quanta biodesign, ltd., world adc summit san diego, october 2016
TRANSCRIPT
Paul D. Davis, Ph.D.Founder, Owner, President and CEO
Quanta BioDesign, Ltd.
Using the dPEG® as the Framework to Uniquely Load and Protect Payloads in an
ADC Format
…with dPEG® single molecule precision
dPEG® UPDATE:
PREVIEWTechnology Update dPEG® Sidewinder™’s†
In-house chemistry with dPEG®s
Our Quality Commitment Manufacture ALL scales of dPEG®s in-house in Plain
City, Ohio, USA
Our transitioning Business Model…as a privately owned company
†Patent pending
dPEG®: single molecule vs. Traditional PEG: polymer
MALDI-TOF dPEG® structure shown;
QBD: PN10406 (single compound)
FSCE separation uses a 20-base ssDNA modified with a 5-kDa monodispersed PEG
(PI = 1.01)
A dPEG® is a SINGLE molecule ethylene oxide oligomer
…ALL dPEG®s are synthesized as single discrete molecule compounds!
What is a dPEG®*?
K E Y C O N C E P T: As single molecules, multiple dPEG®s can be
designed into constructs that enable the tailoring of ADC performance
by design…as a single molecule!!
…building in and on the powerful properties of each dPEG® **!
** Hydrodynamic vol., in vivo compatibility (solubility, stability, PK protection), non-toxic, cell internalization…all by design
OUR GOAL:To show how the dPEG® can be designed
with a biologic as a chemical infrastructure
…to control and modulate biological function and other key physical
properties
Highlight our focus on the Sidewinder™† dPEG® Chemistry Platform:
Both for Therapy and Diagnostics
†Patent pending
Structural variables of the dPEG® platform for optimizing PK and PD
FG OO N
HO
O NH
HN
OO
TG
O
12 4,12
O
O
AA
1,2,3
12,241,3,9
Reactive Functional Group (FG) for selective conjugation to specific residues
Sidewinder®†s functional amino acid side chain for orthogonal conjugation of dPEG®s, payloads, and biologics
Linear (1) or branched (3, 9) dPEG® construct for further optimization of physicochemical properties
dPEG® spacer to control distance to biologic and modify physicochemical properties dPEG® spacer for repeat
SidewInder® †units (1, 2, 3)
TG for neutral (OMe), polar (OH), and charged (CO2H) end-capping for modifying PK and BD
A General Sidewinder™† dPEG® Chemistry Platform
Conjugation armDrug Loading platform PK/BD modulating
arm(s)
†Patent pending
NH
O O O OO
NH O
NH3+TFA -
HN
HN O O O O
O
HN
O
NH3+TFA -
NH
O O O OO
NH O
ON
NH3+TFA -
O O O O O O O O O O O O O O O O O O O O O O O OO
O9
NH
O O O OO
OHO
NO
O
NH
O O O OO
OHHN O O O O
O
HN
O
NH-PG1
PG2-NHO
NH-PG1
H2NO
NH-PG1
HN O O O O O O O O O O O O O O O O O O O O O O O O
NH
O O O OO
NH O
HN
HN
HN N
HO O O
O
HN
O
HN
NH
O O O OO
NH O
ON
HN
O O O O O O O O O O O O O O O O O O O O O O O OO
O9
X
Y Z+ +
OO
OO
OO
FG or PG2-NH O O O OO
OHX
O O O O O O O O
O O O O O O O OH
OHO
NH
NO O O
NH
O O O OO
OHX
n
QBD PN 11780
AminooxyamineETACBromoacetyl
Building options easilyExample using Lys as the AA loading
platform
NH
OO
OO
ONH O
HN
HN
HN
O
OO
O O
HN
O
HN
O
OO
OO
ONH O
HN
O
OO
OO
OO
OO
OO
OO
OO
OO
OO
OO
OO
O
O
NO
O
O
OO
OO
OO
NH
PN 11780 = MAL-dPEG 12-Lys(t-b
oc)[NH-dPEG 4
-Lys(-t-boc)]2
-NH-m-dPEG 24
Paul Davis 12-7-15
A name could not be generated for this st
ructure.
Chemical Formula: C138H263N11O59
Exact Mass: 3
018.79
Molecular Weight: 3020.60
m/z: 3019.80 (100.0%), 3020.80 (84.6%), 3018.79 (64.7%), 3021.80 (54.1%), 3022.81 (15.0%), 3022.80 (11.4%), 3023.81 (9.1%), 3020.79 (4.0%),
3024.81 (3.5%), 3019.79 (2.6%), 3023.80 (1.6%)
Elemental Analysis: C, 54.87; H, 8.78; N, 5.10; O, 31.25
OO
O
O
OO
NH
O O O OO
NH O
HN
HN
HN O O O O
O
HN
O
HN
O O O O OO
NH O
HN
O O O O O O O O O O O O O O O O O O O O O O O OON
O
O
OOOOOOONH
PN 11780 = MAL-dPEG12-Lys(t-boc)[NH-dPEG4-Lys(-t-boc)]2-NH-m-dPEG24
Paul Davis 12-7-15
A name could not be generated for this structure.Chemical Formula: C138H263N11O59
Exact Mass: 3018.79Molecular Weight: 3020.60
m/z: 3019.80 (100.0%), 3020.80 (84.6%), 3018.79 (64.7%), 3021.80 (54.1%), 3022.81 (15.0%), 3022.80 (11.4%), 3023.81 (9.1%), 3020.79 (4.0%), 3024.81 (3.5%), 3019.79 (2.6%), 3023.80 (1.6%)
Elemental Analysis: C, 54.87; H, 8.78; N, 5.10; O, 31.25
OO
OO
OO
NH
OOOO
ONHO
HN
HN
HNO
OOO
O
HN
O
HN
OOO
OO
ONHO
HN
OOO
OOOOOOOO
OOOOOOOO
OOOOO
O
NO
O
O O O O O O O NH
PN 11780 = MAL-dPEG12-Lys(t-boc)[NH-dPEG4-Lys(-t-boc)]2-NH-m-dPEG24
Paul Davis 12-7-15
A name could not be generated for this structure.
Chemical Formula: C138H263N11O59
Exact Mass: 3018.79
Molecular Weight: 3020.60
m/z: 3019.80 (100.0%), 3020.80 (84.6%), 3018.79 (64.7%), 3021.80 (54.1%), 3022.81 (15.0%), 3022.80 (11.4%), 3023.81 (9.1%), 3020.79 (4.0%),
3024.81 (3.5%), 3019.79 (2.6%), 3023.80 (1.6%)
Elemental Analysis: C, 54.87; H, 8.78; N, 5.10; O, 31.25
OO
OO
OO
NH
OOO
OO
NHO
HN
HN
HN
OOOO
O
HN
O
HN
OOOO
OO
NHO
HN
OOOO
OOOO
OOOO
OOOO
OOOO
OOOO
ON
O
OO O
O OO O
O NH
PN 11780 = MAL-dPEG12-Lys(t-boc)[NH-dPEG4-Lys(-t-boc)]2-NH-m-dPEG24
Paul Davis 12-7-15
A name could not be generated for this structure.Chemical Formula: C138H263N11O59
Exact Mass: 3018.79 Molecular Weight: 3020.60
m/z: 3019.80 (100.0%), 3020.80 (84.6%), 3018.79 (64.7%), 3021.80 (54.1%), 3022.81 (15.0%), 3022.80 (11.4%), 3023.81 (9.1%), 3020.79 (4.0%),
3024.81 (3.5%), 3019.79 (2.6%), 3023.80 (1.6%)
Elemental Analysis: C, 54.87; H, 8.78; N, 5.10; O, 31.25
OO
OO
OO
NH
O O O OO
NH O
HN
HN
HN O O O O
O
HN
O
HN
OO O O O
ONH O
HN
O O O O O O O O O O O O O O O O O O O O O O O OO
NO
O
OOOOOOONH
OO
OO
OO
QBD PN 11780
Fully reduced Herceptin conjugated to dPEG®
Sidewinder™†, DAR = 24
†Patent pending
1 2 3 4260
15
140
1007050403525
10
KDa
1. Size marker2. mAb3. TCEP-reduced mAb4. 11780-mAb
SDS PAGE
Heavy Chain
Light Chain
Antibody Concentration (ng/mL)
Abso
rban
ce
ELISA of Unconjugated mAb vs.mAb-(8X PN11780) (DAR of 24)
Fully reduced Herceptin conjugated to dPEG® Sidewinder™†, DAR = 24
†Patent pending
Fully reduced Herceptin conjugated to dPEG®
Sidewinder™†, DAR = 24
†Patent pending
Herceptin Fab’ X 2 (DAR = 6) -dPEG® Sidewinder™†
ConjugateNH
O O O OO
NH O
HN
HN
HN
O O O OO
HN
O
HN
OO O O O
ONH O
HN
O O O O O O O O O O O O O O O O O O O O O O O OON
O
O
OOOOOOONH
OO
OO
OO
QBD PN 11780
†Patent pending
O ONH
O
NH
O
O
O
O
O
OO
O
OOO
OO
OO
ONH
N
OO
O
HN O O
O O
OO
OO O
O
O
O
O
O
O
OO
OO
O
O O O
O
OOOO
OOOO
OOOO
NH
NH
O
O
HN
OO
HN O O
O OO
O O
O
O
O
O
O
O
O
O
O
O
OO
OO
OO
O
OO
O
O
O
O
OO
O
O
OO
NH
O
O
HN
O
O
HN OO
O OO O
OO
OO
OO
OO
O O
O OO
O OO O
O
OOOOO
OO
OO
OOO
HN
NH
O
O
HN
O
O
O
O
NH
O
NH
OO
O
O
O
OO
OO
OOOO
O
O
O
NH
NO
O
O
HN
O
O
O
O
O
O
O O
O OO
O
O
O
O O
OO
O
O
O
OO
O
OOO
OOOO
OO
OO
ON
H
NH
O
O
HN
O
O
HN
O
O
OO
O O OO
O
O
O
O
OO
O O
O
O
O
O
O
OO
O
OOOO
OO
OOOOOO
NH
O
O
HNO
O
HN
O
OO
O O
O OO O
OO O
OO O
O O
O
O
O
O
O
O
O
O
O
O
O
OO
OOO
O
O
O
HN
NHOO
HN
O O
Herceptin Fab’ X 2 QBD: PN 11803
-dPEG® Sidewinder™† Conjugate
†Patent pending
In-house Chemistry Development:Being the chemistry experts at the chemistry biology interface with dPEG®
Bromoacetamides as an alternative to the maleimide BA is stable with the azide… maleimide is NOT!
DBCO-amine and TFP ester (or acid) to the DBCO-dPEG®x- functional group derivatives… focus on manufacturability at scale.
NH2N
O
NH
N
O
O
OOF
F
FF
NH
O O O O OBrO
O O O O O O O O
O FF
FF
Bromoacetamido-dPEG12-TFP ester; also dPEG4 and dPEG24 Bromoacetamido-dPEG®12-TFP ester; Also -dPEG®4 and -dPEG®24
Exp. flyer: BSA-SH, BA-dPEG®11-N3; DBCO-NH-m-dPEG®24 BSA-dPEG®11-TA-DBCO-NH-m-dPEG®24
New NIR cyanine dyes
NN
S
SO3--O3S O
O
Na
FF
FF
meso-TP-TPF ester-IR775-bis-sulfonate meso-TP-IR 775 TFP ester
N+Cl-N
S
O
OF
FF
F
N+Cl-
N
S
OO O O O O O O O O O O OH
N O
O
F
F
F
Fmeso-TP-IR 775-dPEG®
12 TFP ester
NH
HN
OOOOOOOOOOOOOOOOOOOOOOOO
HN OOOOOOOOOOOOON
H
O
NO
O
O
S
N
N
O
Cl
NH
NH
OOOOOOOOOOOOOOOOOOOOOOOO
HN OOOOOOOOOOOOON
H
O
NO
O
O
SN
N
O
SO3
SO3
Na
NH
HN
OOOOOOOOOOOOOOOOOOOOOOOO
HN OOOOOOOOOOOOON
H
O
NO
O
O
S
N
N
O
Cl
OH
O
Single dPEG® Sidewinder™† w/ NIR dye
†Patent pending
DOTA dPEG®’s for in vivo imaging options for commercial offering
DOTA(TBE)3-amido-dPEG®4-TFP ester
DOTA-amido-dPEG®12-TFP ester
Every dPEG® Product and Intermediate is Made from Scratch in
Plain City, Ohio, USA
Our Process/Scale-up and Quality Commitments:
Produce highest possible quality dPEG® with economy of scale for commercialization
Supply agreement – Supply to specification from pre-clinical to and the scale you need through commercialization
All In-house QA systems are open for audit
Therapeutics and Diagnostics / Approved and Clinical Trials
The therapeutics include whole antibodies, antibody fragments, proteins, peptides and RNA
dPEG®s in Regulated Products
COMPANY PRODUCT INDICATION STATUSUS. UCB Cimzia® Rheumatoid Arthritis ApprovedClinical Diagnostics , multiple >12 MM kits per year Oncology/ POC FDA ApprovedCompany 1 2 Blood disorders Phase II
Eye Disorder Phase ICompany 2 Liver Disorder Phase IIICompany 3 Hematologic
MalignancyPhase I
Company 4 ADC Phase ICompany 5 Lung Cancer Phase ICompany 6 Metabolic Disorders Phase ICompany 7 Oncology Phase ICompany 8 Oncology Phase ICompany 9 Hematologic
MalignancyPhase I
Multiple Companies Multiple Indications Pre-Clinical
We continue to be committed to our catalog business, supplying our innovative
dPEG® linkers and modifiers…
Transitioning to a New Business Model
Our composition IP Portfolio is available for evaluation under an MTA with license options
Beyond Linkers: An Integrated Conjugation Technology using the dPEG® Chemistry
Platform for Improved In Vivo Performance of Biologics
For more information, come see us at Booth No. 30
ACKNOWLEDGEMENTSChemistry My QBD Chemistry Team, James Guyo, Principal Process Scientist
Conjugation & Characterization Our QBD Applications Group, Alex Pokora
Antibody Production and Supply David Colcher, Paul Yazaki; City of Hope
Mass Spec Nan Kleinholz; OSU
QBD Support Staff Wren Davis, CFO
Thank you!
Mass Spectral Data (MALDI-TOF) and Structure of a 9-Branched discrete PEG construct Conjugated to BSA Showing the Compound as a single
compound; QBD PN11487, MW = 15,592.45.
1. BSA MW ≈ 66.2 KDa2. BSA-11487 MW ≈ 81.8 KDaThe single thiol of SEC purified BSA was conjugated to PN11487 in 100 mM sodium phosphate buffer, pH 6.5, at ambient temperature overnight with shaking. The reaction was quenched by passage through two Sephadex G-50 columns in the same buffer, exchanged into deionized water, and analyzed by MALDI TOF MS.
NH
OO
O NH
O
NHO
NH
O O18
O18
O18
O O O O O O
O O O O O O
O O O O O O
OOOOOOOHN
18
OOOOOOOO
HN
18
O
OON
HON
O
O
O
O
NH
OO
ONHO
NHO
NHOO
O
O
OO O
O OO
OO O
O OO
OO O
O OO
OOOO
OOOH
N
O
O
HN OO
O
NH
O
NH
O
NH
O
O
O
O
O OO O
O OO OO O
O OO OO O
O O
OOO
OOOO
NH
O
O
S
1,500
100,000
1,250
1,000
750
500
250
0
60,000 80,000
MALDI TOF MS Spectra of catalase conjugated to PN10458 (TFP-dPEG®
4-(m-dPEG®24)3-ester
Red spectrum (lower concentration): Catalase, 1.80 mg/mL reacted with 200 molar equivalents of PN10458.
Purple spectrum (higher concentration): Catalase, 5.62 mg/mL reacted with 200 molar equivalents of PN10458.
Catalase monomer (CM) MW: 57.53 KDa
dPEG®24-3-BCdPEG® MW: 3.99 KDa
+0 = no PN10458 conjugated to catalase+1 = CM +1 dPEG®
24-3-BCdPEG®, MW = 61.40 KDa+2 = CM +2 dPEG®
24-3-BCdPEG®, MW = 65.34 KDa+3 = CM +3 dPEG®
24-3-BCdPEG®, MW = 69.18 KDa+4 = CM +4 dPEG®
24-3-BCdPEG®, MW = 73.07 KDa+5 = CM +5 dPEG®
24-3-BCdPEG®, MW = 76.97 KDa+6 = CM +6 dPEG®
24-3-BCdPEG®, MW = 80.88 KDa+7 = CM +7 dPEG®
24-3-BCdPEG®, MW = 84.77 KDa
Random Lysine Amine Modification of Catalase at two different concentrations of TFP-dPEG®4-Tris(-NH-m-dPEG®24)3 (dPEG®24-3-BCdPEG®), a 3-
Branched Discrete PEG construct
90,00060,000 70,000 80,000
2,500
2,000
1,500
1,000
500
0