NEON-1: A first-in-human phase I open-label study of ALPN-202, a conditional CD28 costimulator and dual checkpoint inhibitor, in advanced ...
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2020 AACR Virtual Annual Meeting Abstract # 9972 NEON-1: A first-in-human phase I open- label study of ALPN-202, a conditional CD28 costimulator and dual checkpoint inhibitor, in advanced malignancies Jing Yang, Gary Means, Almudena Tercero, Kristi Manjarrez, Jan Hillson, Stanford L. Peng Alpine Immune Sciences, Inc., Seattle, WA
Author Disclosure ❑ All authors are employees of Alpine Immune Sciences, Inc.
ALPN-202: A Conditional CD28 Costimulator and Dual Checkpoint Inhibitor
PD-1/PD-L1 inhibitors fail to elicit anti-tumor activation ALPN-202 (CD80 vlgD-Fc*) mediates PD-L1-dependent
without adequate T cell activation CD28 costimulation along with PD-L1 and CTLA-4 inhibition
Approximately ~70% of Patients Receiving PD-1/L1 Therapy Do Not Respond Tumor cell
Tumor cell
Kamphorst AO et al, Science 2017 ;
Hui E et al, Science 2017
PD-L1 CD80/86
CD80/86 (B7)
Anti-PD-1 (B7)
PD-L1
ALPN-202
ALPN-202
CTLA-4 PD-1 CD28
CD28
CTLA-4
PD-1
Potential Potential Increased
T cell T cell T cell
activation inhibition activation
T cell T cell
*Effectorless IgG1 Fc
Means GD et al. Abstract 2016 USCAP 2020Three Primary Mechanisms of Action of ALPN-202:
Conditional CD28 costimulation and dual PD-L1/CTLA-4 inhibition
1. PD-L1 – PD-1 Antagonism 3. PD-L1-Dependent CD28 Costimulation
3000
100000
Fc Control
2000 ALPN-202
80000
Durvalumab (anti-PD-L1)
MFI
IL-2 (pg/mL)
1000 ALPN-202
60000
No PD-L1
Atezolizumab 40000
(anti-PD-L1)
Fc Control
20000
0
1 10 100 1000 10000 1000001000000
0
[pM] 10 100 1000 10000 100000
Conc (pM)
2. CTLA-4 – B7 Antagonism
60000
ALPN-202 + FR104 (anti-CD28)
60000 ALPN-202 + Durvalumab
50000
Durvalumab (anti-PD-L1)
ALPN-202
40000
IL-2 (pg/mL)
Fc Control
40000 30000
+ PD-L1
MFI
20000
ALPN-202
20000 10000
Ipilimumab
(anti-CTLA-4)
0
Fc Control 1 10 100 1000 10000 100000
0 Conc (pM)
1 10 100 1000 10000 1000001000000
[pM] Primary T cells + K562 ± hPD-L1ALPN-202 Exhibits Potent yet Well-Tolerated Anti-Tumor Activity in vivo
Monotherapy Efficacy Superior to
Safety in Nonclinical Studies
PD-L1 Inhibition Alone
2000
0/11 mice tumor free
• Well tolerated in rats and cynomolgus
Median Tumor Volume (mm3)
Fc Control
ALPN-202 monkeys (MTD not reached)
1500 durvalumab (anti PD-L1)
• No evidence of cytokine release or
p < 0.0001 systemic agonism at all dose levels up to
1000 ALPN-202 vs
150 mg/kg (rat) or 200 mg/kg (monkey)
durvalumab
2/11 mice tumor free
500 • No clinically-significant colitis or other
immune-related AEs as previously
0
8/11 mice tumor free reported with dual checkpoint blockade in
0 10 20 30 40 cynomolgus monkeys*
Dosing Day hPD-L1-MC38 Tumors
* Selby et al. PLoS One 11:e061779, 2016Study NEON-1: ALPN-202 in Advanced Malignancies (Phase 1)
Study Part A: Dose Escalation 20 mg/kg Study
Population 10 Endpoints
3 20 mg/kg
• Adults • Safety: DLTs,
1 10 adverse events,
• Advanced solid
0.3 3 immunogenicity,
malignancies and
cytokines
lymphoma
1
• Refractory or • Efficacy: ORR, DOR,
0.3 3+3
resistant to DCR, PFS, OS
standard therapy 0.1 mg/kg N=3~6 IV Q3W regimen
• PK and PD: target
including CPIs 10 mg/kg N=3 ~6 IV Q1W regimen saturation,
1 mg/kg Starting dose: Single Pt immunophenotyping,
• Measurable disease N=1 IV Q1W regimen
MABEL ex vivo costimulatory
• ECOG: grade 0-2 capacity analysis
• Adequate
hematological, Part B: Expansion Cohorts (N=15/cohort)
renal and hepatic • Specific PD-1-refractory indications and/or populations
function
• Biomarker-selected when appropriate
PK/PD model: Yang J et al, Abstract 705, ASCPT 2019Summary
• Current checkpoint inhibitor therapies may be limited by a lack of sufficient T cell costimulatory
ligands (e.g., the CD28 ligands CD80 and/or CD86) in the tumor microenvironment
• ALPN-202 is a first-in-class:
- Conditional (i.e., PD-L1-dependent) CD28 costimulator, and,
- Dual checkpoint (PD-L1 and CTLA-4) inhibitor
• Preclinical studies demonstrate superior anti-tumor efficacy vs. checkpoint inhibition alone with
excellent tolerability in GLP toxicology studies
• NEON-1 (NCT04186637) is:
- An open-label, dose escalation & expansion study of ALPN-202 in advanced malignancies
- Currently open for enrollment
Email: jing.yang@alpineimmunesciences.comYou can also read
