Phage Display Libraries

XOMAAntibody Platform Technologies ExpandTarget Opportunities while Generating Antibodies with Novel Properties

▪ The XOMA antibody platform is built as a combination of novel technologies and unique know-how

▪ XOMA’s access to major commercial phage libraries provides knowledge and experience for creating top-performing custom libraries

▪ Novel expression-enhancing advancements improve the functional activity of all phage libraries

▪ Optimized panning techniques developed at XOMA maximize specific hits to cell-surface targets, including GPCRs, and help ID antibodies with unique modulatory function

▪ Novel yeast and mammalian display platforms accelerate Ab discovery by allowing rapid IgG reformatting and FACS-based antibody screening

The XOMA antibody platform accelerates antibody discovery and is making difficult cell‐surface targets and mechanisms of action accessible

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XOMA’s Phage Display Libraries have SeveralXOMA Phage Display Technology

• XOMA089 TGFb: Ph1• Licensed to Novartis

• XOMA358 insulin receptor: Ph2• Congenital

Hyperinsulinism• Post-Gastric Bypass

Hypoglycemia

Clinical Validation

XOMA’s Phage Display Libraries have SeveralCompetitive Advantages

XOMA has some of the most diverse phage display antibody libraries• Picomolar affinity antibodies routinely selected with limited screening• Antibody fragments with different target specificities and diverse epitope coverage can

be isolated from a single panning campaign

Competitive Advantages of XOMA’s Technology

Vector Design Library Structure Freedom to Operate2 31

• Three tags (V5‐6His‐c‐myc)

• Amber codon

• Gene 3 stump

• Very large (>1011)

• Fully human

• Natural repertoire

• Choice of fragment format

• High percentage of open reading frames

• No gatekeeping

• Unique IP package

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XOMA031 Fab Library Characteristics

▪ 30 healthy donors▪ 14 PBMC, 15 bone marrow, 1 lymph node

▪ Total library size: 3.4 x 1011

▪ Kappa sub‐library: 1.8 x 1011

▪ Lambda sub‐library: 1.6 x 1011

▪ Full human repertoire▪ All VH, VL, and VK families

▪ Expression▪ 69% of Kappa clones express full length fragments

▪ 81% of Lambda clones express full length fragments

0

10

20

30

40

50

VH

1V

H2

VH

3V

H4

VH

5V

H6

VH

7

VL1

VL2

VL3

VL4

VL5

VL6

VL7

VL8

VL9

VL1

0

VK

1V

K2

VK

3V

K4

VK

5V

K6

% F

req

ue

ncy

Human XOMA031

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2020Library Validation Summary for 3 Panning Rounds

XOMA031 Fab LibraryTarget Panning

MethodPlates

ScreenedHit Rate Total Unique Unique VH Unique VL

Gastrin Soluble 5 38% 21 16 17

FITC-BSA Immobilized 6 41% 108 103 102

Transferrin Soluble 1 55% 35 27 35

TIE-2 Soluble 4 51% 66 40 37

XOMA040 scFv Library Characteristics

▪ 33 healthy donors▪ 13 PBMC, 5 bone marrow, 13 spleen and 2 thymus

▪ Total library size: 3.8 x 1011

▪ Kappa sub‐library: 1.38 x 1011

▪ Lambda sub‐library: 2.44 x 1011

▪ Full human repertoire▪ All VH, VL, and VK families

▪ Expression▪ 71% of Kappa clones express full length fragments

▪ 71% of Lambda clones express full length fragments

0

10

20

30

40

50

60

VH

1V

H2

VH

3V

H4

VH

5V

H6

VH

7

VL1

VL2

VL3

VL4

VL5

VL6

VL7

VL8

VL9

VL1

0

VK

1V

K2

VK

3V

K4

VK

5V

K6

%Fr

equ

ency

Human XOMA040

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15kDa soluble protein

Panning and Screening Funnel

3 rounds of soluble panning with a biotinylated 15kDa protein

Primary Screen of 4 96‐well plates as PPE 1) ELISA – 176/372 (47%)2) FACS (Target bound to cell surface receptor) – 165/372 (44%) 3) SPR – 197/372 (53%)

FACS secondary screen of 325 clones (hit in any of the primary screens)1) Target bound to monomeric receptor 12) Target bound to dimeric receptor 1/23) Target bound to monomeric receptor 3

Sequenced 214 clones (hit in secondary screens 1 and/or 2 but not 3)

82 mAbs reformatted

78 mAbs expressed as IgG2

72 mAbs retained binding as IgG2

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▪ 82 unique clones

▪ 66 unique VH

▪ 78 unique VL

▪ 41 Kappa LC

▪ 37 Lambda LC

Family distribution of selected clones

0

15

10

20

30

40

50

H0

1H

02

H0

3H

04

H0

5H

06

H0

7

K0

1K

02

K0

3K

04

K0

5K

06

L01

L02

L03

L04

L05

L06

L07

L08

L09

L10

% F

req

uen

cy

Family Distribution

▪ 72 mAbs with affinities between 1µM and 10pM

▪ 34 mAbs < 10nM

▪ 10 mAbs < 1nM

High Affinity clones discovered from XOMA040 without affinity maturation

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Library Validation Summary for 3 Panning Rounds

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XOMA031 Fab Library

XOMA040 scFv Library

Target Panning Method

Plates Screened

Hit Rate Total Unique Unique VH Unique VL

Gastrin Soluble 5 38% 21 16 17

FITC‐BSA Immobilized 6 41% 108 103 102

Transferrin Soluble 1 55% 35 27 35

TIE‐2 Soluble 4 51% 66 40 37

Target Panning Method

Plates Screened

Hit Rate Total Unique Unique VH Unique VL

ANG‐2 Soluble 6 96% 59 41 50

FITC‐BSA Immobilized 2 96% 134 105 107

XOMA Library Summary

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▪ XOMA040 and XOMA031 utilize all natural frameworks for increased probability of isolating a diverse set of functional antibodies.

▪ All XOMA libraries consistently deliver diverse sets of high affinity antibodies