boehringer ingelheim oncology...gerald d, et al. cancer res 2013;73:1649–57; 4. huang h, et al....

BOEHRINGER INGELHEIM ONCOLOGY

Clinical Development Pipeline

Contents

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10

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30

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32

34

Xentuzumab (BI 836845)

mRNA vaccine (BI 1361849)

VEGF/Ang2 inhibitor (BI 836880)

BET inhibitor (BI 894999)

PD-1 inhibitor (BI 754091)

LAG-3 inhibitor (BI 754111)

SMAC mimetic (BI 891065)

MDM2-p53 antagonist (BI 907828)

LRP5/6 antagonist (BI 905677) and LRP5 antagonist (BI 905681)

SOS1::KRAS inhibitor (BI 1701963) 22

SIRPα antagonist (BI 765063)20

MEK inhibitor24

STING agonist 26

TRAILR2/CDH17 antibody (BI 905711)28

KISIMA cancer vaccine (ATP-128)30

DLL3/CD3 bispecific antibody32

Abbreviations 34

These are investigational compounds and are not approved; their safety and efficacy

have not been established.

2 These are investigational compounds and are not approved; their safety and efficacy


References

1. Weroha SJ, Haluska P. J Mammary Gland Biol Neoplasia 2008;13:471–83; 2. Li R, et al. J Med Chem 2009;52:4981–5004;

3. Friedbichler K, et al. Mol Cancer Ther 2014;13:399–409; 4. Schillaci R, et al. Br J Haematol 2005;130:58–66; 5. Sachdev D,

Yee D. Mol Cancer Ther 2007;6:1–12; 6. LeRoith D, Roberts CT Jr. Cancer Lett 2003;195:127–37; 7. Denduluri SK, et al.

Genes Dis 2015;2:13–25.

XentuzumabA humanized IgG1 monoclonal antibody against IGF-1 and IGF-2 ligands

Mode of action Key information

Clinical development

Xentuzumab is a humanized IgG1 monoclonal antibody that binds to IGF-1

and IGF-2 with high affinity, preventing activation of IGF-1R and IR-A,

respectively.1–3

Increased expression of IGF-1 and IGF-2 is implicated in tumor proliferation,

migration and invasion; high IGF and IGF receptor expression is observed in

both solid tumors and hematological malignancies.4–6

Xentuzumab has shown potent anti-proliferative effects (low nmol/L EC50)

against a range of cancer cell lines, including NSCLC, SCLC, and multiple

myeloma.3

Ongoing clinical trials are evaluating xentuzumab for the treatment of patients

with breast cancer and NSCLC.

Scan for more information on these trials from ClinicalTrials.gov

IGF-1R

Growth/proliferation/survival

Tumor cell

IR-A IR-B

IGF-1

IGF-2

Glucosehomeostasis

Normal celle.g. muscle,

fat, or liver cell

Insulin

InsulinXentuzumab

Supporting citation: reference 7



References

1. Kowalczyk A, et al. Vaccine 2016;34:3882–93; 2. Sebastian M, et al. BMC Cancer 2014;14:748; 3. CureVac AG. RNActive®

cancer immunotherapies and prophylactic vaccine. http://www.curevac.com/rna-platform/rnactiver/ (Accessed: April 2019);

4. NCT00923312. https://clinicaltrials.gov/ct2/show/NCT00923312 (Accessed: April 2019); 5. Sebastian M, et al. J Clin

Oncol 2012;30(Suppl.): Abstract 2573.

mRNA vaccineBI 1361849: an mRNA-based vaccine with six mRNAs



BI 1361849 is an mRNA-based immunotherapeutic cancer vaccine that might

have the potential to mobilize the patient’s immune system to fight tumors.1

BI 1361849 consists of six mRNAs that code for six diff erent antigens, which are

frequently expressed in NSCLC: NY-ESO-1, MAGE C1, MAGE C2, TPBG (5T4),

survivin and MUC1.2 It is hypothesized that translation of encoded proteins

and presentation to APCs may lead to expansion of antigen-specific T and B

cells to give a balanced humoral cellular response to tumors.3

A Phase I/IIa trial with a BI 1361849 predecessor (NCT00923312, CV9201-003)4

demonstrated that antigen-specific immune responses occurred in 65% of

patients.5

BI 1361849 is being investigated in combination with durvalumab and

tremelimumab in a Phase I/II trial in NSCLC patients.

Scan for more information on this trial from ClinicalTrials.gov

BI 1361849 is an mRNA-based

immunotherapeutic cancer vaccine that

might have the potential to mobilize the

patient’s immune system to fi ght tumors.1

BI 1361849 consists of six mRNAs that code

expressed in NSCLC: NY-ESO-1, MAGE C1,

MAGE C2, TPBG (5T4), Survivin and MUC1.2

It is hypothesized that translation of

encoded proteins and presentation to

antigen-presenting cells may lead to

expansion of antigen-specifi c T and B cells

to give a balanced humoral cellular response

to tumors.3

A Phase I/IIa trial with a BI 1361849

predecessor (NCT00923312, CV9201-003)4

demonstrated that antigen-specifi c immune

responses occurred in 65% of patients.5

mRNA uptakeStimulation of innate immune systemTarget expression and presentationAdministration

Skin Antigen-presenting cell Lymph node Blood Target

Activation of adaptive immune systemExpansion of antigen-specific T- and B-cells

Balanced cellular and humoral immune response

Proteasome MHCI

Ribosome

Lysosome

TLR

MHCII

Cytokine releaseMemory

B-cell

mRNA-encodedantigen

B-cell

helper T-cell

T-cell

Cytokine help

CD8+

CD4+

Memory T-cell

CTLs

Plasma cells

Tumor

Virus

mRNA uptakeStimulation of innate immune systemTarget expression and presentationAdministration

Skin APCs Lymph node Blood Target

Activation of adaptive immune systemExpansion of antigen-specific T and B cells

Balanced cellular and humoral immune response

Proteasome MHCI

Ribosome

Lysosome

TLR

MHCII

Cytokine releaseMemory

B cell

mRNA-encodedantigen

B cell

Helper T cell

T cell

Cytokine help

CD8+

CD4+

Memory T cell

CTLs

Plasma cells

Tumor

Virus



References

1. Hofmann I, et al. Presented at the 8th Euro Global Summit on Cancer Therapy 2015; poster; 2. Fukumura D, et al.

Nat Rev Clin Oncol 2018;15:325–40; 3. Gerald D, et al. Cancer Res 2013;73:1649–57; 4. Huang H, et al. Nat Rev Cancer

2010;10:575–85; 5. Girard N, et al. J Clin Oncol 2020;38(Suppl. 15): Abstract 9566 and poster.

VEGF/Ang2 inhibitorBI 836880: a humanized bispecific nanobody against VEGF and Ang2



BI 836880 is a humanized bispecific nanobody® comprising blocking domains

for VEGF and Ang2 and an additional portion for extending the half-life.1

BI 836880 potently and selectively inhibits VEGF and Ang2.1

Signaling via VEGF and Ang2 have different but complementary functions

in tumor angiogenesis.2,3 Ang2 interrupts signaling via Tie2, allowing the

destabilization of established blood vessels. This promotes remodeling and

is a prerequisite for sprouting angiogenesis.3,4 Signaling via VEGF regulates

endothelial cell proliferation and migration, and vessel sprouting.3,4

Dual blockade of signaling via VEGF and Ang2 is itself a promising anti-angiogenic

strategy for cancer therapy.2 Combined inhibition of VEGF, Ang2 and PD-1 has

potential for complementary antitumor effects, namely increasing vascular

normalization and promoting an antitumor immune response.

BI 836880 showed tumor growth inhibition and inhibition of angiogenesis

in vivo.1

BI 836880 is being investigated in clinical studies as a monotherapy and in

combination with the PD-1 inhibitor BI 754091.

Initial results from a Phase Ib study of BI 836880 in combination with BI 754091

showed the combination has a manageable safety profile in patients with

advanced non-squamous NSCLC; preliminary antitumor activity was also

observed.5


Maturedendritic cell

Anti-angiogenic normalization of tumor vasculature

Reprogramming the tumor microenvironment

of VEGF and Ang2 inhibiting VEGF and Ang2

BI 836880

Adding PD-1 inhibitor drives T-cell mediated tumor cell death

BI 754091

Tumor cell

CD8+ T cell

Treg cellImmaturedendritic cell

Myeloid-derived suppressor cell

BI 836880

VEGF Ang2

VEGFR2

Endothelial cell membrane

Tie2

Dying tumor cell

M1 tumor-associated

macrophage(antitumor)

M2 tumor- associated

macrophage(pro-tumor)

Supporting citations: references 1–4



References

1. Tontsch-Grunt U, et al. Presented at AACR-NCI-EORTC 2015; Abstract B79 and poster; 2. Tontsch-Grunt U, et al.

J Clin Oncol 2016;34(Suppl.): Abstract 11574; 3. Doroshow DB, et al. Ann Oncol 2017;28:1776–87; 4. Fu LL, et al.

Oncotarget 2015;6:5501–16; 5. Xu Y, Vakoc CR. Cold Spring Harb Perspect Med 2017;7:pii: a026674; 6. Aftimos PG,

et al. J Clin Oncol 2017;35(Suppl.): Abstract 2504.

BET inhibitorBI 894999: a small molecule inhibitor of the BET protein family



BI 894999 is an oral, potent, and selective inhibitor of the BET family of

bromodomain-containing proteins that bind to acetylated histones, inducing

transcription.1–3

Inhibition of BRD4, a member of the BET family that is considered a key

epigenetic regulator, triggers suppression of target gene transcription, e.g. the

oncogene Myc.1–3

BRD4 deregulation is implicated in a number of hematological and solid tumors

such as NUT carcinoma.4,5

BI 894999 is highly active in vitro and in vivo in hematological malignancies

and solid tumors.1,2,6

BI 894999 is being investigated in a Phase I study as a single agent in patients

with advanced solid tumors.


Tumor cell

Nucleus

Chromatin

Histones

Histones

CTD

BET(BRD4)

DNA

Target genes

e.g. C-Myc

mRNA

Cyclin T

Target genes

BET(BRD4)

Cyclin T

BI 894999

Supporting citations: references 2, 6



References

1. Zettl M, et al. Presented at the Annual Meeting of the American Association for Cancer Research 2018; Abstract 4558

and poster; 2. Martinez-Lostao L, et al. Clin Cancer Res 2015;21:5047–56.

PD-1 inhibitorBI 754091: a monoclonal antibody blocking the PD-1 receptor from interaction with its ligands PD-L1 and PD-L2

Mode of action

BI 754091 is a humanized PD-1-targeting monoclonal antibody that blocks the

interaction between PD-1 and its ligands, PD-L1 and PD-L2.1

T cells are inactivated by the interaction of PD-1 and PD-L1. BI 754091 blocks

the interaction of PD-1/PD-L1, leading to activation of T cells.1 Activated T cells

can secrete, for example, perforin and granzyme B to kill tumor cells.2

Inactive T cell

Tumor cell

Tumor cell death

PD-1

PD-L1

TCR

MHC

Active T cell

Inhibitory signal

Antigen

Cytotoxic granules

BI 754091

BI 754091



BI 754091 is being investigated as monotherapy and as a backbone combination

partner for multiple immuno-oncology approaches.


Key information

BI 754091 is a backbone combination partner for multiple immuno-oncology

approaches to cancer treatment.



References

1. Zettl M, et al. Presented at the Annual Meeting of the American Association for Cancer Research 2018; Abstract 4547

and poster; 2. Turnis ME, et al. Eur J Immunol 2015;45:1892–905; 3. Johnson ML, et al. J Clin Oncol 2020;38(Suppl. 15):

Abstract 3063 and poster; 4. Kang Y-K, et al. J Clin Oncol 2020;38(Suppl. 15): Abstract 3054 and poster.

LAG-3 inhibitorBI 754111: a monoclonal antibody blocking the interaction between LAG-3 and MHC class II



BI 754111 is a humanized LAG-3-targeting monoclonal antibody that inhibits

the interaction between LAG-3 and MHC class II.1

LAG-3 is an immune checkpoint receptor located on the surface of T cells in

the tumor microenvironment.2 MHC class II molecules on the surface of tumors

present antigens that are recognized by T-cell receptors, initiating a signaling

pathway that promotes an adaptive immune response to the tumor.2

In the presence of an antigen, LAG-3 binds to the MHC class II molecule on

the tumor cell, starting a signaling cascade that reduces T-cell activation

and proliferation. LAG-3 inhibition may be able to restore T-cell activation,

enabling an improved immune response to the tumor.2

Combined targeting of PD-1 and LAG-3 may have a synergistic effect,

reactivating the T-cell response in the tumor microenvironment.

BI 754111 is being investigated in combination with the PD-1 inhibitor BI 754091

in patients with solid tumors, and in combination with the PD-1 inhibitor BI 754091

and the MDM2-p53 antagonist BI 907828.

Analysis of data from three Phase I and one Phase II trials investigating BI 754111

in combination with BI 754091 in patients with advanced solid tumors showed

that treatment was relatively well-tolerated with a safety profile similar to other

checkpoint inhibitors.3 Treatment was also well-tolerated in Asian patients and

preliminary signs of antitumor activity were observed.4


Inactive T cell

Tumor cellAPC

Antigen

Inhibitory signal

MHCII

TCR

LAG-3PD-1

PD-L1

Active T cell

Tumor cell deathAPC

Cytotoxic granules

BI 754111 BI 754091

BI 754091

BI 754111




References

1. Bai L, et al. Pharmacol Ther 2014;144:82–95; 2. Impagnatiello MA, et al. Presented at the Annual Meeting of the

American Association for Cancer Research 2017; Abstract 2330 and poster; 3. Turnis ME, et al. Eur J Immunol 2015;

45:1892–905; 4. Zettl M, et al. Presented at the Annual Meeting of the American Association for Cancer Research 2018;

Abstract 4558 and poster; 5. Beug ST, et al. Nat Commun 2017;8:14278.

SMAC mimeticBI 891065: a small molecule that induces degradation of cIAP

Mode of action


SMAC is a pro-apoptotic mitochondrial protein that is released into the cytosol

in response to cellular stress.1 SMAC binds directly to some members of the

IAP family, and induces the degradation of other IAPs.1

BI 891065 (a SMAC mimetic) and BI 754091 (a PD-1 inhibitor) have been shown,

in preclinical studies, to work together to re-activate and amplify the immune

response to tumor cells.2 Together, the compounds initiate a ‘virtuous cycle’

consisting of a first and second Punch.

First Punch: SMAC mimetics bind to cIAP1, inducing degradation of cIAP

proteins and activating caspase-8 provoking tumor cell death.1 This marks

the first step in a set of events resulting in an anticancer immune response:

the ‘First Punch’.2

Second Punch: T cells in the tumor microenvironment have been shown

to express high levels of PD-1 and often exhibit an ‘exhausted’ phenotype,

with an inability to control tumor growth.3

Combined therapy with BI 754091, which blocks the interaction between

PD-1 and its ligands, PD-L1, and PD-L2,4 has been shown to re-activate

these T cells in preclinical studies.2 This reactivation enables potent T cell-

mediated eradication of tumor cells,2 and delivers the ‘Second Punch’ of

the immune response.

BI 891065 is being investigated in combination with the PD-1 inhibitor BI 754091

in Phase I studies in patients with solid tumors.


PD-1 inhibitor

CD8+ T cell

Active T cell

Immature dendritic cell

Mature dendritic cell

DAMPs/tumor antigens

Dying tumor cell

Tumor cell

SECOND PUNCHT-cell-mediated

cancer cell killing

FIRST PUNCHImmunogenic cell death

T-CELL ACTIVATION

Circulation

Tumor

Lym

ph n

ode

DENDRITIC CELL

ACTIVATIONBI 891065

BI 891065

BI 754091

ADDITION OF PD-1 INHIBITORPOTENTIATES

SECOND PUNCH

Cytotoxicgranules

BI 754091

Tumor cell Dying tumor cell

PD-1

PD-L1

TCR

Antigen

MHC

Inactive T cell Active T cell

Supporting citations: references 2, 4, 5



References

1. Rudolf D, et al. Presented at the Annual Meeting of the American Association for Cancer Research 2018; Abstract 4868 and poster; 2. Boehringer Ingelheim. Data on file; 3. Nag S, et al. J Biomed Res 2013;27:254–71; 4. Landré V, et al. Oncotarget 2014;5:7988–8013; 5. Rinnenthal J, et al. Presented at the Annual Meeting of the American Association for Cancer Research 2018; Abstract 4865 and poster; 6. Wang HQ, et al. Presented at the Annual Meeting of the American Association for Cancer Research 2018; Abstract 5560 and poster; 7. Guo G, et al. Cancer Res 2017;77:2292–305; 8. Zhao Y, et al. Acta Biochim Biophys Sin (Shanghai) 2014;46:180–9; 9. Montes de Oca Luna R, et al. Nature 1995;378:203–6.

MDM2-p53 antagonistBI 907828: a small molecule inhibiting the interaction between MDM2 and p53



BI 907828 is a small molecule MDM2-p53 antagonist1 that may promote

p53-mediated cell cycle arrest and apoptosis.2

In human cancers, the TP53 gene encoding the tumor suppressor p53 is

frequently mutated or deleted, or the function of wild-type p53 is inhibited by

high levels of MDM2, a negative regulator of p53, which leads to downregulation

of the p53 pathway.3

BI 907828 blocks the interaction between MDM2 and p53 by binding to free

MDM2.2 p53 signaling contributes to the regulation of multiple cellular processes,

including progression through the cell cycle, DNA repair, senescence, and

apoptosis.3,4

BI 907828 induced tumor regression in TP53 wild-type models of various

tumor types (e.g. acute myeloid leukemia, osteosarcoma, dedifferentiated

liposarcoma, NSCLC and brain tumors).1,2,5

The pharmacological properties of BI 907828 allow for high-dose intermittent

schedules that are expected to mitigate on-target thrombocytopenia (class

effect).5 In preclinical models, BI 907828 penetrated the blood–brain barrier.2

The immunomodulatory properties of MDM2-p53 antagonists support combination

with PD-1 inhibitors.6,7

BI 907828 is being investigated as a monotherapy in patients with TP53

wild-type-enriched solid tumors in a Phase I trial. A Phase I trial of BI 907828

in combination with the PD-1 inhibitor BI 754091 and the LAG-3 inhibitor

BI 754111 in patients with advanced solid tumors is also ongoing.


Dying tumor cell

Memory T cell

Decrease in Treg population

p53 wtMDM2

Nuclear translocation

p53 degradation

p53

MDM2 p53 wt

p53

Target gene induction

Apoptosis/cell cycle arrest/ senescence/DNA repair

+ PD-1 inhibitor

Non-inflamed tumor microenvironment Immuno-modulation

BI 907828

BI 907828

BI 754091

Tumor cell

CD8+ T cell

Treg cell

1

Increase in CD8+ T-cell population

2

Induction of antitumor immune memory

3

Tumor cell

Supporting citations: references 1, 3, 5–9



References

1. Fuerer C, et al. EMBO Reports 2008;9:134–8; 2. Boehringer Ingelheim. Data on file; 3. Zinzalla V, et al. Presented at

the Annual Meeting of the American Association for Cancer Research 2019; Abstract DDT01-01 and presentation;

4. Zhan T, et al. Oncogene 2017;36:1461–73; 5. National Cancer Institute. RNF43. https://portal.gdc.cancer.gov/genes/

ENSG00000108375 (Accessed: February 2020).

LRP5/6 antagonist and LRP5 antagonist Humanized nanobodies consisting of blocking domains for the Wnt ligand co-receptors LRP5 and LRP6 (BI 905677) or LRP5 (BI 905681)



BI 905677 and BI 905681 both act by inhibiting Wnt/β-catenin signaling.

BI 905677 is a humanized bispecific nanobody consisting of blocking domains

for the Wnt ligand co-receptors LRP5 and LRP6. BI 905677 binds to LRP5 and

LRP6 with high affinity, blocks binding of Wnt ligands, and inhibits Wnt ligand/

β-catenin-driven cancer proliferation and survival.1–3 Wnt/β-catenin signaling

activation was shown to drive resistance to checkpoint inhibitors through loss

of dendritic cell function and T-cell exclusion, which is blocked by BI 905677.

LRP5/6 antagonist (BI 905677): cancer cell-targeted mode of action3,4

BI 905681 is a humanized nanobody monotargeting LRP5 that blocks the

binding of Wnt ligands to LRP5, thereby inhibiting Wnt ligand/β-catenin-driven

tumor cell proliferation and survival.1,2

RNF43-inactivating mutations and R-spondin-3 fusion transcripts (genomic

alterations driving ligand-dependent Wnt/β-catenin signaling activation) have

been identified in a subset of solid tumors.3,5

Preclinical data have shown that BI 905677 potently and selectively blocks

ligand-dependent Wnt signaling and induces tumor growth inhibition in

RNF43 mutation-positive and R-spondin-3 fusion-positive tumors.3

BI 905667 and BI 905681 are currently undergoing clinical investigation as

monotherapy in patients with advanced solid tumors.

Scan for more information on the BI 905667 trial from ClinicalTrials.gov

Scan for more information on the BI 905681 trial from ClinicalTrials.gov

Wnt/β-catenin signalingWnt/β-catenin signaling

β-cateninβ-catenin

β-catenin

β-catenin

Cancer proliferation and survival

Cancer proliferation and survival

LRP5/6 LRP5/6

Frizzled

WntBI 905677



References

1. Evelyn CR, et al. Chem Biol 2014;21:1618–28; 2. Hofmann, MH et al. Mol Cancer Ther 2019;18(12 Suppl): Abstract PL06-01

and presentation; 3. Hofmann, MH et al. Poster presented at AACR Annual Meeting 2020.

SOS1::KRAS inhibitor BI 1701963: a small molecule that binds to SOS1, reducing the formation of active, GTP-loaded KRAS


KRAS functions as a molecular switch, existing in two states: the GDP-bound ‘off ’

state and the GTP-bound ‘on’ state. Active KRAS-GTP activates downstream

effector pathways, including the RAF/MEK/ERK pathway.1

The KRAS GDP–GTP cycle is regulated by guanine nucleotide exchange factors

(such as SOS1) which promote nucleotide exchange and formation of ‘active’

KRAS-GTP.1

SOS1::KRAS inhibitors bind to SOS1 and inhibit the interaction between KRAS and

SOS1 proteins, reducing the formation of GTP-loaded KRAS.1 SOS1 inhibitors

also antagonize the negative feedback relief induced by RAF/MEK/ERK pathway

inhibitors.2

KRAS is one of the most frequently mutated oncogenes with high prevalence

of alterations in pancreatic, colorectal, and non-small cell lung tumors.3

BI 1701963, a SOS1::KRAS inhibitor, is a first-in-class protein::protein interaction

inhibitor that prevents the association of KRAS with a key regulator, SOS1.3

BI 1701963 has shown broad activity against G12, G13 mutant KRAS alleles,

including the most prevalent G12C, G12D and G12V oncogenic variants.3

While SOS1 inhibition yields cytostasis in cancer cells addicted to KRAS signaling,

the synergistic combination of a SOS1 inhibitor with a MAPK pathway inhibitor

results in a more profound blockade of KRAS signaling. This provides a strong

rationale for development in combination with a MAPK pathway inhibitor.

BI 1701963 in combination with MEK inhibition has shown strong in vivo efficacy

in a broad range of tumor mouse models of KRAS-driven cancers and time- and

dose-dependent modulation of transcriptional target genes in the MAPK pathway.3

SOS1 inhibition also sensitizes KRAS mutant cancer cells to the effect of irinotecan;

BI 1701963 in combination with irinotecan also showed in vivo efficacy in tumor

mouse models.3

BI 1701963 is being investigated alone and in combination with a MAPK pathway

inhibitor in patients with KRAS mutation-positive solid tumors.

KRASGDP

KRASGTP

Proliferation/survival

Gene transcription

Active

MAPK pathway ‘ON’ MAPK pathway ‘OFF’

Inactive

Nucleus

Receptor tyrosine kinase


ERK

MEK

ERK

KRASGDP

KRAS

GTP


Apoptosis and tumor regression

Gene transcription

SOS1

MEKFeedback mechanism

SOS1::KRAS inhibitor

MAPK pathwayinhibitor

MAPK pathwayinhibitor

SOS1

Tumor cell







References

1. Boehringer Ingelheim. Data on file; 2. Barclay AN, et al. Nat Rev Immunol 2006;6:457–64; 3. Weiskopf K. Eur J Cancer

2017;76:100–9; 4. Gauttier V, et al. Cancer Res 2018;78(Suppl.): Abstract 1684.

SIRPα antagonistBI 765063: a monoclonal antibody blocking CD47/SIRPα interaction



BI 765063 is a first-in-class monoclonal antibody that blocks the interaction

between SIRPα on the surface of myeloid cells and CD47.1 CD47 is a ‘don’t eat

me’ signal that is expressed on the surface of tumor cells.2

The CD47/SIRPα axis is a regulator of macrophage and other myeloid cell

activation, serving as a myeloid-specific immune checkpoint.3 CD47/SIRPα

interaction inhibits phagocytosis of tumor cells.2,3 Blocking the interaction

between CD47 and SIRPα restores the immune functions of myeloid cells in

the tumor microenvironment, resulting in antigen uptake and presentation,

and linking the innate and adaptive immune systems.2,3

The link between innate and adaptive immunity points to combination therapy

with an adaptive immune checkpoint inhibitor.2,3 Preclinical studies in mouse

tumor models have demonstrated benefit of SIRPα inhibitor monotherapy.3,4

These studies also indicate that clinical outcomes may be enhanced through

combination therapy with a PD-1 inhibitor or with a costimulatory agent, such

as an anti-4-1BB monoclonal antibody, which would provide dual activation

of innate and acquired immunity.3,4

BI 765063 is being investigated as a single agent and in combination with the

PD-1 inhibitor BI 754091 in patients with advanced solid tumors.


Phagocytosis

SIRPα

CD47

Basal chemokine secretion

Modified chemokine secretion

Chemokine receptor

T-cell migration

Macrophagemigration

Tumor cell phagocytosis

Tumor cell

Macrophage

BI 765063

BI 765063

Supporting citations: references 1, 3, 4



References

1. Evelyn CR, et al. Chem Biol 2014;21:1618–28; 2. Boehringer Ingelheim. Data on file; 3. Lake D, et al. Cell Mol Life Sci 2016;

73:4397–413; 4. Hofmann MH, et al. Mol Cancer Ther 2019;18(Suppl. 12): Abstract C133.

MEK inhibitor BI 3011441: a small-molecule allosteric inhibitor that binds adjacent to the ATP pocket of MEK

Mode of action

MEK is a component of the MAPK pathway, a signaling cascade also involving

RAS and ERK that regulates gene expression, drives proliferation, and prevents

apoptosis.1

BI 3011441 (LNP3794) is a small-molecule allosteric inhibitor that binds adjacent

to the ATP pocket of MEK, resulting in inhibition of MEK activity.2 In tumor cells,

treatment with BI 3011441 results in downregulated MAPK pathway signaling,

reduced cell proliferation, and induction of apoptosis.2

MEK functions downstream of SOS1, KRAS, and RAF. MAPK pathway activity

is strictly regulated by the gatekeeper ERK, which also mediates negative

feedback loops within the MAPK pathway, for example by phosphorylation

of upstream components such as receptor tyrosine kinases, SOS1, and RAF.3

Drugs that selectively inhibit MEK are able to block MAPK pathway activity,

leading to reduced cell proliferation and cell death.

However, negative feedback resulting from MEK inhibition can lead to an

increase in SOS1-mediated KRAS activation, which subsequently results in

re-activation of the MAPK pathway.3

SOS1::KRAS inhibition reduces the formation of GTP-loaded, activated KRAS,

thereby inhibiting MAPK pathway signaling.4 By simultaneously blocking

the ERK-mediated negative feedback loop, SOS1::KRAS inhibition sensitizes

KRAS-dependent cancers to MEK inhibition, resulting in complete blockade

of the pathway and tumor regression in vivo.4

Further clinical studies of BI 3011441 in combination with a SOS1::KRAS inhibitor

are expected to commence at the end of 2020.2



Tumor cell

MAPK pathway

ERK

KRASGDP

KRASGTP


Apoptosis andtumor regression

Gene transcription

SOS1

MEK


MEK inhibitor




References

1. Foote JB, et al. Cancer Immunol Res 2017;5:468–79; 2. Vatner RE, Janssen EM. Mol Immunol 2017;110:13–23;

3. Boehringer Ingelheim. Data on file; 4. Barber GN. Nat Rev Immunol 2015;15:760–70.

STING agonist A small molecule agonist of the STING pathway



Stimulator of interferon genes (STING) is a signaling molecule that plays a

critical role in the cytosolic detection of tumor-derived DNA, i.e. in the sensing

of a tumor by our innate immune system.1,2

Once activated, the STING pathway induces transcription of Type I interferons

by intratumoral dendritic cells. This, in turn, promotes tumor antigen-specific,

T-cell priming and infiltration of cytotoxic T cells into the tumor microenvironment.1

STING is, therefore, a key precursor required for the activation of dendritic cells

that link the innate and adaptive immune responses to cancer.1,2

This compound is a small molecule agonist of the STING pathway. Preclinical

data show that intratumoral injection of a STING agonist activates dendritic

cells and APCs in the tumor microenvironment, inducing a systemic antitumor

immune response. These effects are increased in combination with an anti-PD-1

antibody.3

The first-in-human study of this compound as a single agent and in combination

with the PD-1 inhibitor BI 754091 in patients with advanced solid tumors is

planned to start in 2020.

T

Non-inflamed tumor microenvironment

Tumor-associated immune cells

Type I interferon secretion drives T-cell priming,

activation, and infiltration

T cell-infiltrated tumor microenvironment

Dying tumor cell

Active T cell

Dendritic cell

Immature dendritic

cell

Tumor cell

Tumor-derived DNA

cGAS

Cyclic dinucleotide

Target gene activation

STING STING agonist

+ PD-1 inhibitor

BI 754091

Supporting citations: references 1, 4




References

1. Garcia-Martinez JM, et al. Presented at the American Association for Cancer Research Annual Meeting 2019;

Abstract 2051; 2. Ashkenazi A, Dixit VM. Science 1998;281:1305–8; 3. Ashkenazi A, et al. J Clin Invest 1999;104:155–62;

4. Naval J, et al. Cancers (Basel) 2019;11: pii: E444.

TRAILR2/CDH17 antibody BI 905711: a bispecific antibody consisting of TRAILR2 and CDH17 binding domains



This compound is a tetravalent bispecific antibody that cross-links the

pro-apoptotic TRAILR2 receptor with CDH17, an anchor target in the tumor

cell membrane. CDH17-dependent clustering of TRAILR2 permits BI 905711

to selectively induce apoptosis in CDH17-expressing tumor cells.1

TRAILR2 is a pro-apoptotic receptor of the extrinsic apoptotic pathway and

is widely expressed on tumor cells.2,3 Clustering of TRAILR2 is required for

activation and downstream signaling.4 CDH17 is a cell adhesion protein that

was selected as the anchor target due to its restricted expression mostly on

malignant cells and, in particular, a lack of expression in normal liver tissue

that will potentially avoid the clinical hepatotoxicity associated with TRAILR2

agonism. This anchor protein makes this compound a targeted treatment

strategy for CRC and other CDH17-positive tumors.1

This TRAILR2/CDH17 antibody has shown in-vivo efficacy in xenograft models

of CRC, with tumor regression up to ~30 days. Reduction in tumor size correlated

with changes in markers of apoptosis.1

BI 905711 is being investigated in patients with advanced gastrointestinal cancers.

CDH17

No apoptosis induction

TRAILR2

Tumor-specific apoptosis induction

Tumor cell (CDH17 present)

Liver cell (CDH17 absent)

TRAILR2/CDH17 antibody





References

1. Boehringer Ingelheim. Data on file; 2. Boehringer Ingelheim. Press release. https://www.boehringer-ingelheim.com/

press-release/acquisitionamal-therapeutics (Accessed: February 2020); 3. AMAL Therapeutics. Therapeutic Vaccines.

http://amaltherapeutics.com/science/therapeutic-vaccines/ (Accessed: February 2020); 4. Belnoue E, et al. JCI Insight

019;4:e127305.

KISIMA™ cancer vaccine (ATP-128)A self-adjuvanting peptide vaccine built on the KISIMA® technology platform

Mode of action

Key information

This compound is a modular, self-adjuvanting, peptide-based cancer vaccine

that has the potential to strengthen the capability of the patient’s immune

system to recognize and kill tumor cells.1–3 Designed using the KISIMA technology

platform, the vaccine includes three components:1–3

• a cell-penetrating peptide for antigen delivery

• a multi-antigenic cargo that is tailored to raise an immune response against

colorectal tumors

• a toll-like receptor (TLR) peptide agonist as an adjuvant1–3

The cancer vaccine is engineered to induce an efficient immune response and

promote immunological memory via activation of cytotoxic T cells and helper

T cells.1–3

1. The cell penetrating peptide facilitates delivery of the vaccine into dendritic cells

2. The TLR component induces the upregulation of costimulatory molecules

activating dendritic cells

3. Cancer-specific antigens are processed and resulting epitopes presented

to T cells

4. Cytotoxic T cells become primed and educated to recognize and target tumor

cells and helper T cells become primed, triggering the release of cytokines

5. Cytokine release from T cells, as well as dendritic cells, leads to a cytotoxic

T-cell response

Preclinical evidence supports the immunogenicity of a previous generation of the

cancer vaccine in an in-vivo model of CRC.4 This leads to immunological memory

and high vaccine efficacy with increased intratumoral leukocyte infiltration.4

Combination with PD-1 blockade has been shown to have an additive effect

and to significantly increase the efficacy of the vaccine invivo.1 As the vaccine

enhances T-cell infiltration, this could sensitize tumors that are resistant to

PD-1 inhibition (some of which have been shown to have limited immune

infiltration) to checkpoint inhibitors.1,4

This self-adjuvanting peptide vaccine is being investigated as monotherapy

and in combination with the PD-1 inhibitor BI 754091 in patients with

histologically or cytologically confirmed Stage IV CRC.





References

1. Boehringer Ingelheim. Data on file; 2. Hipp S, et al. Cancer Res 2019;79(13 Suppl.): Abstract 549; 3. National Center for

Biotechnology Information. DLL3 delta like canonical Notch ligand 3 [Homo sapiens (human)]. https://www.ncbi.nlm.nih.gov/

gene/10683 (Accessed: February 2020); 4. Owen DH, et al. J Hematol Oncol 2019;12:61; 5. Saunders LR, et al. Sci Transl

Med 2015;7:302ra136.

DLL3/CD3 bispecific antibody A bispecific T-cell engager directed against tumors expressing DLL3


The DLL3/CD3 bispecific antibody functions as a T-cell engager, acting as a

bridge between DLL3-expressing tumor cells and cytolytic T cells.1,2

This compound has an extended half-life and directs activity of cytolytic T cells

selectively to DLL3-expressing tumors.1

The pharmacological effect of the DLL3/CD3 bispecific antibody depends on it

binding simultaneously to CD3 on T cells and to DLL3 expressed on tumor cells.1

DLL3 is an inhibitory Notch ligand that is expressed in tumors with a

neuroendocrine origin, such as SCLC and glioblastoma multiforme, but not

in normal adult tissue.3–5

Preclinical studies demonstrate the antitumor activity of the DLL3/CD3

bispecific antibody in a variety of DLL3-positive tumor models.2

The binding of the DLL3/CD3 bispecific antibody to CD3 may lead to PD-1

upregulation in activated T cells and PD-L1 upregulation on malignant cells.2

Preclinical evidence supports the combination of the DLL3/CD3 bispecific

antibody with PD-1 inhibitors in order to revert this upregulation.1,2

The first-in-human study of the DLL3/CD3 bispecific antibody is planned to

commence in 2020.1



DLL3/CD3bispecific antibodyDLL3/CD3

bispecific antibody

Inactive T cell

Tumor cell

Active T cell

Cytolyticsynapse

Cytolyticgranules

DLL3 DLL3

CD3 CD3

MAPK, mitogen-activated protein kinase

MDM2, murine double minute 2

MEK, mitogen-activated protein kinase

MHC, major histocompatibility complex

mRNA, messenger ribonucleic acid

MUC1, mucin 1

Myc, myelocytomatosis

NSCLC, non-small cell lung cancer

NY-ESO-1, New York esophageal squamous cell carcinoma 1

P, phosphate

PD-1, programmed cell death protein-1

PD-L1/2, programmed death-ligand 1/2

RAF, rapidly accelerated fibrosarcoma

RAS, rat sarcoma

RNA, ribonucleic acid

RNF, ring finger protein

SCLC, small-cell lung cancer

SIRPα, signal regulatory protein alpha

SMAC, second mitochondria-derived activator of caspases

SOS1, Son of sevenless homolog 1

STING, stimulation of interferon genes

TCR, T-cell receptor

Tie, tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains

TLR, toll-like receptor

TP53, tumor protein p53

TPBG, trophoblast glycoprotein

TRAILR2, tumor necrosis factor-related apoptosis-inducing ligand receptor

Treg, regulatory T cell

VEGF(R), vascular endothelial growth factor (receptor)

Wnt, wingless/integrated

Abbreviations

4-1BB, receptor belonging to the tumor necrosis factor superfamily

AC, acetylation

Ang, angiopoietin

APC, antigen-presenting cell

ATP, adenosine triphosphate

BET, bromodomain and extra-terminal domain

BRD4, bromodomain protein 4

CD, cluster of differentiation

CDH, cadherin

CDK, cyclin-dependent kinase

cGAS, cyclic GMP-AMP synthase

cIAP, cellular inhibitor of apoptosis

CRC, colorectal cancer

CTD, C-terminal domain

CTL, cytotoxic T lymphocyte

DAMP, damage-associated molecular pattern

DLL3, delta-like ligand 3

DNA, deoxyribonucleic acid

ERK, extracellular signal-regulated kinase

GDP, guanosine diphosphate

GTP(ase), guanosine triphosphate (hydrolase)

IAP, inhibitor of apoptosis

IGF, insulin-like growth factor

IGF-1R, insulin-like growth factor-1 receptor

IgG, immunoglobulin G

IR-A/B, insulin receptor A/B

KRAS, Kirsten rat sarcoma

LAG-3, lymphocyte activation gene 3

LRP, low-density lipoprotein receptor-related protein

MAGE, melanoma-associated antigen

34

Cancer takes. Takes away time. Takes away

loved ones. At Boehringer Ingelheim

Oncology, we are giving patients new hope,

by taking cancer on.

We are dedicated to collaborating with

the oncology community on a shared

journey to deliver leading science.

Our goal is treatment breakthroughs that

can transform the lives of patients and

help win the fight against cancer.

TAKING CANCER ON

Copyright © 2019 Boehringer Ingelheim International GmbH.

All rights are reserved. August 2020. Vault ID: SC-CRP-05037

To learn more about the Boehringer Ingelheim

Oncology Clinical Development Pipeline, please

speak to your local Boehringer Ingelheim contact

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