On the route to Biobetters: from alternative binding ... · On the route to Biobetters: from alternative binding proteins to tuning in vivo half-life! ... (RCC), breast, colorectal

Prof. Dr. Arne Skerra

Global Engage 2nd Biologics & Biosimilars Congress: Berlin – 2nd Feb. 2016

On the route to Biobetters:

from alternative binding proteins to tuning in vivo half-life!


The Expanding Universe of Therapeutic Proteins ...

Need for classification: Group I: Protein therapeutics with enzymatic or regulatory activity

Ia: Replacing a protein that is deficient or abnormal (e.g.: insulin, hGH, FVIII) Ib: Augmenting an existing pathway (e.g.: erythropoietin, interferon-α2a/b, tPA, exenatide) Ic: Providing a novel function or activity (e.g.: asparaginase, hirudin, streptokinase)

Group II: Protein therapeutics with special targeting activity IIa: Interfering with a molecule or organism (e.g.: pegvisomant, enfuvirtide, MAbs & Scaffolds ...) IIb: Delivering other compounds or proteins (e.g.: ADCs & Bispecifics ...; Zevalin, Mylotarg ...)

Group III: Protein vaccines IIIa: Protecting against a deleterious foreign agent (e.g.: HBsAg, HPV vaccine) IIIb: Treating an autoimmune disease IIIc: Treating/preventing cancer (e.g.: Cervarix)

Group IV: Protein diagnostics In vivo imaging agents for cancer (e.g.: Arcitumomab)

(Leader et al. 2008 Nat. Rev. Drug Discov.)

The area of Protein- or Peptide-based Biotherapeutics has seen tremendous growth during the last decade:   1982: market approval of the first recombinant protein, insulin (Humulin)   2000: 84 approved biologics in the US + EU   2010: ≥ 200 biopharmaceuticals on the market

(Walsh: Biopharmaceutical Benchmarks – 2003 & 2010)   2013: 907 medicines and vaccines under development in the US,

among those 338 Monoclonal Antibodies (MAbs) (America's Biopharmaceutical Research Companies 2013 Report)

MAb

hGH

Exenatide


Two Approaches to Biobetters: Anticalins® and PASylation®

The term BIOBETTER refers to a therapeutic protein that is functionally similar (not identical) to an established biopharmaceutical but has improvements over the original in critical attributes and clinical performance. (See, e.g.: Beck, A. (2011) Biosimilar, biobetter and next generation therapeutic antibodies. mAbs 3, 107-110.)

Some examples of Biobetters:

Insulin: Humulin (1982) ⇒ Lantus (2000)

Interferon: Roferon A (1986) ⇒ Pegasys (2002)

G-CSF: Neupogen (1991) ⇒ Neulasta (2002)

Antibody: Herceptin (1998) ⇒ Kadcyla (2013)


Anticalins® based on the lipocalin scaffold: next generation 'Antibodies'

Advantages:

  simpler architecture (one polypeptide chain) -  easier manufacturing

and manipulation -  facile fusion with

enzymes or toxins (bispecific Duocalins)

-  high stability -  monovalency -  lack of Fc effector module

  smaller size -  better tissue penetration -  tunable plasma half-life -  new routes of administration

(inhalation etc.)

Antibody Anticalin (X-ray structure in

complex with CTLA-4)

Target ('Antigen')


The Lipocalin family of ligand-binding proteins: prominent members

*Crystal structure known (human members of the family)


The menagery of human lipocalins: a β-barrel fold with 4 variable loops

Schiefner & Skerra, Acc. Chem. Res. 2015


Lipocalins & Antibodies: structural plasticity in the loop region

10 Fv fragments of different antibodies 6 "prototypic" lipocalin structures: RBP BBP MUP EPA BLG BDA


Targeted in vitro randomization of a scaffold protein

loop #1 loop #2 loop #3 loop #4

lipocalin cDNA deg. oligo #1 deg. oligo #3

deg. oligo #4 deg. oligo #2

PCR primer

PCR primer

Loop #1 Loop #2 Loop #3 Loop #4

Lipocalin scaffold

combinatorial mutagenesis in vitro


In vitro evolution of Anticalins: a funnel-like combinatorial design process

Anticalin Library

Target-Specific Clinical Candidate

Phage display selection E. coli surface display High throughput ELISA Secondary ELISA screen

(specificity etc.) Optionally: affinity

maturation Preparative expressions

and biochemical characterization

In vivo activity PK/PD in vivo

Target

Target


Theoretical aspects of combinatorial library design for a protein scaffold

no. of randomized positions: 12 16 20 24 codons

NNS mutagenesis 32 18 24 30 36 codon mutagenesis 19 15 20 25 30 'informed' mutagenesis ≈10 12 16 20 24


Evolution of Lcn2-based Anticalin libraries: choice of randomized positions

1 25 50 75 90 . . . . . Lcn2 QDSTSDLIPAPPLSKVPLQQNFQDNQFQGKWYVVGLAGNAILREDKDPQKMYATIYELKEDKSYNVTSVLFRKKKCDYWIRTFVPGCQPG Protein ...........................h...........x.x.x.xx.xx...................x.xx...x.x.a.....s... Hapten ...........................h....x..x....x..........x.x.............x.x........x.x.....s... New ...........................h.......x...xx.......x..x...............x.x.xx...x.x.x.....s... ====A=====------#1------===B=== ===C===--#2---===D==== 101 125 150 178 . . . . Lcn2 EFTLGNIKSYPGLTSYLVRVVSTNYNQHAMVFFKKVSQNREYFKITLYGRTKELTSELKENFIRFSKSLGLPENHIVFPVPIDQCIDG Protein ..........xxx.....................x.xx.x.x.a..i.......a................................. Hapten ...........................................x.x.x......a................................. New .....x...x..x..x..................x.x....x.x............................................ ==E=----#3-----===F==== ===G===---#4---===H===

Protein Hapten New


Tailored Anticalins can tightly bind target molecules of different kinds!

αHepcidin

αCTLA-4

αAβ

αED-B

α


  Fibronectin (FN) was one of the first genes reported to undergo alternative splicing, resulting in 3 isoforms: ED-A, ED-B, IICS.

  Isoform B of the extracellular matrix protein FN was found to be associated with neovasculature of solid tumors.

  ED-B is identical in several vertebrates, including mice and humans.

  ED-B arises exclusively at sites of tissue remodelling (such as during wound healing or in endometrium) but is absent in plasma and normal tissue FN.

  ED-B is abundantly expressed around newly formed blood vessels, including neovasculature of various solid tumors, e.g., melanoma, renal cell carcinoma (RCC), breast, colorectal, and non–small cell lung cancer.

Ideal target with broad therapeutic applicability across various cancer types!

Neri & Bicknell 2005 Nat Rev Cancer

Carnemolla et al. 1989 J Cell Biol


Three Anticalins against ED-B show distinct modes of epitope recognition

Relative orientation of the Anticalins N7A, N7E, and N9B with respect to ED-B:

Relative orientation of ED-B with respect to the Anticalins N7A, N7E, and N9B:

Superposition of ED-B

Superposition of the Anticalins N7A, N7E, and N9B

Gebauer et al., JMB 2013


Anticalins detect ED-B on primary glioblastoma (WHO°IV GBM) tissue

C

A B

D

E F

G H

Anticalin N7A

Anticalin N7E

ααCD31 (endothelial cell marker)

wtLcn2 (negative control)

wtLcn2 N7A

  Immunohistochemical detection of ED-B on human glioblastoma tissue sections: Strep-tag II labeled Anticalin N7A, StrepMAB-Immo, biotinylated α-mouse Ig, streptavidin-HRP / DAB chromogen  Cell nuclei were counterstained with hematoxylin.

Albrecht et al., IJC 2016


Barinka et al., PEDS, published online.


Prospects for Anticalins in Research, Diagnostics (in vivo) & Therapy

PRS-050, a VEGF antagonist: Safe, well tolerated, biologically active

  Safe and well tolerated in a 26-patient Phase I trial (repeated dose escalation study, completed in 2011)

  Lack of immunogenicity (no Anti-Drug Antibodies in 17 pts with ≥ 5 doses; one patient was tested for ADA after 17 doses)

  Dose proportional pharmacokinetics (6-day half-life for the 40 kDa PEGylated protein)

  Durable target engagement

  VEGF undetectable in plasma > 21 days following a single i.v. dose

  Pro-hypertensive effect consistent with anti-VEGF activity

  Sustained inhibition of downstream circulating biomarker


EUROCALIN Consortium boosts clinical development of αα-Hepcidin project

ααHepcidin

Pieris Pharmaceuticals, Inc.

  Human data demonstrating desired drug-like properties -  26 solid tumor patients with VEGF-A antagonist -  36 healthy volunteers with hepcidin antagonist

  Several R&D partnerships generating $50+ M in revenue -  Potential for future milestone and royalties -  Retained commercial rights in major markets

  High Caliber Investors -  OrbiMed Advisors (~19%), Tekla Capital Management (~10%), Lombard Odier (~6.5%); Ally

Bridge Group, Auriga, Emerald Mutual Fund, Forbion, Gilde, GLSV, Novo Nordisk, Sphera Funds, Zydus

-  $110M equity capital raised

Proprietary Next-generation Therapeutic Proteins With Several Degrees of Validation

Anticalins

Non-Confidential 21

22

Anticalin Product Pipeline

Product Target(s) Indication Partner Discovery Preclinical IND-enabling Ph 1 P1b/2a

PRS-080 Hepcidin Anemia

PRS-060 IL4Ra Asthma

PRS-343 CD137/HER2

Immuno-Oncology

PRS-342 CD137/GPC3

PRS300s n.d/n.d.

Roche n.d.

Daiichi Sankyo

n.d. n.d.

n.d. n.d.

Sanofi Pseud. aeuruginosa Inf. Dis.

Zydus cMet Oncology

Stelis n.d. Ophtha

n.d. = not disclosed

PEGylated Anticalin

inhalable Anticalin

mAb-Anticalin fusion

1. Validated Targets

2.  IO

3. Non-IO Partnered Programs

Non-Confidential 22

Stelis

Ac/Ac-Fc fusion

multispecifics

February 2016 – Not for public distribution!

Short plasma half-life: the problem of most biopharmaceuticals

kidney: excretion

volume of distribution

Therapeutic Brand Name Size Plasma half-life Sales 2008 Protein e.g. [kDa] [h] (Humans) [Mio. US$]

  Epoetin Epogen® 34.0 4-13 5162   G-CSF Neupogen® 18.8 3.5 1341   INFα2b IntronA® 19.3 2-3 234   INFβ1a Avonex® 22.5 10 5351   h-GH Nutropin® 22.1 2.1 3376   IL1-Ra Kineret® 17.3 3.8 75

i.v. injection

0

50

100

0 1 2 3 4

% ID

τ1/2 Size-dependent glomerular filtration


Drug Brand Name Indication PEGylation PK effect Sales 2009

PEG-interferon α2b PEG-Intron® Hepatitis C 12 kDa x 10 844 Mio. US$ PEG-interferon α2a Pegasys® Hepatitis C 40(2) kDa x 12 1539 Mio. US$ PEG-G-CSF Neulasta® Neutropenia 20 kDa x 4 3355 Mio. US$

Drawbacks of PEGylation:

  High Cost of Goods

  Chemical coupling & processing steps

  Often low biological activity

  Accumulation in organs (renal tubular cells, macrophages, choroid plexus epithelial cells ...)

  Expanded volume

  Retarded kidney filtration

Chemical coupling +

PEG Protein drug

PEGylation: an established technology to prolong PK

Ifn

PEG

Clinical development of various PEGylated protein drugs has been terminated or put on hold:

PEGsunercept, PEGylated αIL1β Fab, GlycoPEGylated factor VIIa ...

HO

OX

n


Increased risk awareness of PEGylated drug products

  Cellular vacuolation in macrophages and/or histiocytes in various organs and in renal tubular cells

  Cases of cellular vacuolation of the choroid plexus epithelial cells (ependymal cells) have been observed in repeat-dose toxicity studies conducted with proteins PEGylated with molecules ≥ 40 kDa

"The ependymal cells of the choroid plexus are the main source of cerebrospinal fluid (CSF) secretion and form the blood-CSF barrier. As such, the choroid plexus is responsible for establishing and maintaining the extracellular milieu throughout the brain and the spinal cord. In addition, the choroid plexus appears to be a source of CSF-borne hormones and growth factors."

"Hence, until more data are available, the risk for ependymal cell vacuolation needs to be addressed before conducting longer term clinical trials in the paediatric population."


PASylation®®: a biological alternative to PEGylation

Computer model of a PASylated Fab fragment

(superposition of 24 PAS conformers)

  Pro/Ala-rich Sequences comprising the L-amino acids Proline, Alanine, and/or Serine form a highly soluble biological polymer that can be (i) chemically conjugated or (ii) directly produced as fusion protein with the biopharmaceutical, using various expression systems.

  Similar to PEG, PAS polypeptides adopt a stable random coil structure with large apparent volume under physiological conditions, which effectively increases the dimension of the conjugated drug beyond the pore size of the renal glomeruli and, thus, slows down kidney filtration.

  PAS sequences are stable in the blood plasma but are efficiently degraded by intracellular enzymes.

  PAS sequences are compatible with all biotechnological production systems and allow high secretion titers.

  PAS sequences are uncharged and only marginally influence the biological activity of the drug, and they are not immunogenic in animals.

  PASylation with 200-1000 residues typically leads to a plasma half-life extension by a factor of 10-100 !

H2N

HN

NH

HN

NH

OH

O

O

O

O

On

R

R

R

R

R

RO

OO

OCH3

n

O


xl020 PAS-hGH Growth Deficiency xl050 ααCD40L Fab-PAS Inflammation xl080 PAS-IFNαα Infection & Inflammation xl081 PAS-IFNantagonist Virology / HIV xl082 PAS-IFNsuperagonist Multiple Sclerosis xl100 PAS-Leptin Obesity / Diabetes xl101 PAS-SLMA Metabolic diseases

xl110 PAS-Exenatide Diabetes xl130 PAS-IL-1Ra Inflammation (RA) xl150 PAS-GMCSF Oncology xl180 PAS-ClottingFactor Hemostasis xl210 ααHer2 Fab-PAS Imaging: Oncology xl220 ααCD20 Fab-PAS Imaging: Oncology xl310 Ex4-PAS-PYY Bispecific: Metab. Disease xl510 PAS substance PEG substitute for coupling

Project status Project Compound Indication

Lead Opt.

In vivo Efficacy

Preclin. GMP

Discovery

IND

XL-protein leverages the versatility of PASylation® as broadly applicable enabling technology!

Clinic

PASylation® platform: Product Development up to in vivo PoC

XL-protein Partnering or Spin-off


Collaboration partners and financiers ...

and several more ...


PASylation®®: a biological alternative to PEGylation

  Cheap manufacturing: No in vitro coupling steps

  Homogeneous product: No polydispersity of the PAS tag

  Biodegradability: Efficient degradation by kidney enzymes

  Biological activity: High target affinity is maintained

  No immunogenicity: No immunogenicity in mice

  Extended half-life: Tunable from 10x to 100x

Expression plasmid

One-step expression

Disordered PAS Chain PAS

Therapeutic protein

gccTCTCCAGCTGCACCTGCTCCAGCAAGCCCTGCTGCACCAGCTCCGTCTGCTCCTGCT ||||||||||||||||||||||||||||||||||||||||||||||||||||||||| AGAGGTCGACGTGGACGAGGTCGTTCGGGACGACGTGGTCGAGGCAGACGAGGACGAcgg AlaSerProAlaAlaProAlaProAlaSerProAlaAlaProAlaProSerAlaProAla

(Receptor)

Therapeutic protein

Pro / Ala / Ser encoding gene cassette:

One polypeptide:

E. coli, P. pastoris, CHO, HEK etc.


Biosynthetic preparation of the monodisperse PA(S) polymer

Carrier Protein: e.g. TrxA

PA(S)

Protease / BrCN

!

!

Reverse phase HPLC:

Analytical SEC:

ESI-MS:

= PAS601

H2N-(Pro/Ala)n-COOH


0

500

1000

1500

2000

0

10

20

30

40

50

60

0 5 10 15 20 25

A225A280

A332

Abs

orpt

ion

at 2

25 n

m /

280

nm [m

AU

]

Absorption at 332 nm

[mA

U]

Elution volume [ml]

Vo Vt

Iodoacetyl-PAS: conjugation to thiol-derivatized peptides or drugs

ESI-MS (deconvoluted):

!

calculated: 48372.23 Da

0

20

40

60

80

100

120

140

160

0 5 10 15 20 25 30

Abs

orp

tion

at 2

25 n

m [m

AU

]

Elution volume [ml]

underivatized PAS600(reference)

PAS600-IA

!

Anion exchange chromatography: Size exclusion chromatography:

0

200

400

600

800

1000

1200

0

10

20

30

40

50

60

0 5 10 15 20 25

A225A280

A332

Abso

rptio

n at

225

nm

/ 28

0 nm

[mAU

]

Absorption at 332 nm [m

AU]

Elution volume [ml]

Coupling with 7-mercapto-4-methylcoumarin:

O OHS

CH3

INH

HN

O

O

(Pro/Ala)n-1-COOH


Site-directed coupling to multiple thiol groups

0

20

40

60

80

100

20

25

30

35

40

11 12 13 14 15 16 17 18 19

A 225 [

% m

ax.] B

uffer B [%

]

Retention time [min]O OHO

HN

OI

OH

O

HS

SH

HS

H2N

H2N COOH SH SH SH

H2N COOH SH

H2N COOH SH SH

Analytical reverse phase HPLC:

Coupling with Fluorescein

iodoacetamide

NHNH

HNNH

NH

O

O

O

O

O

HN NH2

NH HN

HO2C

O

N

O

O

S

S

S

H2N

S

S

S

H2N

Coupling with cyclic RGD peptide

ESI-MS (deconvoluted): Cys-PA200-Cys-PA200-Cys

PA2x200(Cys-Fluorescein)3




Gaertner et al. (2012) Eur. J. Nucl. Med. Mol. Imaging 39, S126-138. Bledzka et al. (2013) Circ. Res. 112, 1189-1200


Comparison of viscosities between PA(S) and PEG polymers

 Ranking according to intrinsic viscosity: PA(200) < PEG10kDa < PEG20kDa < PA(600) < PEG30kDa < PEG40kDa

  Note that the plasma half-life extending effect of PA(600) lies between PEG(30k) and PEG(40k)!

  Viscosity of a PASylated (or PEGylated) drug also strongly depends on fusion/conjugation partner.

PA(200)

PEG(20k)

PA(600)

PEG(40k)

Comparison of viscosities between PA(S) and PEG polymers

0

5

10

15

20

25

30

35

0 20 40 60 80 100

Visc

osity

[mP

a·s]

Concentration [g/L]

(measured on a µVISCTM microviscometer with VROC® chip in PBS)


Leptin: a key regulator of energy homeostasis and fat control

Patients with genetic Leptin deficiency before/after 18 m daily treatment with rec. Leptin:

Friedman&Halaas, Nature 1998

Licinio et al., PNAS 2004

Wabitsch et al. N Engl J Med 2015 Asp79→→Tyr

Metreleptin

Arg84→→Trp * * * * * *


Leptin: a potential biologic to treat obesity and/or diabetes?

Coppari R. & Bjørbæk C. (2012) Leptin revisited: its mechanism of action and potential for treating diabetes. Nat. Rev. Drug Discov. 11, 692-708.

Leptin in clinical settings: new attention as potential drug to treat diabetes

  Small peptide hormone (16 kD) ⇒ short plasma half-life (50–150 min)   Central role in control of appetite, energy control and metabolism   Amgen: initially developed as anti-obesity drug – up to clinical phase II (attempts to develop a PEGylated drug failed)   AstraZeneca: US approval of metreleptin (MYALEPT™) to treat congenital or acquired generalised lipodystrophy (2/14)   Aptiv Solutions: orphan designation by EC for metreleptin to treat Lawrence syndrome   Therapeutic potential for genetic Leptin deficiency, Lipodystrophy, Diabetes (as combination therapy)

Leptin

PAS


Efficient production of PAS-Leptin in the periplasm of E. coli

  Periplasmic secretion in E. coli   Purification via IMAC, AEX, SEC


Strongly extended half-life owing to expanded molecular volume

Leptin: ττ1/2 = 26 min

PAS600-Leptin: ττ1/2 = 19.6 h



PK study in C57BL6/J mice:   Proteins were injected i.p. and samples were

taken at time points from 0.17 to 48 h (N=9)   Protein concentration in plasma was

determined by sandwich ELISA, followed by fit to the Bateman function


Strong receptor engagement by PAS-Leptin in the hypothalamus

HEK293 cells transfected with murine Leptin receptor and STAT3-regulated luciferase reporter gene

SPR sensor chip charged with murine LepRb-Fc

KD = 4.2 nM


PAS-Leptin: strong decrease in food intake & weight loss in mice

Pharmacodynamics (PD) of Leptin treatment (± PAS) of C57BL/6J mice:   male C57BL/6J mice (N=8): measurement of weight and food intake   daily i.p. injection of PBS/E, interspersed by single injection of drug on day 0 (0.287 nmol/g b.w.)

  Considerably improved efficacy of PASylated Leptin compared to unmodified Leptin!

  Superactive Mouse Leptin Antagonist (SMLA) shows the inverse PD effect!

  PASylated Leptin efficiently crosses the blood brain barrier (BBB) in the hypothalamus


Repeated PAS#1(600)-Leptin injections in male B6.V-Lepob/J mice

Prof. Dr. Martin Klingenspor Lehrstuhl für Molekulare Ernährungsmedizin N = 4

Collaboration with the laboratory of:


Normalization of body weight, glucose tolerance and insulin level

Insulin levels (not fasted)

Oral Glucose Tolerance Test (day 19)

Glucose Dose = (Lean Mass + 0.2 x Fat Mass) x 2.8 mg/g

ADA assay: No immunogenicity

Day 19 plasma samples, diluted 1:1000, probed with anti-mouse polyvalent Ig-AP, using the following targets:


PASylation®®: boosting the clinical potential of Fab fragments!

Advantages of recombinant Fab fragments:

  no dimerization (receptor clustering etc.) [e.g. thrombocytopenia: Avastin; c-Met signalling]

  no immunological side effects [e.g. thrombosis: αCD40L Antova]

  high yield bacterial production [cf. Cimzia®, MetMAb®]

  better stability than scFv fragments

Bottle neck:

  Very short circulation in comparison with IgG, unless PEGylated or otherwise modified

PASylation® provides a cheap and effective solution!

Fab fragments in disease therapy:

  αGPIIb/IIIa Abciximab (Reopro®)   αVEGF Ranibizumab (Lucentis®)   αTNF Certolizumab pegol (Cimzia®)

Fab fragments for in vivo imaging:

  αCEA 99mTc-Arcitumomab (CEA-Scan®)   αCEA/NCA90 99mTc-Sulesomab (Leukoscan®)   αCA125 99mTc-Igovomab (Indimacis®)

Fab fragments as antidotes:

  αDigitalis DigiFab®   αDigitalis Digibind®   αSnake venom CroFab®

Fab fragments in clinical development:

  αFibrin D-dimer 99mTc ThromboView®

  αCD4 99mTc-Fab fragment   αMetastasis-ass. 5T4 Naptumomab estafenatox   αCD40L CDP7657 (UCP / Biogen Idec)   αTNF DLX105 (Delenex)   αPcrV KB001 (Kalobios / Sanofi Pasteur) ... etc.


PASylation®® leads to a drastically prolonged plasma half-life

Quantification via sandwich ELISA: 1)  wells coated with rec. HER2/ErbB2 2)  detection of Fab with αhuCκ-AP conjugate)

Protein sample AUC [h·µg/ml] CL [ml/h/kg] !1/2" PK [h] Fold improvement

Fab 17 293 1.34 1

Fab-PAS#1(100) 123 40.5 2.71 2.0

Fab-PAS#1(200) 254 19.6 5.20 3.9

Fab-PAS#1(400) 870 5.75 14.4 10.7

Fab-PAS#1(600) 1751 2.85 28.2 21.0

Fab-2xPAS#1(200) 2915 1.72 37.2 27.8

Fab-ABD 2376 2.10 28.9 21.6

Fab-PEG(20)2 2726 1.83 35.3 26.4

Pharmacokinetics in Balb/C mice after i.v. injection:

Fab – PAS 200

400 600


Fab PAS-100 PAS-200 PAS-400 albumin binding Rituximab domain

VH VL

CH

1

CL

AB

D

VH VL

CH

1

CL

VH VL

CH

1

CL

VH VL

CH

1

CL

Optimal imaging contrast for PAS-200!

Stronger background with albumin-mediated

plasma half-life extension!

VH VL

CH

1

CL

CH

3 C

H2

PET imaging of CD20+ Granta tumors 24 h p.i. in xenograft mice with PASylated αCD20 124I-Fab

ααCD20 PAS-Fab fragment as optimized in vivo imaging reagent


Contributors & Collaboration Partners

Pieris: Steffen Schlehuber Gabriele Matschiner Stefan Trentmann Andreas Hohlbaum and others ... IBA: Thomas Schmidt Wacker Biosolutions: Günter Wich Thomas Maier Carsten Bornhövd XL-protein: Uli Binder Lars Friedrich Alexandra Lensch and others ...

TUM lab: Michaela Gebauer Antonia Richter Evelyn Eggenstein Volker Morath Mikhail Barkovskiy Claudia Mendler Sabine Rauth Till Giese Andreas Eichinger Martin Schlapschy and many others ... IBAS Prague: Cyril Barinka Jakub Ptacek Zora Novakova NIH/NIAID: Daniel Douek Krystelle Nganou Makamdop

TUM & MRI: Dirk Haller Martin Klingenspor Markus Schwaiger Hans-Jürgen Wester LMU: Valerie Albrecht Rainer Glaß Jörg-Christian Tonn Transregio 127: Bruno Reichart Eckhard Wolf Elmar Jäckel (MHH) Fatih Noyan (MHH) Weizmann Inst.: Daniel Harari Gideon Schreiber

Documents

On the route to Biobetters: from alternative binding ... · On the route to Biobetters: from alternative binding proteins to tuning in vivo half-life! ... (RCC), breast, colorectal