A new platform of personalized neoantigen cancer vaccines directed by checkpoint inhibitor antibodies to improve cancer immunity
Y. Mishima1, F. Isoda1, N. Matsumoto1, K. Hiranuka1, T. Yamada1, N. Fujinami2, M. Shimomura2, T. Suzuki3, T. Nakatsura2, N. Nakamura1
1 BrightPath Biotherapeutics Co., Ltd., Kawasaki, Japan, 2 Exploratory Oncology Research & Clinical Trial Center,
National Cancer Center, Chiba, Japan, 3 Department of Pharmacology, School of Medicine, Teikyo University, Tokyo, Japan

Results

Personalized neoantigen vaccines havedemonstrated robust tumor-specific immunityand preliminary evidence to cure patients withmelanoma and other cancers. To improve theefficacy of personalized cancer vaccine, weherein, describe a novel vaccine platform using
neoantigen peptides that contain a high affinity
binding motif for dendritic cells (DCs)-targeting
antibodies.

BP1209 vaccine accumulates in DCs via DCtargeting antibody

Dendritic cellDC-targeting
antibody

Fc-binding
motif (17aa)

XXX

vaccinepeptideX

CD8+ T cells

CD4+ T cells

Fc-binding motif (17 mer in red) non-covalently binds to Fc-region ofDC-targeting antibodies, resulting efficient antigen delivery to DC.

512312

Fluorescentvaccine

-

11.7

11.7-

11.7 11.7

α-CD40antibody-

polyICLC

88200-

83-

8Fig. 4200

88(µg/injection)

Fig. 2

Sensitivity%

Vaccine design
-

10.5-

10.5-

10.5-

10.5-

-

200200-

----

200

200

88888

Positeive100%

Negative
680%
60%

4829

3725

29

40%
20%
0%

55
110-1

2213

1-2
2-3
Algorithm Score

3-44-

Peptide-antibody binding is critical for enhanced
therapeutic potential of BP1209 vaccine

Mice were subcutaneously inoculated with EG.7 cells on day 0.
Anti-CD40 Ab was subcutaneously administrated with BP1209
OVA-vaccine or BP1209 OVA vaccine with mutations that
impair IgG binding capacity on day 4 and day11.
The mice treatedFig. 3polyICLC
with BP1209 vaccine
2000
OVA-BP1209 peptide
exhibited tumor
OVA-BP1209 peptide + αCD40
regression in all theOVA-BP1209 peptide
mice tested, while the1500(non-IgG-binding)
OVA-BP1209 peptide + αCD40
vaccine lacking IgG(non-IgG binding)binding property didvaccine
1000
not, suggesting thatvaccineenhanced antitumor
500
efficacy results fromthe assembly ofpeptide-antibody
0051015complex (Fig.3).
Days after Inoculation

1000
800

polyICLC
vaccine600

Adpgk BP1209 peptide

vaccineAdpgk BP1209 peptide +mCD40Ab
Adpgk BP1209 peptide +Atezolizumab

400

Atezolizumab (IP)200

07142128

Days after Inoculation

6040

Area
Std. Error
95% CI
P value

200204060

80

0.68710.032190.6240 to 0.7502<0.0001100

100% - Specificity%BP1209 vaccines allow CTL immune-induction of
weakly immunogenic neoantigen epitopes
We analyzed the genomic
sequence of MC-38 tumor cells
and predicted thirty neoantigenepitopes. Their peptides inlength of 27aa with (BP1209
peptides) or without (SLPs)
IgG-binding motif weresynthesized. SLPs or antiCD40 Ab-conjugated BP1209
peptides were immunized
C57BL/6 mice with polyICLC
three times at weekly intervals.
CTL induction were analyzed
by ELISPOT using spleensfrom these mice. The BP1209
vaccines substantially induced
specific CTLs even in weakly
immunogenic epitopes at SLP
format (Fig. 5).

14000800

SLP vaccine(µg/injection)robust1200

100-Fig. 6

Japan and BrightPath Biotherapeutics.

HLA Tg mouse immune responseGroupBP1209 vaccine enhances in vivo CTL responseby combining with DC-targeting antibodies

polyICLC

Mice were subcutaneously inoculated with MC-38 cells on day 0,
then anti-CD40 Ab or Atezolizumab were subcutaneously
administrated with or without BP1209 vaccine against
neoantigen of Adpgk gene on day 4 and 11. The mice treatedwith BP1209 vaccine exhibited delayed tumor growth (Fig.6).
Notably, Atezolizumab conjugated BP1209 vaccine maintainedcomplete tumor regression in all the mice until study end (n=9).

*The study was approved by IRBs and GDS at both National Cancer Center

0BP1209 OVA vaccine
8exhibited an enhanced CTL
induction when administrated
6with anti-CD40 Ab or
4
atezolizumab. Vaccine pepitde
without binding ability had
2limited response evenadministered with these0
antibodies, suggesting OVA peptide(BP1209 format)
that vaccine-antibody
OVA peptide
binding is critical for(non-IgG-binding)enhanced immuneαCD40 mAb
Atezolizumabinduction (Fig.2)

We conducted neoantigen prediction from tumor tissues frompatients with hepatocellular carcinoma (HCC) and metastatic
colorectal carcinoma (mCRC) using our prediction pipeline(Fig.4 left) and validated its accuracy by in vivo vaccination
experiments with four types of human leukocyte antigen (HLA)transgenic mice. By evaluation of a total of 275 epitopes, we
successfully demonstrated capability of our pipeline to predict
neo-peptides (AUC = 0.687, p<0.0001).

NGSFAM+ cells in DC (%)

10BP1209 neoantigen vaccine exertedantitumor effect in therapeutic setting

Fig. 5Conclusion

 BP1209 vaccine dramatically enhanced CTL inductionand exhibited robust anti-tumor effect in vivo.
 Enhanced antitumor efficacy required the binding
ability of peptides to IgG.
 We developed neoantigen prediction pipeline andvalidated the accuracy by the analysis using patientderived neoantigen and HLA transgenic mice.

800

ELISPOT spot number / 2x106 splenocyte

Schematics of BP1209 vaccine

15Tetramer+ cell/CD8+T cell (%)

We developed a novel vaccine platform(BP1209 vaccine) in which we employedpeptides consisting of a neoantigen-epitope andan IgG binding motif. The peptides form adivalent peptide complex per antibody moleculeby simply mixing with therapeutic antibodies inphysiological condition. Initially, we selectedovalbumin (OVA) as a model antigen andevaluated the efficacy of this vaccine format in
combination with dendritic cell (DC)-targeting
antibodies in vivo. Next, we generated series of
neoantigen peptides in both human and murine
origins using in-house bioinformatic algorithms
and evaluated the advantages of this vaccine
platform.

cDC2

cDC1

20Tumor volume (mm3) ± SEM

Methods

BP1209 vaccine peptide
was fluorescently labeled
and inoculated
subcutaneously with orwithout anti-CD40 antibody.
Six hours later, proximal
lymph nodes were resected
and the peptide uptake into
cDC1 and cDC2
in the lymph nodes wasevaluated by flow cytometry,
confirming enhanced
uptake of the BP1209
vaccine into DCs (Fig. 1).

Fig. 1Development of tumor Neoantigen predictionpipeline and validation

Tumor volume (mm3)Background

Epitope Prediction

1005P700

 BP1209 vaccine provides an ideal option to improve
neoantigen vaccine therapy.

600
500
400

Disclosure300

Mishima Y.: Employee of BrightPath Biotherapeutics

200
100027mer
SLPsSLP

αCD40-conjugatedαCD40 AbBP1209 peptides
peptide+BP1209

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