clinical challenges and engineering therapeutic … · 9/17/2020 · therapeutic solutions: the...

CLINICAL CHALLENGES AND ENGINEERING THERAPEUTIC SOLUTIONS: THE COVID-19 PANDEMIC

Therapeutic Pipeline for COVID-19

Facilitating Translation of Potential Candidates

September 17th, 2020

Daniel S. Chen MD PhDChief Medical OfficerIGM Biosciences

DISCLOSURES

I am an employee of IGM Biosciences

The information presented is solely intended to foster the exchange of scientific and medical information.

WHAT DOES A PARADIGM SHIFT ACTUALLY LOOK LIKE?

Chen DS, MIT TIM Talk 2020

GLOBAL PANDEMIC: COVID-19 HAS BEEN A PARADIGM SHIFT FOR OUR GLOBAL SOCIETY

Global COVID-19 DeathsGlobal COVID-19 Cases

Chen DS COVID19 Therapeutics 2020

COVID-19 PANDEMIC: FIRST GENERATION COVID-19 THERAPEUTICS HAVE MOVED INCREDIBLY FAST

Acosta and Singer, Eur Resp J Aug 2020

• Most First Generation COVID19 therapeutics have represented re-purposed or recycled efforts

• eg Vaccine platforms used for SARS-CoV-1 or cancer vaccines

• eg anti-viral SMI for HIV• eg immune modulators used for

autoimmune disease • eg anti-viral antibodies that rely on

IgG format rather than IgAVaccines(RNA, AdVir, etc)

SMI (remdesivir, etc)Immune modulators(anti-IL6R, JAK-inhibitor, dex, etc)Neutralizing Abs

(IgG IV)


FIRST GENERATION COVID19 THERAPEUTICS…

What does this mean?

If First Generation therapeutics for COVID19 struggle, why might they struggle and how do we address these limitations?

Due to need for speed, few of these efforts have incorporated new data or insights into the virus and disease


WHAT WE’VE LEARNED ABOUT COVID-19 AND SARS-COV-2 IN 2020

• Vaccines- given growing evidence for the importance of CD8 T cell responses to SARS-CoV-2, current vaccines may be suboptimal for CD8 T cell responses?

• SMI- lack potency and specificity?• Immune modulators- not directed at the specific hyperinflammation?• Neutralizing antibodies- poor protection in mucosal compartment? Impacted by virus variants? ADE risk?

Subbarao and Mahanty Immunity 2020

-5 80 12 21+Symptoms(100%)

Dyspnea(16-20%)

Discharge/DeathARDS(5-12%)

Hospital Intubated (6%) Prolonged ventilation→ →

→Prophylactic Ab

-XExposure

Therapeutic Ab

“Early” à ”Pulmonary” “Hyperinflammation”“Incubation”Protection in mucosal space?

Hyperinflammation not driven by IL-6

IFN pathway suppression and-Importance of CD8 T Cell response?

Viral variants in S protein?

ADE risk?

Longevity of COVID19 immune response?

Viremia, thrombosis, cardiac, CNS, renal, visceral infection and morbidity

“long-haulers”


WHAT ARE THE OPPORTUNITIES TO IMPROVE UPON FIRST GENERATION COVID19 THERAPEUTICS?…

Gap OpportunityVaccines prioritized humoral immunity against S rather than CD8 T cell immunity

Enhance CD8 T cell immune response, memory T cell response; increase longevity of protective humoral response;

Anti-Viral non-specific for SARS-CoV-2, sub-optimal potencyIncrease potency with SARS-CoV-2 specific oral inhibitors

Immune Modulators Poor understanding of COVID-19 immune response, hyperinflammationSpecifically target hyperinflammatory biology; Stimulate cellular immune response early in disease, inhibit inflammation late;

Neutralizing Abs (nAbs) IgG with poor mucosal penetration; decreased binding to viral variantsIncrease neutralization in primary infection compartments; increase inhibition of viral variants;


HOW CAN ENGINEERED THERAPEUTICS HELP ADDRESS THE CHALLENGE OF COVID-19?

Proteasome

Co-s%mulatorymolecules

Pro-inflammatorycytokines

Dendri.cCell

An%genPresenta%on

CD8Tcells.mula.onMHCI

NF-κB

ImmuneS%mula%on

TAP

ssRNA

TLR7/8

polypep.de

RNA-LPX


COVID-19 THERAPEUTICS: SECOND GENERATION APPROACHES AND TECHNOLOGIES

Epitope/Target

Multi-target/modulation

Antibody Platform

Administration Route

Chen DS COVID19 Therapeutics 2020Nebulizer Intranasal atomizer Dry powder inhalers

IgM IgA CAR-TPegylated protein nanobodyTRAP

multispecific Antibody fusionsCombination antibodies

DARPIN

BISPECIFIC ANTIBODIES

Bispecific mAb targeting SARS-CoV-2 and NKp46 EXAMPLE:


Gautier et al. Cell 2019

ENGINEERING COVID-19 THERAPEUTICS: TISSUE COMPARTMENTS, INTERACTIONS AND SARS-COV-2 INFECTION

Sites of SARS-CoV-2 infection1. Lung2. Heart/blood vessels3. Brain4. Eyes5. Nose/upper respiratory tract6. Liver7. Kidneys8. Intestines M

MM

M

M includes mucosal compartment

Wadman et al. Science 2020

~100-150 nmSARS-CoV-2

Therapeutic IgG in bloodLeMessurier et al. 2020Mucosal barrier


NANOBODY DIRECT PULMONARY DELIVERY

Schoof et al. pre-print 2020

Trimeric-mNb6 kd of 1.0x10-6 s-1femtomolar affinitypicomolar neutralization

EXAMPLE:Trimeric nanobody targeting SARS-CoV-2 with direct

pulmonary administration


Roitt et al., Immunology 5th ed

High affinity and avidity for SARS-CoV-2 spike protein

HOW TO SOLVE FOR AN ENEMY THAT EXHIBITS VARIABILITY AND MUTATION?

Steric hinderance

Emerging spike protein variants

Korber et al., 2020


MULTIVALENT ANTIBODIES WITH ACTIVE MUCOSAL TRANSPORT

EXAMPLE:Engineered IgM antibody with high affinity and high

avidity targeting of SARS-CoV-2


MULTIVALENT ANTIBODIES WITH ACTIVE MUCOSAL TRANSPORT

multivalent

high affinity, high specificity

lacks FcgRIII binding

Bharathkar et al. 2020

IgM or IgA

IgMIgA

Active transport to mucosal compartment

~30nm

Koff for IGM-2323: unmeasurable

0.001 0.01 0.1 1 10 1000

25

50

75

100

Antibody concentration (nM)

Perc

ent M

ax B

indi

ng IGM-2323

Bispecific IgG

IgM CD20xCD3

IgG CD20xCD3


WE ARE IN THE MIDST OF A GLOBAL PANDEMIC UNLIKE ANYTHING MOST OF US HAVE EVER SEEN IN OUR LIVES…

The need for advancements in virology, immunology and therapeutics could not be greater

Problem Statement for Pandemic Respiratory VirusPrevent infection, inhibit viral spread, modulate immunity

• Challenges for Antibody Engineering:

• How to irreversibly neutralize virus?• How to block viral variants?• How to provide appropriate access to viral sites of infection?• How to limit inflammation but enhance anti-viral immunity?• How to reduce Antibody Dependent Enhancement risk?• How to block re-infection?• How to generate CD8 T cell responses?• How to block thrombosis?• How to block involvement beyond URT and GI

• Best scenario for use? Combinations?Chen DS COVID19 Therapeutics 2020

• COVID-19 has emerged as threat to our global society and way of life

• First generation therapies have sped into clinical trials

• If these first generation therapies should fail to completely protect us from COVID-19, next generation therapies may utilize learnings in biology and advances in therapeutic engineering

CONCLUSIONS


It is our responsibility as a community to conquer this pathogen as rapidly and successfully as possible, with as many different approaches as we

are capable of. It is a difficult challenge, but with appropriate collaboration and effort, it is doable.

Failure is not acceptable.


ACKNOWLEDGEMENTS

• Angus Sinclair• Beatrice Wang• Tasnim Kothambawala• Ling Wang• Manal Amoury• Steve Carroll• Maya Kotturi• Marvin Peterson• Avneesh Saini• Madeline Tran

IGM Biosciences• Bruce Keyt• Kathy Miller• Paul Hinton• Dean Ng• Keyu Li• Kevin Carlin• Sachi Rahman• Deepal Pandya• Yasinee Ng• Nemil Vora• Janet Tang

• Wayne Godfrey• Eric Humke• Genevieve Hernandez• Maya Leabman• Iris Sison• Rachel Mejia

• Ramesh Baliga

• Fred Schwarzer • Misbah Tahir

325 East Middlefield Road Mountain View, CA 94043Chen DS COVID19 Therapeutics 2020

It Takes An Orchestera

APPENDIX

clinical challenges and engineering therapeutic … · 9/17/2020 · therapeutic solutions: the...

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