Desenvolvimento Biofármacos Oncologia Martin Bonamino

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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

Biofármacos - câncer

VEGF CD20 EGFR CTLA4

Microambiente tumoral

Biotecnologia como abordagem

para combate ao câncer

• Bloqueio de fatores estimuladores

• Anticorpos Monoclonais específicos para o tumor

• Anticorpos Monoclonais imuno-moduladores

• Terapia celular/gênica

Scott et al, Nat Rev Cancer 2012

Weidle et al, Cancer Gen Proteom 2013

mAbs: estruturas e alternativas

Anticorpos Monoclonais

tumor como alvo

Rituximab – mAb quimérico anti CD20 - IgG

www.genm

ab.com

Anticorpo anti CD20 – Nova geração

www.genmab.com

Cetuximab – mAb quimérico anti EGFR – IgG1

Panitumumab – mAb humanizado anti EGFR – IgG2

Scott et al, Nat Rev Cancer 2012

Anticorpos Monoclonais

sistema imune como alvo

Microambiente tumoral

Bloqueio de CTLA-4

T Cell Activation by TCR and

Co-stimulation Through CD28

Dendritic

cell T cell

MHC

TCR

CD28

Antigen

CTLA4

CTLA4 Receptors Are Up-Regulated Following

T-Cell Activation

Dendritic

cell T cell

MHC

TCR

CD28

Antigen

CTLA4

Dendritic

cell T cell

MHC

TCR

CD28

Antigen

CTLA4

CTLA4 Negatively Modulates

T-Cell Activation

Dendritic

cell T cell

MHC

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.

Adapted from ASCO 2008 meeting. Suzanne Louise Topalian, MD

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

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%

Metastatic Melanoma Response to Ipilimumab

Before Ipilimumab

04/22/11

After Ipilimumab

08/05/11

Years

Immunotherapy

rce

ali

1 2 3 0

Targeted therapy

rce

ali

1 2 3 0 Years

Immunotherapy vs targeted therapy for melanoma

Bloqueio de PD1

Células tumorais são capazes de matar

linfócitos efetores infiltrantes

http://www.bmsimmunooncology.com/tumor-immunosuppression.aspx

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

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

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

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

Outros alvos de intervenção

Kwek et al, Nat Rev Cancer 2012

Combinação de Imunoterapias e Terapias alvo-específicas para Melanoma?

Anticorpos Bi-específicos

Frankel and Baeuerle, Curr Opin Chem Biol 2013

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

Terapia celular

Tumor Infiltrating Lymphocytes

Immunotherapy

Rosenberg and Dudley, Curr Opin Immunol 2009

ACT: Transferência adotiva de células

NMA: Não Mieloablativo

Terapia gênica

Transferência gênica de TCR

Receptores Quiméricos de Antígenos

(CARs)

Redirecting lymphocyte specificity

for tumor elimination

Chimeric Antigen Receptor (CAR)

Adapted from Pule et al, 2003

MHC-independent antigen

recognition;

High affinity for the antigen;

Independent of patient-

derived TILs

Multiple signals required

T lymphocyte activation

1st generation

2nd generation

3rd generation

Chimeric Antigen Receptor (CAR)

Clinical trials – 1st generation CAR

Nature Medicine, 2008

Kochenderfer et al, Blood 2010

NHL – B cells

CAR 19-28z

Clinical trials - 2nd generation CAR

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

Sadelain et al, Cancer Disc 2013

Front. Oncol., 30 January 2012

Terapia Gênica na Imunoterapia

Chicaybam et al, 2014

Terapia Gênica na Imunoterapia

Sleeping Beauty Transposon

Chicaybam et al, 2013

Sleeping Beauty Transposon

Chicaybam et al, 2013

Cada paciente = 1 terapia

1 paciente = 1 terapia

(terapia celular/serviço)

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

Cada paciente = 1 terapia?

1 doador = muitos pacientes

(Biofármaco/Produto)

Zinc Finger Nucleases – Edição sítio-dirigida

Edição sítio-dirigida

TALENs

CRISPRs

Linfócitos para Imunoterapia

1 doador para todos os pacientes -

Biofármaco