Analysis of the Current AntibodyLandscape and Meeting Highlights

William R Strohl, BiStro Biotech ConsultingIBC Antibody Engineering MeetingSan Diego, CADecember 15, 2017B

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CD281. Antibody

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scFv

“Naked” IgG and fragments Examples of bispecific antibody formats

Examples of immunocytokine formats Examples of Fc fusion formats

Example of ADC CAR-T

Examples of Antibody Formats Represented in Clinical Trial Candidates

Drugs and Antibodies Approved by the FDA by Year 1997-Present

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Small molecule NMEs approved by FDAAntibodies and Fc-fusion proteins approved by FDABLA Biologics approved by the FDA

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Drugs and Antibodies Approved by the FDA by Year 1997-Present

1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017

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2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017

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2016 Biologics $163B total sales by category – 66% mAbs/Fc Fusions

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110 Antibodies/Fc Fusion proteins ($107B)Insulins ($20.6B)xCSF (immunostimulatory) ($5.7B)Growth factor/FSH ($3.8B)Erythropoietins ($5.8B) Interferons (a and b) ($5.4B)Coagulation factors ($7.9B)Enzyme replacements ($4.9B)Other proteins ($7.55B)

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Current and Projected Number of Marketed MAbs and Fusion Proteins

Database lock12/10/17 –©BiStro Biotech

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Human MAb

Fc fusion protein

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Murine MAb

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At ~75% POS (industry ave.),would yield approx ca. 132marketed Mabs & Fc fusionproteins by ~2021

First HumanizedMAb Zenapax

approved 1997

ReoProlaunched

1994

At least 73 Mabs and Fc fusion proteins currently post-Phase IIb or in Phase III trials

79 different Mabs and Fc fusionproteins have been approvedin major markets by Dec 10, 2017

First Human MAb Humira

approved 2002

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1x ADC1x Bsp Ab

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1x ADC

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1x Bsp Ab

(EU only)

1x ADC

Questions?

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Antibody FormatStage of Development

TotalsPhase I/II Phase III Approved

Naked IgG 418 54 55 527Naked antibody fragments 10 2 4 16Immunocytokines 9 2 0 11Fc fusion proteins 26 4 11 41Bispecific antibodies 72 0 3 75Antibody-drug conjugates 73 7 4 84Radioimmunoglobulins 11 2 2 15Mixtures 8 0 0 8Antibodies only 627 71 79 777

T or NK cells CAR antibodies 204 0 2 206

Totals 831 71 81 983

Clinical Stage and Approved Antibody-based Drugs

Database lock 12/10/17 – ©BiStro Biotech

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Primary Indication Phases 1 and 2 Phase 3 Approved Totals

Inflammation including RA 70 6 14 90

Asthma 25 2 5 32

Psoriasis 10 2 7 19

Inflammatory bowel diseases 19 2 2 23

SLE 16 5 1 22

Multiple sclerosis 12 0 5 17

Ophthalmological/neurological 11 6 2 19

Alzheimers and neuro-related 18 4 0 22

Pain and Migraines 3 6 0 9

Infectious diseases 36 6 4 46

Bone/muscle 12 4 2 18

Blood homeostasis 11 1 5 17

Cardiovascular 5 0 2 7

Diabetes 13 0 1 14

Other or not identified 18 1 1 20

All non-oncology indications total 279 (44%) 45 (63%) 51 (65%) 375 (48%)

Oncology indications 348 (56%) 26 (37%) 28 (35%) 402 (52%)

Breakdown of Clinical Stage Antibodies for Indications other than Oncology

These numbers vary slightly from those reported in Strohl, 2017 due to categories used, new candidatesidentified, and use of “primary indication” only

Waterfall plot of 325 unique targets represented in clinical trials of mAbs, Fcs, CARs

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192 Targets with 1 clinical candidate:Cancer 94

Inflammation/Autoimmune 51Infectious disease 6

Ophthalmology 3Cardiovascular/Metabolism 7

Muscle/Bone 4Pain 4

Neurobiology 6Blood homeostasis 14

Other 3

CancerInflammation/AutoimmuneInfectious diseaseOphthalmologyCardiovascular/MetabolismMuscle/BonePainNeurobiologyBlood homeostasis

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Database lock12/10/17 –©BiStro Biotech

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84 ADCs = 49 different targets• Ranging from 8 clinical candidate ADCs/target (Her2)

to 1 clinical candidate ADC/target (38 targets)

75 Bispecific Antibodies = 57 different targets• 38/75 bispecifics are immune cell redirected• Other than CD3 (n=36), range from 8 clinical

candidates (EGFR) to 1 candidate (37 targets)

206 Unique CARs = 42 unique targets• CD19 – targeted 78 times• Highest other antigens: CD22, BCMA, GD2,

mesothelin, EGFRvIII

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gExciting new areas in Therapeutic Antibodies to watch:

Antibody-engineering related• T cell redirection• Bispecific antibodies• ADCs• Immunocytokines• IgMs, Hexamers, IgAs, novel high avidity approaches• CAR-Ts• Sweeping antibodies, pH/pI effects on antibody trafficking

Target/disease/indication related• Checkpoint modulators• Immunogenic cell death (ICD) and related adaptive immunity-driven therapies• BBB for ERT and neurodegenerative diseases

Delivery-related• Multiple antibody mixtures• Specific IVIG from transgenic cows• Targeted nanoparticles• Intracellular delivery of IgGs• Gene- and vector-based delivery of IgGs

Oncology Antibodies

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LM Strohl

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Format Phase 1 / 2 Phase 3 Approved Totals

Targeted Naked IgGs, Fragments,

Fc fusions

93 15 13 121

Naked IgGs, Fragments, Fc fusions

targeting “factors” (e.g. VEGF)

26 0 5 31

Checkpoint targets 78 2 6 86

Immunocytokines 9 2 0 11

ADCs 70 7 4 81

Radioimmunoglobulins 11 2 2 15

Bispecific Abs – direct targeting 26 0 0 26

Bispecific Abs – T cell redirection 35 0 2 37

Total antibodies 348 28 32 408

CAR-Ts 203* 0 2 205

Totals 551 28 34 613 (of 983 total)

Clinical Stage Antibodies and CARs in Oncology

* Note: One clinical CAR-T program targets HIV Database lock12/10/17 –©BiStro Biotech

Questions?

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# Target Primary indications Number of Approved and Clinical Candidates

ADC Bispecific* IgG CAR-T Other Total

1 CD19 B cell leukemias and lymphomas (e.g., DLBCL, ALL, CLL) 5 4 4 78 0 91

2 Her2 Breast cancer 8 7 6 7 0 28

3 EGFR Solid tumors (e.g., MCRC, HNC) 5 4 9 3 3 24

4 CD20 B cell leukemias and lymphomas (e.g., CLL, NHL, FL) 1 4 8 7 0 20

5 CD22 B cell leukemias and lymphomas (ALL, DLBCL, CLL, HCL) 4 1 1 13 0 19

6 BCMA Multiple myeloma 2 3 1 10 0 16

7 GD2 Solid tumors (e.g., neuroblastoma, osteosarcoma) 0 1 3 10 1 15

8 CD123 AML 2 3 1 6 1 13

9 Mesothelin Mesothelioma, ovarian, pancreatic cancers 3 0 1 9 0 13

10 CD33 AML, other myeloid malignancies 2 2 1 5 1 11

11 CD30 Hodgkin’s Lymphoma 1 1 0 8 0 10

12 MUC1 Solid tumors (e.g., ovarian, liver, pancreatic, lung cancers) 1 1 3 3 1 9

13 CEA Solid tumors (e.g., GI cancers, MCRC 0 3 1 3 2 9

14 EGFRvIII Glioblastoma, pancreatic cancer 1 0 1 6 0 8

15 Glypican Hepatocarcinoma and other solid tumors 0 1 1 6 0 8

16 PSMA Prostate cancer 1 2 0 3 2 8

17 CD38 Multiple myeloma 0 1 3 3 0 7

18 EpCAM Solid tumors (e.g., liver, stomach, pancreatic, breast

cancers

1 1 1 3 0 6

Top targets for direct killing of cancer cells

Database lock 12/10/17 –©BiStro Biotech

* Not including 37 CD3s, found in T cell redirecting bispecifics

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Target Activity Indication area Clinical Candidates Approved Totals

PD-1 Antagonists Oncology 19 2 21

Agonists Immunology 1 0 1

OX40 Antagonists Immunology 3 0 3

Agonists Oncology 9 0 9

CD28 Antagonists Immunology 3 0 3

Agonists Oncology 1 0 1

GITR (TNFRSF18) Antagonists Immunology 0 0 0

Agonists Oncology 8 0 8

CD40 Antagonists Immunology 7 0 7

Agonists Oncology 7 0 7

CD40-ligand Antagonist Immunology 2 0 2

CD80/86 Antagonists Immunology 0 2 2

CTLA4 Antagonists Oncology 3 1 4

PD-L1 Antagonists Oncology 0 3 3

PD-L2 Antagonists Oncology 1 0 1

B7H3 Antagonists Oncology 4 0 4

Tim3 Antagonists Oncology 3 0 3

LAG3 Antagonists Oncology 3 0 3

VISTA Antagonists Oncology 1 0 1

TIGIT Antagonists Oncology 2 0 2

LIGHT Antagonists Oncology 1 0 1

CD47 Antagonists Oncology 4 0 4

NKG2A Antagonists Oncology 1 0 1

NKG2D Antagonists Immunology 1 0 1

B7RP Antagonists Immunology 1 0 1

ICOS-ligand Antagonist Immunology 1 (part of bispecific) 0 1

BAFF/BLyS Antagonists Immunology 4 3 7

KIR3DL2 Antagonists Oncology 1 0 1

KIRs Antagonists Oncology 1 0 1

ICOS Agonists Oncology 3 0 3

CD137 Agonists Oncology 2 0 2

CD27 Agonists Oncology 1 0 1

Totals -- -- 98 11 109

Current Clinical-stage and Approved Check-point-targeting Antibodies for allIndications

Database lock12/10/17 –©BiStro Biotech

Kill cells:• ADCC – Antibody-dependent cellular cytotoxicity (typically NK, monocyte driven)• ADCP – Antibody-dependent cell phagocytosis (typically MAC and PMN driven)• T/NK/PMN/MO cell directed or redirected killing• Complement mediated cell death• Apoptotic programmed cell death• Non-apoptotic programmed cell death• Immunogenic cell death (ICD)• Necrotic cell death• Antibody-drug conjugate-directed killing

Modulate immune set-point:• Block cytokine-receptor interaction• Inhibit migration of immune cells• Down-regulate immune receptor• Immune checkpoint inhibition• Immune checkpoint activation• Block cell-cell signaling • Block APC MHC/TCR signal

Modular physiological set-point:• Inhibit physiological pathway• Block intracellular signaling• Block ligand-receptor interaction• Agonize receptor in place of ligand• Allosterically modulate receptor in

presence of ligand

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Target Selection for Biologics – What kinds of activities?

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gImmunogenic Cell Death (ICD)-inducing Molecules

Significance: Cancer cell death followed by stimulation of adaptive immune responseInducers of ICD: Classic cytotoxic molecules: e.g., doxorubicin, oxaliplatin, mitoxantrone,

bleomycin, bortezomibPotential antibody approaches to maximize ICD:

• ICD Chemo-inducer + anti-PD-1, CTLA4, PD-L1• ICD Chemo-inducer + anti-CD96• ICD Chemo-inducer + anti-SEMA4D or anti-CSF1• ICD Chemo-inducer + Oncolytic vaccinia virus

Trial Watch: Immunogenic cell death inductionby anticancer chemotherapeuticsA.D. Garg et al. (Guido Kroemer)OncoImmunology, 2017

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Four basic forms of multi-specific antibodies

1. Bivalent, bispecific IgG-like antibodies with heteromeric heavy chains (e.g., Duobody, knobs-into-holes, Triomab, etc):

2. Engineered antibody fragments linked by short peptide linkers which can be made into bivalent, trivalent, or tetravalent formats addressing two to three targets (e.g., BiTE/BiKE, DARTs, TandAbs):

3. Tetravalent multispecific antibodies that are essentially IgGs with other binding domains fused to either the N- or C-termini of either the heavy or light chains (e.g., DVD, Mabtyrin, FynomAb).

4. IgGs to which additional binding sites have been added within the structure (e.g., Genentech two-in-one Abs, F-STAR)

“hole” “knob”

Triomab KIH Duobody

DVD MAbtyrin

TandAbBiTE

DART

2-in-1 F-STAR

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a-EpCAM

MouseIgG2a

a-CD3

RatIgG2b

IgG-scFv fusion

S-S

HOOC COOH

2HN NH2

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Antibody Engineering coupled with multispecific antibodies to address biology and multiple targets simultaneously (75 total)

Cancercell

IgG-scFv fusionDuobodies

Bivalent,bispecific

Tetravalent,bispecific

T cell redirection• Silenced Fc (safety)

Targeting multiple soluble ligands• Elongated half-life

potential

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Cancer cell

T cell

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38 redirected BispAbs(37 T cells, 1 NK cell)

Bacterial antigens (1)

12 targeting twodifferent targets

on same cell

2 targetingsame targetson same cell

9 targeting cellsurface target &

soluble target

10 targetingtwo soluble

targets

3 targetingnanoparticle

and cell target

• Often times including higher ADCC, ADCP, and/or CDC

IBC Antibody Engineering Meeting Highlights

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gNumber of “Mentions” in Talks Given at 2017 Antibody Engineering and Therapeutics Meeting

Broad Categories Number of talks

Cancer antibodies, cancer therapy 34

T cells and NK cells (including innate vs adaptive immunity, checkpoints, etc) 25

Antibody structure/function; engineering (including pH dependent binding, Fc

engineering, glycoengineering, stability/developability, bispecific antibodies)

21

Localized delivery; Targeting antibodies to compartments (BBB, intracellular,

lungs, local activation)

9

Targets, target identification, immunome, surface-ome 7

Immune responses and anti-inflammatory antibodies 7

Tumor microenvironment, targeting TME, TME components 7

Antibodies for neurological disorders including Alzheimer’s disease 7

Antibody drug conjugates 6

Antibodies targeting viruses 5

Developability, biophysical, biochemical, PTMs 4

Antibody discovery including libraries, display systems, etc 4

Antibodies for metabolism and cardiovascular indications 3

Delivery of antibodies by nucleic acid- or vector-based approaches 3

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gSignificant Themes

1. T cells, T cells, T cells• Depletion of Tregs, even if the research did not start out that way…• Activation of CD8+ T cells• Sequencing and mining TCRs for libraries and information

2. Localized delivery• BBB• Lung• Intratumoral antibody delivery• Virus to tumor to produce antibody locally• AAV to brain• Intracellular antibodies• Gene based approach to antibody delivery

3. Big target and antibody data (-omes, repertoires, deep sequencing, etc)• Mining and understanding data from enormous data sets• Turning big data into real antibody/target solutions• Human antibody repertoire mining including surface-ome, antibody epitopes• Computational approaches• TCR mining for novel therapeutic approaches

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gSignificant Themes

4. Oncology approaches• Turning cold tumors into hot tumors• DC activity link key to adaptive immunity• Checkpoints beyond PD-1 – especially OX40, GITR, etc• Combining X with checkpoints, where X = ADCs, Oncolytic viruses, cancer vaccines, etc• Next generation approaches including multiple checkpoint targeting• Targeting repressive cell types: Tregs, MDSCs, ILCregs (NKregs), Bregs

5. Antibodies for neurological disorders – growing rapidly• Still need to solve the BBB issue; 2-3 % of injected dose/g brain tissue might be the key number• Interest in solving neurobiology problems using antibody approaches is growing• Antibody approaches to tackle Proteinopathies

6. Antibody engineering is becoming more sophisticated• pH/pI engineering to optimize target removal• Targeting individual FcgRs or only complement• Hexamer formation for agonist effects• Glycan analysis and engineering for enhanced effector function• Bispecific antibodies• Novel antibodies including Nanobodies nearing approval and bispecific Probodies• Half-life extension approaches

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gSignificant Themes

7. Antibody drug conjugates• Broadening of uses, including targeting tumor associated vasculature• Different forms of ADCs – including superoxide

8. Discovery approaches, processes• Libraries• Paired VH/VL repertoires• Selecting for biophysical properties in discovery

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gBiStro’s Biased Highlights

1. Impressive “big data” approaches to mine human antibody repertoire, targets, TCRs, etc– Jim Crowe and several others

2. pH/pI, and TwoB engineering of Abs to remove high concentration antigens – Kenta Haraya, Taichi Kuramochi

3. 2-3% injected dose/gram – perhaps the magic number for BBB – will this become a standardin the future? - Bill Pardridge, Jasi Atwall

4. Treg depletion intratumorally, but not necessarily systemically and with reagents that perhaps“could” but did not reduce CD8+ T cells – Frederick Arce Vargas and several other presentations

5. Targeting not only cancer cells, but the neovasculature that supports them, appears to increaseefficacy in anti-tumor approach – Mitko Dimitrov

6. NOD201 – pan-integrin targeting and its possibility as a universal “combinator” for solid tumorantibody therapy – Jennifer Cochran

7. Coupling of innate to adaptive responses exemplified by anti-CD47 approach, involving DC uptakeof mitochondrial DNA – Yang-Xin Fu

8. Targeting of TNFR-related checkpoints – Nicholas Wilson, Rony Dahan, Greg Lazar

9. ILC regulatory cells (a new class of repressive cells in tumors?) – Sarah Crome

10. Hexamerization of anti-OX40 agonist – Greg Lazar

Questions?

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