECTION DOESN'T SEEM TO BE
SUFFICIENT.
SO THE NEXT QUESTION WE ASKED IS
THAT CAN WE FIND ANTIBODY THAT
BINDS HIGHLY ABUNDANT, HIGHLY
CONSERVED, AND STABLY EXPRESSED
EPITOPES.
THAT MEANS THAT THEY'RE FATALLY
EXPRESSED INVITRO AS WELL AS
INFECTION AND THIS ANTIBODY AS
RECOVERED FROM CONVALESCENT
PATIENT AND THIS ANTIBODY FALLS
INTO DIFFERENT CLASSES, SOME
ANTIWIDES BINDS TO PROTEINS SO
CAN YOU SEE THAT WITH THIS 1
THERE'S GOOD BINDING BUT
INFECTION, THE CLUMPING FACTORA
IS NOT WELL EXPRESSED SO IT'S A
GOOD EPITOPE FOR OUR AAC.
WE HAVE GLYCOSYLATEDDED PROTEINS
WE HAVE LCA, PEP TID O GLYCAN
AND WILD-TYPE ACID SO GIVEN THE
EFFECTS PLOT SHIFT, WE CHOSE TO
USE THE WILD TECH EPITOPE AND
SUGSO JUST A LITTLE PRIMER ON
WHAT [INDISCERNIBLE]-ACID, IT'S
BOUND TO THE PEP TID O GLYCAN OF
THE GRAM CELL WALL HERE, SHOWN
HERE OF MRSA.
AND SO THE BINDING IS MEDIATED
BY TAG O GLCNAC, AND THE
GLUCOSAMINE IS APPENDED TO IN 2
ORIENTATIONS.
BY 2 SEPARATE GLUE MARIOUS
COSILLEGALS TRANSFERASES WHICH
APPEND THE GLUCOSAMINE IN THE
BETA BOND AND TAR M IN THE ALPHA
BOND AND WE HAVE ANTIBODY
AGAINST BOTH FORMS OF THE
GLYCOSYLATEDDED WTA.
AND SO, WE WERE ABLE TO SHOW
THAT THIS ANTIBODY WAS SPECIFIC
USING GENETICS HERE.
WE SHOW THAT THE ANTIBETTA WTA
BINDS TO WILD-TYPE AND TO BE
ALPHA ALSO BINDS TO WILD-TYPE
BUT CAN YOU SEE HERE THAT IN THE
M-MUTE ANT, WE NO LONGER SEE,
THE FACTS SHIFTUTESSING THE
ALPHA ANTIBODY AND THEN THE
MUTANT WE SEE THE CONVERSION.
IF I TOLD YOU THE ABUNDANCE OF
THE EPITOPE ON THE SURFACE OF
THE ANTIBODY,OT SURFACE OF THE
BACTERIA WILL BE IMPORTANT
BECAUSE IT DICTATES THE NUMBER
OF ANTIBIOTIC THAT WE CAN COAT
THE BUG WITH.
SO FOR THAT REASON WE ACTUALLY
CHOSE THE BETA WTA ANTIBODY
BECAUSE WHEN WE MEASURE THE
BINDING SITES PER BACTERIUM, WE
FOUND THERE ARE 50,000 BINDING
SITES FOR THE ABET BODY AND ONLY
16 THIS HAPPENED SITES FOR THE
ALPHA: AND ALSO BETA, WTA OR
TAR S THAT APPENDS BETA WTA IS
HIGHLY CONSERVED ACROSS ALL
STAFF AUREUS.
SO WITH 50,000 BINDING SITES O
THEORETICALLY 1 CAN COAT PER
BACTERIUM A HUNDRED THOUSAND
COPIES OF RIFA LOG.
SO WHAT ABOUT THE LINKER?
WELL, WE WANT TO SHOW THAT THIS
IS CLEAVABLE IN VIVO AND STABLE
INVITRO.
SO WHAT WE HAVE DONE HERE IS USE
THE FRAC TECHNIQUE WHERE THE
ALEXIA 488 IS QUENCHED BY
TAMARA, AND IT'S ONLY ABOUT
CLEAVAGE OF THIS VALVE LINKER
THAT WE WILL SEE THE GREEN
FLUORESCENCE.
SO WE THEN HAVE MACROPHAGE THAT
IS BEING--HAVE INTERNALIZED THE
STAFF AUREUS, AND YOU CAN SEE
THE ABILITY OF 5 MINUTES OF
INFECTION, WE BEGENERATED TO SEE
THE GREEN FLUORESCENCE INSIDE
THE CELL SHOWING THAT THIS
LINKER IS INDEED CLEAVED
INTRACELLULARLY.
AND IT IS REALLY THE CLEAVAGE OF
THE LINKER THAT RELEASES ACTIVE
ANTIBIOTIC BECAUSE YOU CAN SHOW
HERE THAT THIS AAC HAS NO
ACTIVITY AGAINST STAPH AUREUS,
IT ONLY HAS ACTIVITY WHEN THE
CATAPP SIN IS ENTERED IN THE
AREA.
SO YOU CAN SEE THAT CLEAVABLE
AAC IS ABLE TO CLEAR INFECTION
IN MACROPHAGE BUT WHEN WE ALTER
THE ALANINE TO A D ALANINE WE NO
LONGER--THE LINKER IS NO LONGER
CLEAVABLE AND THE YOU SEE THE
NONCLEAVABLE AAC DOES NOT KILL
BACTERIA WITHIN MURINE
MACROPHAGE: THIS KILL SUGGEST
NOT SPECIFIC TO THE MOUSE
BECAUSE WE HAVE ALSO TESTED
MULTIPLE HUMAN CELL TYPE AND THE
DATA IS CONSISTENT WITH THE
ACTIVITY OF THIS AAC IN
MACROPHAGES AS WELL AS IN
EPITHELIAL AND ENDOTHELIAL
CELLS.
SO THIS IS ALL IN GOOD.
WE HAVE ACTIVITY INVITRO.
THE QUESTION IS THAT CAN WE SHOW
ACTIVITY IN VIVO?
NOW IN ORDER FOR THIS AAC TO
WORK, WE WANT TO SHOW THAT IT IS
ACTUALLY BETTER THAN THE
ANTIBIOTIC STANDARD OF CARE
THAT'S BEING USED BECAUSE THAT'S
THE UNMET NEED THAT WE WANT TO
TACKLE.
AND SO, FIRST WE WANT TO SAY
WHAT IS THE ANIMAL MODEL THAT
CAN HELP US DEMONSTRATE THIS
SUPERIORITY AND SO, I KIND OF
ALLUDED TO THIS DAT WHEN I
SHOWED YOU THAT THE TREATMENT
ANIMAL MODEL USING VANCO MICEIN
AND MICE TREATED TO VANCOMICEIN
TREATED LIKE 1 HOUR POST
INFECTION, IT'S VERY
EFFICACIOUS.
BUT IF YOU NOW BEGIN TO DELAY
TREATMENT AT WHICH POINT MANY OF
THE BACTERIA ALREADY ENTERED
INTO CELLS, YOU CAN SEE HERE
THAT BY 24 HOURS POST INFECTION
VANCO CAN ONLY HAVE A MINIMAL
IMPACTED OF A LOT KILLING.
IT'S NO LONGER ABLE TO CLEAR
INFECTION.
SO WE ASKED THEN WOULD THE AAC
ABLE TO CLEAR INFECTION WHEN YOU
BEGIN TREATMENT AT 24 HOURS POST
INFECTION WHEN VANCO DOES NOT
WORK AS WE THINK WOULD MIMIC THE
CLINICAL CONDITION.
SO HERE'S THE EXPERIMENT.
SO WE HAVE MICE THAT WERE
TREATED WITH SALINE, MICE THAT
WERE TREATED WITH THE ANTIBODY
ALONE.
THE ANTIBODY USED THROUGH AAC,
THAT IS MINIMAL EFFECT, VACIN
HCO IS PARTIALLY EFFECTIVE BUT
THE AAC IS NOW ABLE TO CLEAR
INFECTION.
LET SO DEMONSTRATING THAT IT IS
SUPERIOR TO VACIN, COMICEIN IN
THIS ANIMAL MODEL.
WE ALSO TEST THAD THE ABILITY OF
THIS AAC SUPERIORITY IN THE
MODEL, LIKE INDEPT O MICEIN.
SOPHISTICATED IF WE BEGIN
TREATMENT POST INFECTION, WE SEE
THIS VARIABLE EFFECT, RIGHT?
THERE IS SOME TREATMENT EFFECT
BUT OTHERS ARE NOT WELL
CONTROLLED FOR THE DAPTOMYCIN,
IT IS CLEARED AND WE SEE THERE
IS NO NEGATIVE-NEGATIVE DRUG
INTERACTION.
THERE THE DATA ARE ENCOURAGING
BUT 1 CAVEAT IS THAT MICE ARE
NOT NATURAL COLONIZERS--ARE NOT
NATURALLY COLONIZED WITH STAPH
AUREUS, SO THEY DON'T HAVE NTWA
ANTIBODY IN THE SERUM.
MANY OF US AREICALONNIZED WITH
THE STAPH AUREUS AND MANY DO
HARBOR NTWA IN OUR SYSTEM.
SO THAT COULD COMPETE AND
DETERMINE THE AMOUNT OF ANTIBODY
THAT COULD BE FOUND IN HUMAN SO
WE MIMIC THIS ENVIRONMENT NOW BY
FIRST TREATING THE MICE, NOW WE
USE SKID MICE WITH IGIV AT 10
MICRO GRAM PER MILL AND SO NOW
THIS MICE HAVE NTWA ANTIBODY IN
THEM.
AND THEN WE REPEAT THE
EXPERIMENT AS I'VE SHOWN YOU
BEFORE AND YOU CAN SEE HERE THAT
EVEN IN THE PRESENCE OF
COMPETING WTA ANTIBODY, THIS
[INDISCERNIBLE] ALSO WORKS WELL.
AND WE ALSO ADDED THE CONTROL,
IN THIS CASE ANTIMRSAAAC, AND
YOU SEE AND YOU
WONDE-PRESCRIBING WHY?
WELL STAPH AUREUS, AS YOU KNOW
CONTAINS PROTEIN A AND IT WILL
BIND ANY ANTIBODY BUT OBVIOUS
LEAP, THE AMOUNT OF PROTEIN A ON
THE STAPH AER EUS IS MAGNITUDES
LESS AND WE SEE THAT THE
EFFICACY WE SEE HERE IS DUE TO
ANTICMTAA BINDING TO PROTEIN A.
BUT I DID TELL YOU THAT THE
ANTIBIOTIC THAT WE IDENTIFIED,
IT'S A VERY POTENT AND EXCITING
MOLECULE IN AND OF ITSELF.
MAYBE THE ANTIBODY ITSELF IS
GOOD ENOUGH FOR ACTHAT WE SEE.
SO THIS IS--ACTIVITY THAT WE
SEE.
SO THIS IS EXPERIMENT TO TEST
THAT IDEA IS SO HERE SAME
EXPERIMENT AS I SHOWED
PREVIOUSLY EXCEPT THAT WE HAVE
TRIED TO ADDRESS 2 OTHER
QUESTIONS: IF WE USE
NONCLEAVABLE AAC, WE ARE NOT
ABLE TO SEE EFFICACY.
IF WE JUST USE THE ANTIBIOTIC
ALONE EITHER A SINGLE TREATMENT
OR DAILY TREATMENT WE ALSO DO
NOT SEE EFFICACY.
SO THIS BRINGS HOME AN IMPORTANT
LESSON.
THAT WE THINK THAT THIS PLATFORM
COULD PROVIDE FOR ANTIBIOTIC.
FOR ANTIBIOTIC THAT CANNOT ENTER
CELLS VERY WELL OR ANTIBI THETIC
THAT HAS POOR FARM CO KINEETICS.
BY LINKING ANTIBIOTIC TO THE
ANTIBODY WE CAN NOW HAVE THE
FARM COKINETTIC AS THE ANTIBODY
OF THE DRIVER.
SO WHAT I TOLD YOU HERE TODAY IS
THAT WE HAVE A NOVARTIS AND HE
WILL POTENT EFFECT EVALUATION
PROCESS TREATMENT AGAINST MRSA.
THE EFFICACY OF AAC SUGGESTS
THAT INTRACELLULAR INFECTION
DOES CONTRIBUTE TO FAILURE OF
SOC ABET BIOTICS.
I SHOWED YOU THAT VANCOMICEIN
AND DAPTOMICEIN AND ANTIBODY OF
THE AAC PROVIDES SUPERIOR PK AND
THIS AAC IS PRESENT IN THE HUMAN
SYSTEM AS A PRO DRUG THAT IS
CONSTANTLY CIRCULATING IN THE
ASPECT BODY AND WHENEVER THERE
IS STAPH AUREUS, IT WILL BIND TO
STAFF OR DRIVE IT INTO THE CELL
AND ONLY INSIDE THE CELL IS
ANTIBEING RELEASED.
AND SO WE ARE HOPEFUL THAT THIS
PLATFORM WILL ENABLE THE USE OF
MORE TOXIC ANTIBIOTIC BECAUSE OF
THE DILUTION EFFECT THAT I TOLD
YOU ABOUT AS AS IT WILL BE ABLE
TO SPARE HUMAN MICRO BIOME AND
WE THINK THAT THIS IS A PROOF OF
CONCEPT STUDY THAT SUGGESTS THAT
THE AAC PLATFORM COULD BE USED
TO TREAT OTHER BACTERIAL
INFECTIONS AS WELL.
SO 1 THING THAT I LIKE TO KIND
OF MAKE A PLEA TO SCIENTIFIC
COMMUNITY IS THAT OFTEN TIMES WE
GET RID OF ANTIBIOTIC THAT ARE
EITHER TOXIC OR HAVE NO GOOD PK
BECAUSE IT'S NOT POSSIBLE TO
DEVELOP THAT MOLECULE AT THE
STAND ALONE ANTIBIOTIC TO TREAT
INFECTION.
MENT BUT THOSE MOLECULES COULD
POTENTIALLY RESCUED BY USING
THIS PLATFORM.
SO IF YOU ARE AWARE OF ANY
ANTIBIOTIC THAT IS POTENT BUT
HAS POOR PK AND MAYBE EVEN A
LITTLE TOXIC, WE MIGHT STILL BE
ABLE TO TEST WHETHER THAT
ANTIBIOTIC COULD BE USED IN THIS
CONTEXT.
AND WOULD BE AN ANTIBIOTIC
AGAINST GRAM NEGATIVE BACTERIA
OR AGAIN TB.
SOPHISTICATEDY WITH THAT I WANT
TO THANK AS YOU CAN APPRECIATE
THE LARGE AMOUNT OF WORK THAT'S
NEEDED TO BUILD AND FIND THIS
ANTIBODY SO THE INFLUENZA TEAM
SHOWN IN GREEN ARE THE
INDIVIDUALS WHO ARE SPEAR
HEADING THE PROGRAM.
WE WANT TO THANK THE CDC FOR
TESTING SOME OF THE
[INDISCERNIBLE] AND FOR THE
VOLUNTEERS AND PATIENTS.
THIS MOLECULE IS IN THE PHASE 2
B CLINICAL TRIAL.
SO WE'RE AWAITING ANXIOUSLY TO
HAVE THE DATA UNBLINDED IN THE
FUTURE AND FOR THE AAC PROGRAM
[INDISCERNIBLE] TAKE OTHER
LEADERS ON TED BIOLOGY,
CHEMISTRY AND CONJUGATION OF THE
EXPERIMENT, AND SOVEY DID MOST
OF THE EXPERIMENT THAT I
PRESENTED AND I WANT TO
ACKNOWLEDGE RICK WHO HAD THE
FORESIGHT TO START INFECT YOWS
DISEASE RESEARCH IN GENENTECH,
UTILIZING THE AND LEVERAGING THE
KNOW-HOW ON ANTIBODY AND USE IT
FOR INFECTION DISEASE.
WE DO HAVE OTHER PROGRAMS IN
SMALL MOLECULE AND HOPEFULLY IN
THE NEAR FUTURE WE WILL BE ABLE
TO TELL YOU ABOUT THEM AS WELL
AND WITH THAT I TANK YOU FOR
YOUR ATTENTION AND I--I THANK
YOU FOR YOUR ATTENTION AND I AM
HAPPY TO TAKE QUESTIONS.
[ APPLAUSE ]
>> [INDISCERNIBLE] FOR THE STAPH
AUREUS, WE HAVE MANY LINKAGE SO
WE HAVE MANY [INDISCERNIBLE] I
WAS WONDERING IF IN THE
DIFFICULT COMPLEX
[INDISCERNIBLE] PLASMA, HOW DOES
THE SURVIVAL OF THOSE SECTION OF
THE AACs THAT COULD BE
AVAILABLE FOR [INDISCERNIBLE]
LIGATION IS KILLING THE
BACTERIA.
>> YEAH, SO WE HAVE SELECTED THE
VALVES THAT LINGER SO WE
EXPERIENCE AND THIS IS WHERE WE
ACTUALLY DREW OUR EXPERIENCE ON
THE AAC FROM THE ANTIBODY DRUG
CONJUGATE PROGRAM IN ONCOLOGY.
SO VAL-SET HAS BEEN TESTED IN
PATIENTS AND ARE STABLE IN HUMAN
SERUM.
SOPHISTICATEDY WE KNOW THAT AND
THEN WE HAVE ALSO TESTED THE
STABILITY OF THIS LINKER TO
PROTEASES THAT HAVE BEEN
PRODUCED BY BACTERIA AND WE
SHOWED THAT THIS LINKER IS
STABLE.
>> SO THE REQUESTY IS WHAT
PRESENTATION BREAKS DOWN--
>> WE'RE GOING TO HAVE VERY FEW
QUESTIONS--
>> SORRY.
>> MY OVERALL QUESTION IS THE
RIFALYNN IF I AM CORRECT, THE
PRONOUNCEIATION, YOU MENTION
SOMETHING INTERESTING REGARDING
THE ACIDIC CONDITION THAT YOU
INDUCE BUT IT WAS A LITTLE BIT
ISOLATED FROM THE EXPERIMENT TO
EXPERIMENT.
THE QUESTION IS WHETHER THE
ACIDIFICATION OF THE ENVIRONMENT
CAN HELP INDUCE HIDROLLISS AND
ALSO HIDE ROLIZES OF THE EO
GOLGI AND IN THE
PLASMID--RIBOSOMAL ENZYMES FOR
RECYCLING AND CHEWING DOWN
PROBABLY THE BACTERIA?
>> LET ME SEE IF I UNDERSTAND
YOUR QUESTION CORRECTLY.
SO WHETHER THE PROTEASE WAS
PRODUCED BY THE HOST ITSELF IS
SUFFICIENT TO--
>> ACIDDIVEIFICATION.
>> ACIDIFICATION.
>> SO ACIDIFICATION ITSELF IS
NOT THE PROCESS FOR THE LINKER,
THE LINKER THAT IS TO BE CLEAVED
BY C ATAPSIN, WHICH IS PART OF
THE ENDOSEDDIC PROCESS, SO THE
ACIDIFICATION HERE IS THE
ENVIRONMENT IN WHICH THE
CATAFSIN IS RELEASED SO WE NEED
THE ANTIBIOTIC TO BE ACTIVE
UNDER THAT ENVIRONMENT.
DID I ADDRESS THAT QUESTION?
>> THAT'S FINE.
THAT'S FINE.
WE CAN TALK.
>> SO BACK TO THE--SORRY, I WAS
WONDERING WHAT'S THE RELATIVE
ENFORCEMENT OF [INDISCERNIBLE]
VERSUS DIRECT ACTIVITY OF THE
ANTIBODY?
THE REASON I ASK IS IF YOU HAVE
A RESISTANCE VIRUS WHERE THE
ANTIBODY CAN STILL BIND, IS THAT
VIRUS STILL PROTECTED AGAINST IN
VIVO?
>> YES, SO I'VE NOT SHOWN THE
DAT AWE HAVE THE DATA
SPECIFICALLY FOR THE INFLUENZA
B: SO WE HAVE ISOLATED
RESISTANT STRAIN THAT ABOLISHS
BINDING AT ACIDIC Ph BUT
RETAINS BINDING AT NEUTRAL Ph.
WE THEN INFECTED MICE WITH THIS
RESISTANT MUTE ANT AND SHOWED
THAT THE--MUTANT AND SHOWED THAT
THE ASPECT BODY CAN PROTECT THE
MOUSE COMPLETELY.
SO THAT SUGGESTS TO US THAT
UNDER THAT CONDITION THE ACC IS
PLAYING THE MAJORITY OF THE ROLE
IN CLEARING INFECTION.
>> THANK YOU SO MUCH WONDERFUL
TALK.
I WAS WONDERING, SPECIFIC
QUESTION, HOW WELL THESE
ANTIBODIES PERFORM IN LOCALIZED
INFECTION MODELS?
YOU KNOW WHERE YOU MAY HAVE
THINGS LIKE BIOFILMS AND ISSUES
LIKE THAT?
AND THEN WHAT CAN WE DO TO MAKE
MONOCLONAL ANTIBODIES AND,A
ACs POTENT AGAINST THE
LOCALIZED TARGET.
>> YES, SO WE HAVE NOT DIRECTLY
ADDRESSED THAT QUESTION AND MY
REQUESTS IS THAT FOR THE
BIOSTUDIES OF MULTIPLE ENDOCRINE
IS NOT GOING TO BE VERY
EFFECTIVE.
BUT TO THE POINT ABOUT HOW DO WE
ELIMINATE BIOFIRM, SO WE THINK
ABOUT THIS AS A PLATFORM OR IF
YOU WANT TO GO SPECIFICALLY TO
BIOFILM 1 COULD THINK ABOUT THE
POSSIBILITY OF FINDING ANTIBODY
THAT BINDS TO BIOFILM, RIGHT?
THE SUBSTRATE OF THE BIOFILM.
ONE CAN CHANGE THE LINKER TO A
LINKER THAT'S CLEAVABLE BY AN
ENZYME THAT'S PRODUCED BY THE
BACTERIA.
AND THE BIOFILM.
SO NOW EFFECTIVELY WHAT YOU HAVE
DONE IS CONCENTRATE THE
ANTIBIOTIC TO THE BIOFILM AND
RELEASED AN ACTIVE ANTIBIOTIC AT
THE BIOFILM SITE.
SO I THINK THE CHALLENGE HERE
WITH AAC IS THAT THE SITE OF
INFECTION WILL BE IMPORTANT
BECAUSE ANTIBODY IS BEING
DISTRIBUTED BY THE BLOOD STREAM
AND SO, IN IN AREAS WHERE
ANTIBODY DOES NOT GET TO WOULD
BE A CHALLENGE TO THE AAC
CONCEPT.
BUT 1 CAN THINK ABOUT HOW WE
MODIFY THE ANTIBODY AS AS LINKER
FOR BIOFILM AND OTHER DISEASES.
>> THANK YOU.
>> HAVE YOU EVER OBSERVED A DRUG
RESISTANCE AGAINST AAC COMPARED
TO WITH [INDISCERNIBLE]--THANK
YOU.
>> SO VERY GOOD QUESTION.
WE HAVE.
IT'S VERY DIFFICULT TO DO THE
EXPERIMENT WHERE WE SCREEN FOR
RESISTANCE AGAINST THE AAC AS A
WHOLE.
WE HAVE DONE--ISOLATE, JUST DO
THE TYPICAL RESISTANCE STUDY
WITH THE DRUG ALONE AND WE CAN
FIND RESISTANCE OBVIOUSLY.
FELT AT LEAST IN THE ANIMALS IN
WHICH WE HAVE BEEN INFECTED THIS
STAPH AUREUS, WE HAVEN'T
RESISTED IT DOESN'T MEAN WE
HAVEN'T RESIST, IT MEANS WE
HAVEN'T FOUND THEM.
THE DIFFICULTLE IN FINDING
RESISTANCE IS BECAUSE UNLIKE THE
ANTIBIOTIC THAT'S FREELYY
FLOATING IN THE SYSTEM SO IT'S
BEEN EXPOSED TO 10 TO THE 16 TO
THE 7 BACTERIUM, AND SO YOU HAVE
NOW, THE RESISTANCE IN 1 TO THE
10 RESISTANT BACTERIA AND YOU'RE
ONLY DRIVING HUNDREDINGS OF
BACTERIA INSIDE 1 CELL SO THE
PROBABILITY OF THE IT BEING
RESISTANT IS GOING TO BE MUCH
SMALLER BUT WE ARE CONCERNED
ABOUT THAT AND IN ORDER FOR THIS
BE EFFICACIOUS AND FOR THE--FOR
WHAT WE DESIGNED IT THE AAC TO
BE DO IN OUR CLINICAL TRIAL WE
ARE GOING TO BE TREATING
PATIENTS WHO ARE ALREADY TREATED
WITH THE STANDARD OF CARE AND
NOT PROGRESSING WELL IN THE
PRESENCE OF THE STANDARD OF
CARE.
AND THEN WE ADD THE AAC TO HELP
THIS 20% OF PATIENTS ARE GOING
TO POTENTIALLY DIE OF THE
INFECTION AND SO EVEN IF THERE
IS RESISTANCE THERE ARE GOING TO
BE 2 MECHANISMS OF RESIEVANCE
THAT THE BUG WILL DEAL WITH.
SO WE DID NOW TEST THE RESISTANT
OR THE RESISTANT MUTE ANT.
WE ARE NOT--THEY DO NOT SO
INCREASED RESISTANCE TO ADAPTER
OR VANCO OR ANY OTHER STANDARD
OF CARE OR ANTIBIOTIC.
SO WITHIN THE SITUATION WHERE
THIS AAC WILL WORK, WILL BE
USED.
WE DO NOT THINK THAT THE
RESISTANCE WILL BE AS CRITICAL.
>> OKAY, THANK YOU VERY MUCH.
THERE IS A REACCEPTION THAT
FOLLOWS THIS SEMINAR RIGHT
ACROSS THE HALL IN THE LIBRARY
AND I THANK YOU ALL FOR COMING
AND MAN-WAH FOR SUCH A BEAUTIFUL
PRESENTATION.
>> THANK
>> [ APPLAUSE ]
YOU.
>> [ APPLAUSE ]