desenvolvimento biofármacos oncologia martin bonamino
TRANSCRIPT
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Desenvolvimento de Biofármacos para
área de oncologia no Brasil: avanços da
biotecnologia
Martin Bonamino
II Seminário Anual Científico e Tecnológico em Imunobiológicos – 30/05/2014
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Biofármacos - câncer
VEGF CD20 EGFR CTLA4
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Microambiente tumoral
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Biotecnologia como abordagem
para combate ao câncer
• Bloqueio de fatores estimuladores
• Anticorpos Monoclonais específicos para o tumor
• Anticorpos Monoclonais imuno-moduladores
• Terapia celular/gênica
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Scott et al, Nat Rev Cancer 2012
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Weidle et al, Cancer Gen Proteom 2013
mAbs: estruturas e alternativas
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Anticorpos Monoclonais
tumor como alvo
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Rituximab – mAb quimérico anti CD20 - IgG
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Rituximab – mAb quimérico anti CD20 - IgG
www.genm
ab.com
Anticorpo anti CD20 – Nova geração
www.genmab.com
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Cetuximab – mAb quimérico anti EGFR – IgG1
Panitumumab – mAb humanizado anti EGFR – IgG2
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Scott et al, Nat Rev Cancer 2012
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Scott et al, Nat Rev Cancer 2012
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Anticorpos Monoclonais
sistema imune como alvo
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Microambiente tumoral
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Bloqueio de CTLA-4
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T Cell Activation by TCR and
Co-stimulation Through CD28
Dendritic
cell T cell
MHC
B7
TCR
CD28
Antigen
CTLA4
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CTLA4 Receptors Are Up-Regulated Following
T-Cell Activation
Dendritic
cell T cell
MHC
B7
TCR
CD28
Antigen
CTLA4
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Dendritic
cell T cell
MHC
B7
TCR
CD28
Antigen
CTLA4
CTLA4 Negatively Modulates
T-Cell Activation
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Dendritic
cell T cell
MHC
B7
TCR
CD28
Antigen
CTLA4
Blocking Antibodies to CTLA4 Allow Positive
Signaling from Costimulatory Molecules to T Cells
Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996;271:1734-1736.
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Adapted from ASCO 2008 meeting. Suzanne Louise Topalian, MD
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Survival Rate Ipi + gp100 N=403 Ipi + pbo
N=137 gp100 + pbo
N=136
1 year 44% 46% 25%
2 year 22% 24% 14%
Ipilimumab Improves Overall Survival
compared to control
Ipi + gp100 (A)
Ipi alone (B)
gp100 alone (C)
1 2 3 4 Years
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What mediates anti-CTLA4-induced
durable tumor regressions?
Brown:
CD8+ T
cells
Blue:
melanoma 2005 Durable
response
> 5 years
Treatment with anti-CTLA4
antibodies
The great majority of responses last years without relapses:
- Longest responder: Ongoing since May 2001
- Response rate: ~10%
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Metastatic Melanoma Response to Ipilimumab
Before Ipilimumab
04/22/11
After Ipilimumab
08/05/11
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Years
Immunotherapy
Pe
rce
nt
ali
ve
1 2 3 0
Targeted therapy
Pe
rce
nt
ali
ve
1 2 3 0 Years
Immunotherapy vs targeted therapy for melanoma
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Bloqueio de PD1
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Células tumorais são capazes de matar
linfócitos efetores infiltrantes
http://www.bmsimmunooncology.com/tumor-immunosuppression.aspx
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Expressão de PD-1L por células tumorais
Marcação periférica Marcação difusa
HPV-Associated Head and Neck Squamous Cell Carcinoma
Lyford-Pike et al. CanRes 2013
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Enhancing Immune Responsiveness
PD1 Ab (MDX1106)
Phase I, single dose,
Tolerable, responses in
Colon, Lung, MM, RCC
Brahmer, ASCO 2008
PDL1 Ab
Phase I trial ongoing
PD1 Ab Phase 1,
multi dose, tolerable,
PRs in RCC, MM and
Lung, Sznol, ASCO 2010
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Durable partial regression of metastatic kidney
cancer following 3 doses of
anti-PD-1 (10 mg/kg)
01/15/08, pre-Rx 07/22/08 04/22/08
72 year old male with RCC metastatic to lung, LN, muscle, bone,
pancreas. Prior therapies included HDAC inhibitor, sunitinib, and
sorafenib.
Brahmer et al., JCO 2010
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34
Percent Change in Tumor Burden in RCC Patients
*Patients treated with the 10 mg/kg dose †Upper horizontal line denotes no change; lower horizontal line denotes 30%
decrease (RECIST threshold for PR).
Abbreviations: PR = partial response; RCC = renal cell carcinoma; RECIST = Response Evaluation Criteria in Solid Tumors
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Outros alvos de intervenção
Kwek et al, Nat Rev Cancer 2012
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Combinação de Imunoterapias e Terapias alvo-específicas para Melanoma?
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Anticorpos Bi-específicos
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Frankel and Baeuerle, Curr Opin Chem Biol 2013
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IL-2
IFN
IL-15
IL-21
Peptide vaccine
DC vaccine
Genetic vaccine
OX40
CD137
CD40
PD1 CTLA4
T cell cloning TCR or CAR
genetic engineering
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Terapia celular
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41
Tumor Infiltrating Lymphocytes
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Immunotherapy
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Rosenberg and Dudley, Curr Opin Immunol 2009
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Rosenberg and Dudley, Curr Opin Immunol 2009
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ACT: Transferência adotiva de células
NMA: Não Mieloablativo
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Terapia gênica
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Transferência gênica de TCR
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Receptores Quiméricos de Antígenos
(CARs)
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Redirecting lymphocyte specificity
for tumor elimination
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Chimeric Antigen Receptor (CAR)
Adapted from Pule et al, 2003
MHC-independent antigen
recognition;
High affinity for the antigen;
Independent of patient-
derived TILs
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Multiple signals required
T lymphocyte activation
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1st generation
2nd generation
3rd generation
Chimeric Antigen Receptor (CAR)
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Clinical trials – 1st generation CAR
Nature Medicine, 2008
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Kochenderfer et al, Blood 2010
NHL – B cells
CAR 19-28z
Clinical trials - 2nd generation CAR
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Porter DL, et al. N Engl J Med 2011 Kalos M, et al. Sci Transl Med 2011
CLL-B
CAR 19-BBz
Clinical trials - 2nd generation CAR
10e7 cels
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Sadelain et al, Cancer Disc 2013
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Front. Oncol., 30 January 2012
Terapia Gênica na Imunoterapia
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Chicaybam et al, 2014
Terapia Gênica na Imunoterapia
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Sleeping Beauty Transposon
Chicaybam et al, 2013
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Sleeping Beauty Transposon
Chicaybam et al, 2013
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62
Cada paciente = 1 terapia
1 paciente = 1 terapia
(terapia celular/serviço)
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63
Cada paciente = 1 terapia
1 paciente = 1 terapia
(terapia celular/serviço)
US$100.000.000
captados
CAR anti CD19
Acordo com transferência
de tecnologia e planta GMP dedicada
CAR anti CD19
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Cada paciente = 1 terapia?
1 doador = muitos pacientes
(Biofármaco/Produto)
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Zinc Finger Nucleases – Edição sítio-dirigida
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Edição sítio-dirigida
TALENs
CRISPRs
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Linfócitos para Imunoterapia
1 doador para todos os pacientes -
Biofármaco
Algumas características dos linfócitos que os tornam específicos
TCR HLA
PD1
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Linfócitos para Imunoterapia
Engenharia Celular
Algumas características dos linfócitos que os tornam específicos
HLA
PD1
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Linfócitos para Imunoterapia
Engenharia Celular
Algumas características dos linfócitos que os tornam específicos
PD1
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Linfócitos para Imunoterapia
Engenharia Celular
Algumas características dos linfócitos que os tornam específicos
PD1 CAR
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Linfócitos para Imunoterapia
Engenharia Celular
Algumas características dos linfócitos que os tornam específicos
CAR
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II Seminário Anual Científico e Tecnológico em Imunobiológicos – 30/05/2014
Obrigado