Selective Expansion of Adaptive NK Cells for Cancer Immunotherapy

BIOTEK2021, 2017 Kalle Malmberg, M.D., Ph.D., Prof. k.j.malmberg@medisin.uio.no

The invention

Klas Kärre, 1979

The “missing self” hypothesis

“NK cell recognition of targets is based on the ability of the NK cells to recognize information that is missing on the target, rather than the opposite (recognition of the presence of something foreign)”

Kärre thesis 1981, Kärre et al. Nature 1986

NK cells sense the “missing self” (absence of HLA class I)

Malmberg and Ljunggren, Nature Reviews Immunology 2007

Virus infection / Tumor transformation

Normal

cell

Cancer/

Infected

cell

Transformation/Infection

Next Gen NK Therapy

CyTOF: 105

Horowitz et al., Science Transl. Med. 2013

Not all NK cells are equal

Prof. Önfelt, KI

Selective expansion of

adaptive NK cells

Expanding tumor-reactive NK cells

Key component of expansion platform (feeder free solutions possible)

Liu et al, Molecular Oncology 2015

- 12 -

Precise Multi-Gene

Engineering

Human

Pluripotent Cells

Single-Cell Clonal

Selection & Banking

Renewable Engineered

Pluripotent Cell Line

Directed Hematopoietic

Lineage Differentiation

Unlimited Access to Engineered

Hematopoietic Progenitor Cells

Partnership with Fate Therapeutics

T cells CD34+ cells NK cells

Inven2:

“what do you want?”

“eh..I don´t know…”

My initial thoughts • Do I want to form a company?

Maybe.. Really?

• Do I want to outlicence/sell the patent and move on?

Maybe.. Yes! Did somebody say I could get 6 million USD upfront?

• Do I want to establish a collaborative agreement?

Maybe… without a license agreement then?

Operate in parallel universes • Form a company

• Outlicense/Sell (very unlikely unless mature and well defined)

• Outlicense and collaborate

• Collaborate only (commissioned research)

Listen!!!

…and try to speak multiple languages

What does the partner want?

• Benchmarking of their own products?

• Your invention, your expertise or both?

• Are you aligned in your expectations both in terms of value and in long-term goals?

Reach out!

• Initial informal discussions at network meetings

• Get CDAs in place, follow up by Tele cons.

• If you have one partner on the hook who is doing due dilligence, others will (if they are interested) appreciate the ”heads up” and chance to discuss opportunities…

Potential partner

We are now entering negotiations of a potential licensing agreement with one company that has expressed a strong interest after initial scrutiny of the IP and us. Just heads up in case you consider entering the NK cell space and if we anticipate that there might be synergies through exploring NK cells as vehicles of CARs.

CSO of Potential partner

Thanks for the heads up Kalle, PP2 has an interest in the space, but moving the Y product towards

registration is taking a lot of energy, so I do not think we will be able to act fast right now. I think this seem as an attractive idea. Also allows you to directly compare with the T cell data. With the focus of PP2 being so much on their first aimed for product,

maybe its best to wait for now and see how things develop?

Partner interactions.. Focus on Science!

Hi all Nice talking to you earlier today. Here are some data from Aline´s work on NK cell homeostasis. Needless to say this is just scratching the surface. She is using three 15-color panels to probe the phenotype, function and metabolism across subsets and generations. Subsets are sorted and sequenced to identify molecular drivers. NKG2C and individual KIR are not shown here but she has full coverage in these experiments. I believe this may serve as a robust platform for monitoring synergistic effects of small molecules and NKG2C stimulation on the reprogramming of NK cells.

I also included a slide with some initial thoughts on areas where we could potentially collaborate to fast track the clinical development of a 2nd gen adaptive NK cell product. Obviously, we would need to work out the details of the experiments and define who should do what etc. Looking forward to hearing from you. Best wishes Kalle

Discussion with the CEO of FATE

Hi S Good luck with the 3Q report later today. Would be good if we could follow up on the

discussion of the collab proposal and the other elements in due course. Although I can not and shall not negotiate the terms in detail, it may be helpful if the two of us could touch base on the best way to move this forward and identify potential bottlenecks? If you think this is a good idea I am rather flexible this week. Or else, we could schedule a telecon with Inven2 and everybody onboard. We have the beads and stem cell cultures cooking and are keen to accelerate and coordinate these effort together with you and J. Best wishes Kalle

- 24 -

Off-the-Shelf Immuno-Oncology Partners

R&D and Translational Therapeutic Collaborations

Michel Sadelain, MD, PhD

Engineered iT Cells

Off-the-shelf T-Cell Therapy

using engineered pluripotent

cell lines

FATE-NK100

First-in-Class Adaptive Memory

Natural Killer Cell Therapy

Jeffrey S. Miller, MD Kalle Malmberg,

MD PhD

Dan Kaufman,

MD PhD

Engineered iNK Cells

Off-the-shelf NK-Cell Therapy

using engineered pluripotent

cell lines

The indecisive partner

Possible opportunity for commissioned research!

Tell them what they need! Be clear under what circumstances you would be willing to operate.

But is there really potential for a good match..?

Dear A.

Sorry for the delay. Here is condensed sketch. Happy to discuss more if you think this aligns with the goals of Z and could be part of an umbrella agreement. Overall Goal: Bring a gene-edited adaptive NK cell product to a Phase I/II trial for treatment of patients with HLA escape variants

Key challenge in IO: Resistance / relapse after check-point inhibition. One possible mechanism is loss of antigen presentation including loss of HLA class I (Zaretsky et al, NEJM July 2016).

Solution: Cell therapy with adaptive NK cells. We have identified a unique approach to selectively expand adaptive (memory) NK cells with unique KIR specificities and killing potential.

Project outline: Exploit background IP (exclusive or non-exclusive license) to generate adaptive NK cells. Aim 1) Use a targeted CRISPR/Cas9 approach to knock down a) HLA-class I (b2m) and b) HLA-A/B (with retained expression of HLA-C) with the purpose of improving persistence of adaptive NK cells following transfer across HLA barriers. Aim 2) Identify new genomic targets that boost survival and functionality of adaptive NK cells……

Hope this is of interest. Look forward to hearing from you.

Have a great summer! Kalle

Indecisive partner…

The mismatch

Partnering with a mismatched partner is likely to be unsuccessful and a waste of everybodies time

The Inven2 perspective

Managing the innovation project

• 2014-2015: Generally routine pre-commercialization activities:

Follow-up & input into R&D plans

Securing IPR protection

Further discussions on commercialization strategy

• Early discussions with inventor on high level commercialization strategy: «What do you want?» understanding investigator expectations & priorities

• 2016H1: Decision on commercialization strategy (licensing)

Industrial partnering

• Investigator-led industry networking at academic meetings (primarily focused on the science)

• Tentative interest registered, leading to preliminary TCs with 3-4 players

• Prioritization based on match on technology and priorities – left with one serious contender

Negotiating & closing the deal • Understanding each other’s motivations & expectations:

what do the parties want from a deal?

do we have a good match with a potential win-win scenario?

• The nitty-gritty discussions on money, scope & structure of agreement – several near-fatal stumbling blocks

• Resolution in sight – we really want to work together and we are approaching agreement on structure & valuation …….

just one «little» issue left

• The little issue suddenly becomes a potential dealbreaker frantic negotiations to find a mutually acceptable solution Acceptable solution found & deal agreed

Lessons learned

• Importance of a pro-active and business-oriented lead investigator

• In a novel field such as cell therapy, industry invests at least as much in competence & scientific leadership as in IPR & specific product candidates

You are generally looking at an extended marriage, and finding the right match is absolutely critical to a good deal

• «Old pharma» deal structures and valuations are not much use

Having sound expectations to the deal will prevent a lot of headache

Malmberg Lab

Oslo University Hospital Julie Hoel

Merete Wiiger

Vincent Yi Sheng Oei

Eivind Ask-Hæggernes

Jodie P Goodridge (Researcher)

Kishan Chudasama

Michelle Sætersmoen

Trevor Clancy (Researcher)

Benedikt Jakobs

Axel Berg-Larsen

Astrid Plessl MD

Dennis Clement

Daniel Palacios

18, F/M: 7/11

MD/PhD: 5/13

Karolinska Institutet Marie Schaffer

Andreas Björklund

Ebba Sohlberg

Aline Pfefferle

Alvaro Haroun Izquierdo

Karolinska Institutet

Per Ljungman

Eva Hellström-Lindberg

Petter Höglund

Klas Kärre

Sten Linnarsson

Björn Önfelt

Sören Lehman

Björn Wahlin

Hans-Gustaf Ljunggren

Mattias Carlsten

Univ. of Minnesota

Jeffrey Miller

Sarah Cooley

Univ. of Cambridge

John Trowsdale

James Traherne

Stanford University

Amir Horowitz

Paul Norman

Peter Parham

Oslo University Hospital (OUH) and UiO

Johanna Olweus

Arne Kolstad

Eivind Hovig

Andreas Brecht

Harald Stenmark

Kjetil Taskén

Ellen Skarpen

Funding

The Swedish Research Council

The Swedish Cancer Foundation

The Swedish Children's Cancer Foundation

The Swedish Royal Society of Medicine

Oslo University Hospital

The Norwegian Cancer Society

The Norwegian Research Council

The South East

KG Jebsen Foundation

EU: Horizon 2020

Acknowlements