Leveraging the natural strengths of humanity and our collective immune systems to source the best cells for life - Kiadis ...
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K I A D I S P H A R M A | T E C H N I C A L P R E S E N TAT I O N | J A N U A R Y 2 0 2 1 EURONEXT: KDS Leveraging the natural strengths of humanity and our collective immune systems to source the best cells for life K-NK-cell therapy to treat cancer and infectious disease
K-NK platform Universal Donor algorithm
Benefit of HLA-KIR mis-match donor NK-cells in HSCT
Higher
overall
survival
Lower GVHD
and rejection
Lower
relapse
Lower
relapse
Ruggeri et al, Science 2002 295: 2007 Giebel et al; Blood 2003
KIADIS PHARMA | www.kiadis.com 3
Association of KIR-B and number of activating KIRs with
relapse-free survival in HSCT
Oevermann, Blood 2014, 124:2744 Cooley, Blood 2010, 116:2411
KIADIS PHARMA | www.kiadis.com 4
Association of number of activating KIR receptors and
risk of ALL
Almalte, 2011. Blood 118:1323
KIADIS PHARMA | www.kiadis.com 5
Association of high affinity CD16 with survival in solid
tumors
Progression Free Survival
Patients with NK cells with high affinity CD16 (10-15% of population):
High affinity CD16
Low High affinity CD16
affinity Low affinity CD16
CD16
Bibeau 2019; Musolino 2008
KIADIS PHARMA | www.kiadis.com 6
Use of different donors allows reduction of risk of
rejection
Relevant literature:
• Platelet transfusions: Modest risk of alloimmunization from
fully mismatched platelets (Bonstein, Blood 2015,
126:3484), median onset 26 days.
• Solid organ transplants: Modest increase in rejection of
fully mismatched solid organs (Opelz et al)
• Granulocyte transfusions: 70 percent of patients would
become alloimmunized to two donors after receiving 11
transfusions (Ford, Transfusion 1982, 22:498).
Opelz, Transplantation 2007, 84:137
KIADIS PHARMA | www.kiadis.com 7
K-NK platform Manufacturing
K-NK activation and expansion: FC21 feeder cell and
PM21 membrane particles
Approach Description Product
• Bridging data on NK cell
FC21 (founding technology): K562 tumor cell expressing mbIL21, phenotype from FC21-
Feeder cell expressing 41bbL and cancer cell co- NK to PM21-NK with
mbIL21 stimulatory ligands clinical material from
past/future trials
Membrane fractions of FC21 that • FDA approval to start
PM21 (patented):
preserve native stimulation Phase 2 with PM21-NK,
Membrane particles
(generated by ‘breaking up’ FC21 after Phase 1 with FC21-
presenting mbIL21
through gas cavitation) NK
KIADIS PHARMA | www.kiadis.com 9
K-NK: 6 weeks proliferation without loss of functionality
Prolonged proliferation with Exponential proliferation Cytotoxicity stable with
mbIL21 versus mbIL15 with mbIL21 for 6 weeks mbIL21
Source: ASGCT 2020 Virtual Annual Meeting, Oyer, et. al., abstract #427
KIADIS PHARMA | www.kiadis.com 10K-NK: prolonged
!"#$!"#%& expansion and proliferation due to
telomere lengthening (versus mbIL15 expanded NK cells)
!"#$!"%&'
Telomerase
!"#$ expression Telomere stability
(% change in telomere length)
p=0.0142
p=0.0088
0.05
TERT expresion (AU)
0.04
0.03
0.02
0.01
0.00
NK
NK
NK
15
21
IL2
+IL
+IL
IL2
IL2
Denman et al., PLoSONE, 7(1), 2012
KIADIS PHARMA | www.kiadis.com 11K-NK cryopreservation: with stable post-thaw cytotoxicity
and viability
Viability and cytotoxicity of K-NK Drug Substance and Ovarian cancer animal model
Robust Process Performance
Drug & Product (INDCharacteristics
Product enabling and full-scale runs) (research)
100 100
Fresh
80
Survival (%)
80 Post-Thaw
60
Percent
60 40
40 20
0
20 010 20 30 40 50
Time from treatment (days)
0 Untreated
Viability Cytotoxicity K-NK (fresh)
(2:1 E:T) K-NK (frozen)
KIADIS PHARMA | www.kiadis.com 12Advantages of the PM21 (feeder-cell free) approach
Large scale manufacturing with long shelf Improved control
life over NK cell culture
conditions
Quality controlled including quantification and
standardization of protein- and IL21 content
Improved product
Removal of feeder cells and reduction of feeder
safety profile
cell related impurities
Simplified and more
Terminally sterilized robust supply chain
KIADIS PHARMA | www.kiadis.com | CONFIDENTIAL 13K-NK improved safety profile: no contamination with
residual tumor cells/DNA in final product, due to PM21
Reduction of contamination in PM21 production Reduction of contamination in KNK production
Contamination
in final product Perc Relevant process steps Perc Relevant process steps
Mechanical rupture of cells,
Residual tumor purification, centrifugation,
100%
cells irradiation (~15.000 Gy),
cryopreservation
Residual tumor
Centrifugation, gradient
DNA and >99% >99.9% Medium exchanges; Wash steps
separation
Proteins
Feeder cell in production process would lead to up to 1% tumor cells and high tumor DNA
contamination in final product, leading to higher tumorgenicity and oncogenicity risk:
• Feeder cells irradiated at only ~50 Gy and only (partially) lysed by NK cells during production
• Cannot wash out tumor cells (NK cell and feeder cell similar size)
KIADIS PHARMA | www.kiadis.com | CONFIDENTIAL 14K-NK: same product across clinical trials (after cryo),
different from normal blood NK cells
Receptor profile Principle component analysis Cytotoxicity
80
60
% lysis
40
20
0
)
X)
P)
9
ne
ST
M
(G
lo
(C
(C
21
21
21
PM
FC
FC
GMP material MDACC and Brazil trials: Cryopreserved FC21-NK cells expanded with FC21 clone9.mbIL21
GMP material OSU trial: Cryopreserved FC21-NK cells expanded with FC21 clone CSTX002
GMP material NK Realm trial: Cryopreserved PM21-NK cells expanded with PM21 particles from CSTX002
NK cells in peripheral blood
KIADIS PHARMA | www.kiadis.com Source: Trikha et.al., EHA abstract EP1487 15K-NK: same product across clinical trials (after cryo),
different from normal blood NK cells
KIADIS PHARMA | www.kiadis.com | CONFIDENTIAL Source: Trikha et.al., EHA abstract EP1487 16K-NK platform Engineering
Genetic engineering of NK cells have been limited by poor
efficacy and NK cell apoptosis
Efficient genetic engineering of K-NK cells
KIADIS PHARMA | www.kiadis.com | CONFIDENTIAL 18Proprietary engineering K-NK Knock out by Cas9/RNP gene
targeting
20+ receptors
CD16 - NKp46
- NKG2D
- KIRs
K-NK Knock out cell
KIADIS PHARMA | www.kiadis.com | CONFIDENTIAL 19Proof of concept for proprietary knock out: CD38 KO
eliminates Daratumumab mediated K-NK cell fratricide
Wild type NK cells: fratricide K-NK CD38 knock out cells: no fratricide
CD38
Knock out No
CD38 fratricide
Daratumumab
Courtesy of D. Lee, G. Ghiaur, et al
Clin Cancer Res. 2018 24(16) 4006-4017
1/15/2021 KIADIS PHARMA | www.kiadis.com CONFIDENTIAL 20K-NK Knock out: high efficiency and no impact on
expansion
High CD38KO efficiency No impact on NK expansion capacity
PERCENTAGE OF CD38-KO EFFICIANCY
100 Effect of CD38KO on expansion
4×107
80 WT
CD38 KO
Total NK number
60 3×107
40 2×107
20
1×107
0
0
1
2
3
4
6
7
day 0 day 2 day 4 day 6
R
R
R
R
R
R
O
O
O
O
O
O
N
N
N
N
N
N
Time
O
O
O
O
O
O
D
D
D
D
D
D
Courtesy of D. Lee, G. Ghiaur, et al
1/15/2021 KIADIS PHARMA | www.kiadis.com CONFIDENTIAL 21Proof of concept for Knock out K-NK: Improved efficacy
through combination of K-NK CD38KO with Daratumumab
High CD38 expression Intermediate/ No CD38 expression
Low CD38 expression
Killing through synergy Killing through additional Killing by NK-cells only
between NK-cells and MAb synergy between CD38KO NK- (Mab independent)
cells and MAb
Courtesy of D. Lee, G. Ghiaur, et al
1/15/2021 KIADIS PHARMA | www.kiadis.com CONFIDENTIAL 22Engineering CAR-K-NK by combining Cas9/RNP gene
targeting with AAV6 gene delivery
CD16
CAR
K-NK Knock in cell
CAR-K-NK
KIADIS PHARMA | www.kiadis.com | CONFIDENTIAL
AAV 6 23W Average specific lysis (%)
ild
ty
p
100
0
20
40
60
80
A e
C AWV N Average specific lysis (%)
K-NK
D ilSd K
33 1tyK ce
C
CAR-K-NK
C ll
100
0
20
40
60
80
A R
pOe
DC
3D3 A NN
K
V-GS Kc
C
33A e1nK ecle
CR 2O
*
lsll
C A
-G N
D R K
33 e-Gn
C e4 ce
P=0,01
A nv2 lls
R
*
-G N
en K
ce
4v lls
2
N
K
Kasumi: sensitive to K-NK
ce
lls
KIADIS PHARMA | www.kiadis.com | CONFIDENTIAL
W C
D
ild 33 Average specific lysis (%)
C ty C
D A pe
R
20
40
60
80
33 - N 0
C G K
A en
R 2 ce
Proof of concept for CAR-K-NK
-G N ll
en K
4v ce
2
****
lls
PK-NK platform Persistence and proliferation in patient
K-NK: In vivo persistence and proliferation in patients of
unique phenotype
Program Field Donor
• At least 5-week persistence
K-NK002 Haplo Allogeneic/
HSCT haplo • 30% chimerism
K-NK003 AML R/R Allogeneic
• Proliferation in patient
Academic Neuro- Autologous
study blastoma • Phenotype preserved in patient
Source: Schafer et.al., EHA abstract S284 and EP1487
KIADIS PHARMA | www.kiadis.com | CONFIDENTIAL 26K-NK002: immune reconstitution and phenotypic
identification in patients (day 14)
Healthy Donor K-NK002 Patient
Product
T cells
K-NK002 K-NK002
“Std” NK “Std”
cells NK cells
35-parameter CyTOF, 8-parameter ViSNE clustering
KIADIS PHARMA | www.kiadis.com Source: Schafer et.al., EHA abstract S284 and EP1487; Ciurea SO, in preparation 27K-NK002: immune reconstitution and phenotypic
identification in patients (day 14)
CD3 CD56 NKp46 NKG2D CD57 Perforin Ki67
Patient #302
(Day 14)
Patient #74
(Day 14)
Healthy donor
K-NK product
Source: Trikha et.al., EHA abstract S284
KIADIS PHARMA | www.kiadis.com | CONFIDENTIAL 28K-NK002: accumulation and proliferation in patients
(multiple doses)
After 2nd dose (>14 days) After 2nd dose (>21 days) After 3rd dose
K-NK cell
Patient K-NK cell addition and
2223690 proliferation proliferation
K-NK cell
Patient K-NK cell addition and
2280059 proliferation proliferation
CyTOF: NK-cells mapped on Profile of Profile of K-NK
Ciurea et al, ASH 2019; multiple attributes; color healthy blood cell drug
Courtesy Dean Lee indicates quantity of cells; NK cells: product:
KIADIS PHARMA | www.kiadis.com 29K-NK002: proliferation in the patient, more than T-cells
Ki67 expression (proliferation marker) in representative Ki67 expression in all
patients (day 14) patients (all timepoints)
100
% Ki67+ of subpopulation
80
60
40
K-NK cells
Std NK cells 20
T cells 0
T-cells
gh NK
K- NK
K
K
T
N
tN
riStd
d
St
rb
pe
Su
Source: Schafer et.al., EHA abstract S284; Ciurea SO, in preparationK-NK003: In vivo persistance for 5 weeks
Patient A Patient B
• Flow cytometry of HLA
HLA-A2 HLA-A2 HLA-Bw6 chimerism between
patient and donor
• 30% NK cell
patient/donor
chimerism achieved
• Donor NK-cells
detected up to day 49
HLA profile of (5 weeks from last
Donor K-NK cells infusion)
• At lowest dose (106
cells/kg)
HLA profile of HLA profile of
Donor K-NK cells Donor K-NK cells
Source: Schafer et.al., EHA abstract S284; Ciurea SO, in preparationFC21-NK: Persistence over 8 weeks with repeat infusions
in pediatric brain tumor patients
• Phase 1 in 9 children with recurrent
medulloblastoma and ependymoma NK cells
10000
• Dosing 3 weekly up to 3 cycles; Total 1000
110 intraventricular infusions
Cells/uL
100
• NK cell concentration increased 11-
10
fold in cerebrospinal fluid
1
• No dose limiting toxicity
0.1
• Autologous NK cells expanded with 0 4 8
FC21 in academic study Week
KIADIS PHARMA | www.kiadis.com Khatua S, Neuro-Onc 2020, in press 32Risks associated with our business
The following are a selection the key risks that relate to our industry and business, operations and financial condition, and to our shares. For further information on the risks that we are subject to, reference is
made to the risk factors included in our financial statements and any prospectus that we may publish from time to time.
• We are dependent on external funding in the foreseeable future and require substantial additional funding to continue our operations, including during the next twelve months. If we are unable to raise
funding when needed or on acceptable terms, we could be forced to delay, reduce or terminate our development programs and may be unable to continue as a going concern and ultimately go into insolvency.
• We have a history of operating losses and will continue to incur operating losses for the foreseeable future. We may never achieve profitability, while our net losses are expected to fluctuate significantly.
• We are early in our development efforts and all of our programs are in early stage clinical development or preclinical development. If we are unable to advance our programs through clinical development,
obtain regulatory approval and commercialize one or more of our product candidates, we may never generate any product revenue and our business will be materially adversely affected.
• Our NK-cell platform and the technologies we are using are new and unproven. The use of NK-cells expressed with PM21 particles and the use of universal donors for NK-cells is a novel and unproven
therapeutic approach without any clinical studies in humans with NK-cells produced with our NK-platform having been performed yet, and our development of our NK-platform and our NK-programs may never
lead to a marketable product.
• In relation to our lead program K-NK002 and K-NK003, investigator-initiated proof-of-concept studies have been performed, which may affect the reliability of the results and data generated in these studies
and the extent that these are of use for the further development of these programs.
• We may experience setbacks in our clinical trials, including delays in commencing, conducting or completing, inability to commence, conduct or complete, or inconclusive or negative results, all of which could
have a material adverse effect on our business, financial condition, results of operations and prospects.
• Due to our limited resources and access to capital, we must prioritize development of certain programs and our decision to pursue these programs may prove to be unsuccessful as they may never receive
regulatory approval or achieve profitability.
• We currently rely on a single contract manufacturing organization to provide supplies of our product candidates for our planned clinical trials. We expect to increase manufacturing capacity by using existing or
other CMOs and potentially in the future developing our own manufacturing facilities for clinical trials and commercial production of our products. We have no experience operating a manufacturing facility,
and we may not be successful in developing our own manufacturing facilities or capacity in the future if we chose this route. If we cannot manufacture our product candidates in sufficient amounts, with CMOs
or ourselves, at acceptable costs and on a timely basis, we may be unable to supply sufficient products for clinical trials or to support commercialization.
• In order to have sufficient NK-cells for our planned clinical trials we need to improve and scale up our NK-cell manufacturing process. This could require the process or parts thereof to be changed, which may
require revalidation, additional comparability or bridging clinical trials and regulatory vetting and we may experience setbacks in our trials if we do not succeed in improving and upscaling this process or
experience delays.
• We rely on third parties who license intellectual property rights to us, including intellectual property relating to our NK-platform. If any such license is terminated, we may be unable to commercialize and
market our products candidates.
• The price of our shares may be volatile and fluctuate significantly.
• Ownership of our shares is highly concentrated and the interests of our significant shareholders may conflict with the interests of our other shareholders.
• Future sales and issuances, or the possibility of future sales or issuances, of a substantial number of shares could significantly lower the price of our shares and dilute the interests of shareholders.
• There may be limited liquidity of our shares, which may affect the price of the shares and make it difficult for investors to sell shares at or above the price paid for them or at all.
• We may implement anti-takeover protection that may prevent a change of control, and Dutch corporate law contains provisions that may delay or discourage a takeover attempt.
KIADIS PHARMA | www.kiadis.com 33When it comes to life-threatening diseases, we are one family. Kiadis is leveraging the natural strengths of humanity and our collective immune systems to source the best cells for life. Our uncompromising approach to serve patients, their families and care givers aims to minimize harm and maximize help – delivering personalized treatments for every single patient to offer hope, reduce suffering and provide new life.
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