Targeting B7-H3 in Squamous Cell Carcinoma of the Head and ...
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©2021 MacroGenics, Inc. All rights reserved. Targeting B7-H3 in Squamous Cell Carcinoma of the Head and Neck: Preclinical Proof-of-Concept with the Investigational Anti-B7-H3 Antibody-drug Conjugate, MGC018 Juniper A. Scribner, Francine Z. Chen, Ying Li, Michael Chiechi, Jeff Hooley, Thomas Son, Scott Koenig, Paul A. Moore, Ezio Bonvini, Chet Bohac, Deryk Loo MacroGenics, Inc., Brisbane, CA and Rockville, MD Presented at the American Association for Cancer Research 2021 Virtual Annual Meeting, April 10–15, 2021 950 Abstract Introduction: Squamous cell carcinoma of the head and neck (SCCHN) is the seventh most common cancer worldwide, accounting for ~4% of all cancers in the United States. Although PD-1-directed therapy has efficacy in SCCHN, 85–95% of patients progress following initial response. B7-H3 is a member of the B7 family of immunomodulatory molecules, is overexpressed in SCCHN, and correlates with disease severity and poor clinical outcome. Furthermore, consistent with its putative coinhibitory function, B7-H3 expression in SCCHN is inversely correlated with the number of tumor infiltrating CD8+ T-cells. We are developing therapeutics targeting B7-H3, including enoblituzumab, an Fc-engineered anti-B7-H3 monoclonal antibody, and MGC018, a duocarmycin- based B7-H3 ADC, both of which are currently being evaluated in clinical studies. Here the potential of MGC018 was explored in preclinical models as a proof of concept for targeting B7-H3 in SCCHN. Methods: Immunohistochemistry studies were performed to define the expression of B7-H3 in SCCHN tissue microarrays (TMA). Single and repeat-dose in vivo efficacy studies were conducted in CD-1 nude mice with cell line-derived SCCHN human tumor xenografts to explore the relationship between C max , exposure and antitumor activity, and to define the minimal efficacious dose in these models. Based on the results in these cell-derived xenograft (CDX) studies, in vivo efficacy studies were extended to a panel of SCCHN patient-derived xenograft (PDX) models, which more closely mimic the biological characteristics of the patient tumor and exhibit heterogenous expression of B7-H3. Results: Analysis of B7-H3 expression on a SCCHN TMA confirmed and extended previously reported expression of B7-H3 in SCCHN. Of the SCCHN samples evaluated, 90% (36/40) of the tumor samples were positive for B7-H3: 35% (14/40) had H-scores greater than 200, with the remaining 22 samples equally distributed between the H-score range of 101–200 and 1–100 (~28% each). MGC018 demonstrated specific, dose-dependent in vitro cytotoxicity toward SCCHN human tumor cell lines. The in vitro cytotoxicity translated to potent antitumor activity in vivo against SCCHN CDX models, with a single administration of 3 mg/kg resulting in complete responses in 7/7 mice in the FaDu model. In the PDX setting (H-scores 120–283), repeat dose administration every week or two weeks with MGC018 at 3 mg/kg/dose, led to regressions and/or stable disease in 10/19 models, and a delay in tumor growth in 5 additional models. Conclusion: B7-H3 is frequently overexpressed in SCCHN. At clinically relevant dose levels, MGC018 demonstrated potent antitumor activity in vivo toward SCCHN CDX models and the majority of SCCHN PDX models examined. These results support SCCHN as a potential indication that may be responsive to ADC-based treatments directed toward B7-H3. Introduction MGC018: A Clinical-stage Anti-B7-H3 ADC Therapeutic B7-H3 ■ Member of the B7-family of immune regulators ■ Overexpressed on solid cancer, including SCCHN, with high tumor-versus-normal tissue binding differential ■ Overexpression in SCCHN correlated with disease severity and poor outcome MGC018 ■ Comprised of a humanized antibody targeting B7-H3 (MGA017) ■ Conjugated to a duocarmycin-based DNA alkylating payload via native cysteines ■ Cleavable peptide linker — facilitates bystander effect ■ Potent antitumor activity in mouse models toward B7-H3-expressing human tumor xenografts at dose levels used in clinical studies, despite model limitations – Unlike humans and non-human primates, rodents express carboxylesterase CES1c that cleaves the ADC payload and limits exposure 1,2 ■ Phase 1/2 clinical study in advanced solid cancers in progress (NCT03729596) Duocarmycin-based Linker Payload O O O s N O O N H N H O O N H O O N I N O O NH O H 2 N N CL O N N HN O OH O OH Cleavable Peptide Self-elimination Module Proteolytic Cleavage and Release of Toxin O N O N O N HN OH Active Toxin (DUBA) vc-seco-DUocarmycin-hydroxyBenzamide Azaindole (DUBA) Structure MGA017 MGC018 Duocarmycin Payload huIgG1 (wild type Fc) Anti-B7-H3 Drug-antibody ratio 2.68 Head and Neck Cancer ■ The majority of head and neck cancers are squamous cell carcinomas – Arising from flat squamous cells in the thin layer of tissue on the surface of structures in the head and neck ■ Head and neck cancer accounts for ~4% of all cancers in the United States 3 ■ It was estimated that in 2020, 65,630 people would develop head and neck cancer and 14,500 people would die from the disease 3 ■ The stage at diagnosis predicts survival rates – The overall 5 year survival rate ranges from 58-71% depending on the type of cancer; however, the rate drops if the cancer has spread to surrounding tissues and/or regional lymph nodes (45-73%) or distant parts of the body (33-48%) 3 Objectives ■ Explore the expression profile and prevalence of B7-H3 in SCCHN ■ Evaluate the therapeutic potential of MGC018 in preclinical models of SCCHN MGC018 Mediates Apoptosis of FaDu SCCHN Tumor Cells Caspase 3/7 Activation of FaDu Tumor Cells In Vitro 24 12 36 48 60 72 84 96 108 120 132 142 0 1x10 6 2x10 6 3x10 6 4x10 6 5x10 6 6x10 6 Hours Integrated Apoptotic Intensity/Image MGC018 (3.0 nM) MGA017 (3.0 nM) Untreated MGC018 Leads to Cell Cycle Arrest of FaDu SCCHN Tumor Cells 4 hours 24 hours 48 hours 0 hours Propidium Iodide Propidium Iodide Propidium Iodide Events Events Propidium Iodide G1 phase G2/M phase S phase Untreated MGC018 (3.3 nM) ■ Cell cycle arrest was observed in S and G2/M phase, consistent with the mechanism of action of duocarmycin MGC018 Mediates Antitumor Activity Toward CDX Models of SCCHN 0 20 10 30 50 70 90 40 60 80 100 0 500 1000 1500 2000 2500 Study Day Tumor Volume (mm 3 ) Vehicle MGC018 3 mg/kg MGC018 6 mg/kg MGC018 10 mg/kg Control ADC 6 mg/kg Control ADC 3 mg/kg Control ADC 10 mg/kg FaDu Hypopharyngeal Carcinoma Dosing 0 500 1000 1500 2000 2500 Study Day Tumor Volume (mm 3 ) Vehicle MGC018 0.3 mg/kg QWx4 MGC018 1 mg/kg QWx4 MGC018 3 mg/kg QWx4 Control ADC 1 mg/kg QWx4 Control ADC 0.3 mg/kg QWx4 Control ADC 3 mg/kg QWx4 Dosing H-Score = 170 0 10 20 30 40 50 60 70 80 MGC018 3 mg/kg MGC018 6 mg/kg MGC018 10 mg/kg Control ADC 6 mg/kg Control ADC 3 mg/kg Control ADC 10 mg/kg Vehicle MGC018 3 mg/kg QWx4 MGC018 6 mg/kg QWx4 MGC018 10 mg/kg QWx4 Control ADC 6 mg/kg QWx4 Control ADC 3 mg/kg QWx4 Control ADC 10 mg/kg QWx4 H-Score = 90 Vehicle Detroit 562 Pharyngeal Carcinoma Dosing Study Day Dosing Study Day Tumor Volume (mm 3 ) Tumor Volume (mm 3 ) 0 10 20 30 40 50 60 0 0 10 20 30 40 50 60 500 1000 1500 0 500 1000 1500 ■ MGC018 exhibited antitumor activity toward FaDu and Detroit 562 xenograft models of SCCHN MGC018 Mediates Antitumor Activity Toward PDX Models of Head and Neck Cancer H-score 283 H-score 193 CTG-0790 CTG-0462 0 500 1000 1500 2000 2500 Study Day Tumor Volume (mm 3 ) Tumor Volume (mm 3 ) 0 10 20 30 0 500 1000 1500 2000 2500 3000 Study Day H-score 175 H-score 160 CTG-3107 CTG-2671 Tumor Volume (mm 3 ) Tumor Volume (mm 3 ) 0 10 20 30 40 0 500 1000 1500 2000 Study Day 0 500 1000 1500 2000 Study Day Vehicle H-score 187 H-score 242 CTG-2183 CTG-0798 Tumor Volume (mm 3 ) Tumor Volume (mm 3 ) 0 500 1000 1500 Study Day 0 10 20 30 40 50 60 70 0 500 1000 1500 2000 2500 Study Day MGC018 3 mg/kg Control ADC 3 mg/kg H-score 175 H-score 160 CTG-2052 CTG-0786 Tumor Volume (mm 3 ) Tumor Volume (mm 3 ) 0 10 20 30 40 0 500 1000 1500 2000 2500 Study Day 0 10 20 30 40 50 0 500 1000 1500 2000 2500 Study Day Dosing Dosing Dosing Dosing Dosing Dosing Dosing Dosing 0 10 20 30 40 50 60 70 0 10 20 30 40 50 60 70 0 10 20 30 40 50 60 70 ■ MGC018 exhibited antitumor activity toward head and neck cancers expressing a range of B7-H3 ■ Additional factors beyond B7-H3 expression appear to influence sensitivity in these PDX models ■ MGC018 was well tolerated in all models, with no impact on body weight PDX Model Characteristics Model Tumor Status Harvest Site Histology Disease Stage Treatment History HPV Status H-Score IV Dosing % T/C Antitumor Activity CTG-0149 Metastatic Skin Squamous cell carcinoma III Naïve 16-/18- 213 Q2W x 3 99 Inactive CTG-0152 Metastatic Skin Squamous cell carcinoma III Pretreated 16-/18- 222 Q2W x 3 58 Inactive CTG-0434 Primary Larynx Squamous cell carcinoma III Not available 16+/18- 230 Q2W x 4 72 Inactive CTG-0462 Metastatic Liver Carcinoma IV Pretreated 16+/18- 193 Q2W x 2 8 Highly Active CTG-0786 Primary Tongue Squamous cell carcinoma II Naive 16-/18- 160 Q2W x 3 15 Active CTG-0787 Primary Buccal Squamous cell carcinoma II Not available 16-/18- 120 Q2W x 2 53 Inactive CTG-0790 Primary Mandible Squamous cell carcinoma III Naïve 16-/18- 283 Q2W x 2 2 Highly Active CTG-0798 Metastatic Lung Ductal adenocarcinoma IV Pretreated 16-/18- 242 Q2W x 4 7 Highly Active CTG-1100 Primary Tongue Carcinoma II Not available 16+/18- 243 Q2W x 4 1 Highly Active CTG-1118 Local metastatic Neck Squamous cell carcinoma III Pretreated 16-/18- 263 Q2W x 4 38 Active CTG-1131 Metastatic Gluteus Squamous cell carcinoma IV Pretreated 16-/18- 123 Q2W x 2 46 Inactive CTG-2052 Primary Mouth Squamous cell carcinoma IV Naive 16-/18- 175 Q2W x 3 19 Active CTG-2175 Primary Larynx Squamous cell carcinoma III Pretreated N/A 153 Q2W x 4 26 Active CTG-2183 Primary Larynx Squamous cell carcinoma IV Naive 16-/18- 187 Q2W x 4 25 Active CTG-2259 Primary Tongue Squamous cell carcinoma IV Naive 16-/18- 150 Q2W x 3 29 Active CTG-2324 Local metastatic Neck Squamous cell carcinoma IV Pretreated 16-/18- 173 Q2W x 4 109 Inactive CTG-2336 Primary Larynx Squamous cell carcinoma IV Naive N/A 190 Q2W x 3 18 Active CTG-2671 Primary Larynx Squamous cell carcinoma III Naive 16-/18- 160 Q2W x 4 26 Active CTG-3107 Metastatic Lung Squamous cell carcinoma IV Pretreated N/A 175 Q2W x 3 11 Active PDX studies performed by Champions Oncology. Antitumor activity evaluated according to National Cancer Institute (NCI) standards: Mean percent Tumor divided by Control; T/C < 10% highly active, T/C ≤ 42% is active, T/C > 42% is inactive. An adaptive repeat-dose protocol was employed for the PDX studies due to rapid clearance of MGC018 in these rodent models. Conclusions ■ B7-H3 is frequently overexpressed in SCCHN – 90% (36/40) of human tumor samples evaluated showed B7-H3 membrane staining on the tumor epithelium with an average H-score of 162 – Detailed analysis revealed that B7-H3 was heterogeneously expressed on both the tumor epithelium and tumor-associated vasculature ■ MGC018 demonstrated antitumor activity in vivo toward SCCHN xenografts – Highly active toward FaDu and Detroit 562 CDX models – Active or highly active toward 13/19 (68%) of PDX models These results support SCCHN as a suitable indication for an ADC-based treatment directed toward B7-H3 References 1. Elgersma et al., Mol. Pharmaceutics 12; 2015. 2. Scribner et al., Mol. Cancer Ther. 19(11); 2020. 3. American Cancer Society’s publication, Cancer Facts & Figures 2020, and the National Cancer Institute. Acknowledgements DUBA linker payload conjugated by and licensed from Byondis B.V., Nijmegen, the Netherlands. Presenter Contact Information: [email protected] Results B7-H3 Is Overexpressed in SCCHN 0 50 100 150 200 250 300 B7 A10 A4 B10 D5 E3 A3 C10 B9 A2 B3 A8 D4 D1 B1 D3 B6 A9 C7 E1 B5 A7 A1 D8 C5 A5 A6 D6 D7 B4 C2 D9 D10 C3 E2 C1 C4 C9 D2 E4 3+ 2+ 1+ 0 Tumor Epithelium H-score Sample ■ 90% of human tumor samples positive for B7-H3, with average H-score of 162 ■ 63% of human tumor samples have H-scores > 100, 35% > 200 Membrane expression evaluated with SP206 rabbit pAb on FFPE tissue microarray. H-score: Semiquantitative method that incorporates the intensity level (0, 1+, 2+, or 3+) and percentage of cells staining; ranges from 0 (no staining) to 300 (maximal staining), using the formula [1(% cells 1+) + 2(% cells 2+) + 3(% cells 3+)]. B7-H3 Tumor Expression and Heterogeneity Is Generally Recapitulated in PDX Models Human Tumor Tissue PDX Models 0 50 100 150 200 250 300 HNES14 HNES3 HNES18 HNES10 HNES9 HNES16 HNES19 HNES4 HNES2 HNES6 HNES12 HNES5 HNES17 HNES1 HNES15 HNES8 HNES11 HNES7 HNES13 Tumor Epithelium 0 50 100 150 200 250 300 HNVS14 HNVS3 HNVS18 HNVS10 HNVS9 HNVS16 HNVS19 HNVS4 HNVS2 HNVS6 HNVS12 HNVS5 HNVS17 HNVS1 HNVS15 HNVS8 HNVS11 HNVS7 HNVS13 0 50 100 150 200 250 300 CTG-0790 CTG-1118 CTG-1100 CTG-0798 CTG-0434 CTG-0152 CTG-0149 CTG-0462 CTG-2336 CTG-2183 CTG-2052 CTG-3107 CTG-2324 CTG-2671 CTG-0786 CTG-2175 CTG-2259 CTG-1131 CTG-0787 Tumor Epithelium 0 50 100 150 200 250 300 CTG-0790 CTG-1118 CTG-1100 CTG-0798 CTG-0434 CTG-0152 CTG-0149 CTG-0462 CTG-2336 CTG-2183 CTG-2052 CTG-3107 CTG-2324 CTG-2671 CTG-0786 CTG-2175 CTG-2259 CTG-1131 CTG-0787 Tumor-associated Vasculature Tumor-associated Vasculature H-score Sample H-score Sample H-score Model H-score Model 3+ 2+ 1+ 0 ■ Heterogeneous expression of B7-H3 observed on both tumor epithelium and tumor- associated vasculature of human tumor samples – 100% of samples were positive for B7-H3 on tumor epithelium and/or tumor-associated vasculature ■ Expression of B7-H3 in PDX models is similar to human tumor samples, but with lower vascular expression Membrane expression evaluated with R&D Systems Goat anti-B7-H3 pAb on FFPE tissues.
Transcript of Targeting B7-H3 in Squamous Cell Carcinoma of the Head and ...
©2021 MacroGenics, Inc. All rights reserved.
Targeting B7-H3 in Squamous Cell Carcinoma of the Head and Neck:Preclinical Proof-of-Concept with the Investigational Anti-B7-H3 Antibody-drug Conjugate, MGC018
Juniper A. Scribner, Francine Z. Chen, Ying Li, Michael Chiechi, Jeff Hooley, Thomas Son, Scott Koenig, Paul A. Moore, Ezio Bonvini, Chet Bohac, Deryk Loo MacroGenics, Inc., Brisbane, CA and Rockville, MD
Presented at the American Association for Cancer Research 2021 Virtual Annual Meeting, April 10–15, 2021
950
AbstractIntroduction: Squamous cell carcinoma of the head and neck (SCCHN) is the seventh most common cancer worldwide, accounting for ~4% of all cancers in the United States. Although PD-1-directed therapy has efficacy in SCCHN, 85–95% of patients progress following initial response. B7-H3 is a member of the B7 family of immunomodulatory molecules, is overexpressed in SCCHN, and correlates with disease severity and poor clinical outcome. Furthermore, consistent with its putative coinhibitory function, B7-H3 expression in SCCHN is inversely correlated with the number of tumor infiltrating CD8+ T-cells. We are developing therapeutics targeting B7-H3, including enoblituzumab, an Fc-engineered anti-B7-H3 monoclonal antibody, and MGC018, a duocarmycin-based B7-H3 ADC, both of which are currently being evaluated in clinical studies. Here the potential of MGC018 was explored in preclinical models as a proof of concept for targeting B7-H3 in SCCHN.
Methods: Immunohistochemistry studies were performed to define the expression of B7-H3 in SCCHN tissue microarrays (TMA). Single and repeat-dose in vivo efficacy studies were conducted in CD-1 nude mice with cell line-derived SCCHN human tumor xenografts to explore the relationship between Cmax, exposure and antitumor activity, and to define the minimal efficacious dose in these models. Based on the results in these cell-derived xenograft (CDX) studies, in vivo efficacy studies were extended to a panel of SCCHN patient-derived xenograft (PDX) models, which more closely mimic the biological characteristics of the patient tumor and exhibit heterogenous expression of B7-H3.
Results: Analysis of B7-H3 expression on a SCCHN TMA confirmed and extended previously reported expression of B7-H3 in SCCHN. Of the SCCHN samples evaluated, 90% (36/40) of the tumor samples were positive for B7-H3: 35% (14/40) had H-scores greater than 200, with the remaining 22 samples equally distributed between the H-score range of 101–200 and 1–100 (~28% each). MGC018 demonstrated specific, dose-dependent in vitro cytotoxicity toward SCCHN human tumor cell lines. The in vitro cytotoxicity translated to potent antitumor activity in vivo against SCCHN CDX models, with a single administration of 3 mg/kg resulting in complete responses in 7/7 mice in the FaDu model. In the PDX setting (H-scores 120–283), repeat dose administration every week or two weeks with MGC018 at 3 mg/kg/dose, led to regressions and/or stable disease in 10/19 models, and a delay in tumor growth in 5 additional models.
Conclusion: B7-H3 is frequently overexpressed in SCCHN. At clinically relevant dose levels, MGC018 demonstrated potent antitumor activity in vivo toward SCCHN CDX models and the majority of SCCHN PDX models examined. These results support SCCHN as a potential indication that may be responsive to ADC-based treatments directed toward B7-H3.
IntroductionMGC018: A Clinical-stage Anti-B7-H3 ADC TherapeuticB7-H3■ Member of the B7-family of immune regulators■ Overexpressed on solid cancer, including SCCHN, with high tumor-versus-normal tissue binding differential■ Overexpression in SCCHN correlated with disease severity and poor outcome
MGC018■ Comprised of a humanized antibody targeting B7-H3 (MGA017)■ Conjugated to a duocarmycin-based DNA alkylating payload via native cysteines■ Cleavable peptide linker — facilitates bystander effect■ Potent antitumor activity in mouse models toward B7-H3-expressing human tumor xenografts at dose levels used in clinical studies, despite model limitations
– Unlike humans and non-human primates, rodents express carboxylesterase CES1c that cleaves the ADC payload and limits exposure1,2
■ Phase 1/2 clinical study in advanced solid cancers in progress (NCT03729596)
Duocarmycin-based Linker Payload
OO
OsN O
ONH
NH
O
ONH
OO
NI
NOO
NHOH2N
N
CL
ON
N
HNO
OH
O OHCleavable Peptide
Self-elimination Module
Proteolytic Cleavageand Release of Toxin
O
NO
NO
N
HN
OH
Active Toxin (DUBA)
vc-seco-DUocarmycin-hydroxyBenzamide Azaindole (DUBA) Structure
MGA017
MGC018
DuocarmycinPayload
huIgG1(wild type Fc)
Anti-B7-H3
Drug-antibody ratio 2.68
Head and Neck Cancer■ The majority of head and neck cancers are squamous cell carcinomas
– Arising from flat squamous cells in the thin layer of tissue on the surface of structures in the head and neck
■ Head and neck cancer accounts for ~4% of all cancers in the United States3
■ It was estimated that in 2020, 65,630 people would develop head and neck cancer and 14,500 people would die from the disease3
■ The stage at diagnosis predicts survival rates – The overall 5 year survival rate ranges from 58-71% depending on the type of cancer; however, the rate drops if the cancer has spread to surrounding tissues and/or regional lymph nodes (45-73%) or distant parts of the body (33-48%)3
Objectives■ Explore the expression profile and prevalence of B7-H3 in SCCHN■ Evaluate the therapeutic potential of MGC018 in preclinical models of SCCHN
MGC018 Mediates Apoptosis of FaDu SCCHN Tumor CellsCaspase 3/7 Activation of FaDu Tumor Cells In Vitro
2412 36 48 60 72 84 96 108 120 132 1420
1x106
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MGC018 (3.0 nM) MGA017 (3.0 nM) Untreated
MGC018 Leads to Cell Cycle Arrest of FaDu SCCHN Tumor Cells
4 hours 24 hours 48 hours0 hours
Propidium IodidePropidium Iodide Propidium Iodide
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Propidium Iodide
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G2/M phaseS phaseUntreated
MGC018(3.3 nM)
■Cell cycle arrest was observed in S and G2/M phase, consistent with the mechanism of action of duocarmycin
MGC018 Mediates Antitumor Activity Toward CDX Models of SCCHN
0 2010 30 50 70 9040 60 80 1000
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FaDu Hypopharyngeal Carcinoma
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■MGC018 exhibited antitumor activity toward FaDu and Detroit 562 xenograft models of SCCHN
MGC018 Mediates Antitumor Activity Toward PDX Models of Head and Neck Cancer
H-score 283 H-score 193
CTG-0790 CTG-0462
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■MGC018 exhibited antitumor activity toward head and neck cancers expressing a range of B7-H3■Additional factors beyond B7-H3 expression appear to influence sensitivity in these PDX models■MGC018 was well tolerated in all models, with no impact on body weight
PDX Model Characteristics
Model Tumor Status
Harvest Site Histology Disease
StageTreatment
HistoryHPV
Status H-Score IV Dosing
% T/C
Antitumor Activity
CTG-0149 Metastatic Skin Squamous cell carcinoma III Naïve 16-/18- 213 Q2W x 3 99 Inactive
CTG-0152 Metastatic Skin Squamous cell carcinoma III Pretreated 16-/18- 222 Q2W x 3 58 Inactive
CTG-0434 Primary Larynx Squamous cell carcinoma III Not available 16+/18- 230 Q2W x 4 72 Inactive
CTG-0462 Metastatic Liver Carcinoma IV Pretreated 16+/18- 193 Q2W x 2 8 Highly Active
CTG-0786 Primary Tongue Squamous cell carcinoma II Naive 16-/18- 160 Q2W x 3 15 Active
CTG-0787 Primary Buccal Squamous cell carcinoma II Not available 16-/18- 120 Q2W x 2 53 Inactive
CTG-0790 Primary Mandible Squamous cell carcinoma III Naïve 16-/18- 283 Q2W x 2 2 Highly
Active
CTG-0798 Metastatic Lung Ductal adenocarcinoma IV Pretreated 16-/18- 242 Q2W x 4 7 Highly
Active
CTG-1100 Primary Tongue Carcinoma II Not available 16+/18- 243 Q2W x 4 1 Highly Active
CTG-1118 Local metastatic Neck Squamous cell
carcinoma III Pretreated 16-/18- 263 Q2W x 4 38 Active
CTG-1131 Metastatic Gluteus Squamous cell carcinoma IV Pretreated 16-/18- 123 Q2W x 2 46 Inactive
CTG-2052 Primary Mouth Squamous cell carcinoma IV Naive 16-/18- 175 Q2W x 3 19 Active
CTG-2175 Primary Larynx Squamous cell carcinoma III Pretreated N/A 153 Q2W x 4 26 Active
CTG-2183 Primary Larynx Squamous cell carcinoma IV Naive 16-/18- 187 Q2W x 4 25 Active
CTG-2259 Primary Tongue Squamous cell carcinoma IV Naive 16-/18- 150 Q2W x 3 29 Active
CTG-2324 Local metastatic Neck Squamous cell
carcinoma IV Pretreated 16-/18- 173 Q2W x 4 109 Inactive
CTG-2336 Primary Larynx Squamous cell carcinoma IV Naive N/A 190 Q2W x 3 18 Active
CTG-2671 Primary Larynx Squamous cell carcinoma III Naive 16-/18- 160 Q2W x 4 26 Active
CTG-3107 Metastatic Lung Squamous cell carcinoma IV Pretreated N/A 175 Q2W x 3 11 Active
PDX studies performed by Champions Oncology. Antitumor activity evaluated according to National Cancer Institute (NCI) standards: Mean percent Tumor divided by Control; T/C < 10% highly active, T/C ≤ 42% is active, T/C > 42% is inactive.An adaptive repeat-dose protocol was employed for the PDX studies due to rapid clearance of MGC018 in these rodent models.
Conclusions■B7-H3 is frequently overexpressed in SCCHN
– 90% (36/40) of human tumor samples evaluated showed B7-H3 membrane staining on the tumor epithelium with an average H-score of 162 – Detailed analysis revealed that B7-H3 was heterogeneously expressed on both the tumor epithelium and tumor-associated vasculature
■MGC018 demonstrated antitumor activity in vivo toward SCCHN xenografts – Highly active toward FaDu and Detroit 562 CDX models – Active or highly active toward 13/19 (68%) of PDX models
These results support SCCHN as a suitable indication for an ADC-based treatment directed toward B7-H3
References1. Elgersma et al., Mol. Pharmaceutics 12; 2015.2. Scribner et al., Mol. Cancer Ther. 19(11); 2020.3. American Cancer Society’s publication, Cancer Facts & Figures 2020, and the National Cancer Institute.
Acknowledgements
DUBA linker payload conjugated by and licensed from Byondis B.V., Nijmegen, the Netherlands.
Presenter Contact Information: [email protected]
Results
B7-H3 Is Overexpressed in SCCHN
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B7 A10 A4 B10
D5 E3 A3 C10 B9 A2 B3 A8 D4
D1 B1 D3 B6 A9 C7 E1 B5 A7 A1 D8 C5 A5 A6 D6
D7 B4 C2 D9
D10 C3 E2 C1 C4 C9 D
2 E4
3+ 2+ 1+ 0
Tumor Epithelium
H-s
core
Sample
■90% of human tumor samples positive for B7-H3, with average H-score of 162■63% of human tumor samples have H-scores > 100, 35% > 200
Membrane expression evaluated with SP206 rabbit pAb on FFPE tissue microarray. H-score: Semiquantitative method that incorporates the intensity level (0, 1+, 2+, or 3+) and percentage of cells staining; ranges from 0 (no staining) to 300 (maximal staining), using the formula [1(% cells 1+) + 2(% cells 2+) + 3(% cells 3+)].
B7-H3 Tumor Expression and Heterogeneity Is Generally Recapitulated in PDX Models
Human Tumor Tissue
PDX Models
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HN
ES14
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ES3
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ES18
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ES10
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ES9
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HN
ES19
HN
ES4
HN
ES2
HN
ES6
HN
ES12
HN
ES5
HN
ES17
HN
ES1
HN
ES15
HN
ES8
HN
ES11
HN
ES7
HN
ES13
Tumor Epithelium
0
50
100
150
200
250
300
HN
VS14
HN
VS3
HN
VS18
HN
VS10
HN
VS9
HN
VS16
HN
VS19
HN
VS4
HN
VS2
HN
VS6
HN
VS12
HN
VS5
HN
VS17
HN
VS1
HN
VS15
HN
VS8
HN
VS11
HN
VS7
HN
VS13
0
50
100
150
200
250
300
CTG
-079
0CT
G-1
118
CTG
-110
0CT
G-0
798
CTG
-043
4CT
G-0
152
CTG
-014
9CT
G-0
462
CTG
-233
6CT
G-2
183
CTG
-205
2CT
G-3
107
CTG
-232
4CT
G-2
671
CTG
-078
6CT
G-2
175
CTG
-225
9CT
G-1
131
CTG
-078
7
Tumor Epithelium
0
50
100
150
200
250
300
CTG
-079
0CT
G-1
118
CTG
-110
0CT
G-0
798
CTG
-043
4CT
G-0
152
CTG
-014
9CT
G-0
462
CTG
-233
6CT
G-2
183
CTG
-205
2CT
G-3
107
CTG
-232
4CT
G-2
671
CTG
-078
6CT
G-2
175
CTG
-225
9CT
G-1
131
CTG
-078
7Tumor-associated Vasculature
Tumor-associated Vasculature
H-s
core
Sample
H-s
core
Sample
H-s
core
Model
H-s
core
Model
3+ 2+ 1+ 0
■Heterogeneous expression of B7-H3 observed on both tumor epithelium and tumor-associated vasculature of human tumor samples
– 100% of samples were positive for B7-H3 on tumor epithelium and/or tumor-associated vasculature
■Expression of B7-H3 in PDX models is similar to human tumor samples, but with lower vascular expression
Membrane expression evaluated with R&D Systems Goat anti-B7-H3 pAb on FFPE tissues.
