Alpha Beta Therapeutics

Developing novel antibodies to treat cancer

About

Alpha Beta Therapeutics goal is to create novel therapies that arm tumor-associated macrophages to trigger cancer cell killing.

We have developed fully humanized antibodies (Patent Pending) that trigger Macrophage-Mediated Antibody-Dependent Cellular Cytotoxicity (ADCC).

Mission

icon-antibodies-attacking

Develop human antibodies that potentiate immune destruction of cancer

icon-anti-tumor

Engineer anti-tumor antibodies that selectively engage and activate relevant tumor-localized effector cells

icon-cancer

Can be used in a broad range of cancers including lung, pancreas, colon, breast, brain and kidney

icon-drug-resistance

Capable of targeting drug-resistant cancers and enhancing standard-of-care

laboratory

Advance the knowledge that was created through the years of basic scientific development and prior clinical trials

Alpha Beta Therapeutics - Team

Integrin avβ3 mediates wound repair, remodeling

Epithelial cancer cells hijack this pathway to overcome stress

Epithelial cells use cell-cell and cell-matrix cues to “enforce boundaries”

  • During a wound response, cells must rapidly gain the ability to “overcome boundaries”.
    • Stress tolerance
      • Lack of Cell/matrix attachment
      • Hypoxia
      • Inflammatory cells & cytokines
    • Migration/invasion/proliferation
    • De-differentiation
  • After wound repair, cells differentiate and return to an epithelial phenotype.

Epithelial to mesenchymal transition (EMT)

Mature epithelial cells lack avβ3, but it is upregulated by cellular stress, hypoxia inflammatory cytokines

  • Gain of avβ3 is required for tissue remodeling and repair:
    • Endothelial cells during angiogenesis
    • Epithelial cells during wound repair
    • Cardiomyocytes after ischemia
  • Cancer cells “hijack” integrin avβ3
    • Adaptive response to cancer therapy
    • De-differentiated(mesenchymal state)
    • Drives anchorage independence, metastasis, invasion, drug resistance, and cancer stemness

Highlights: Cheresh lab research on integrin avβ3

1990’s (Characterization of integrin avβ3)

Generation of LM609, the first monoclonal antibody to recognize the intact avβ3 heterodimer (PNAS, 1987)

Role of avβ3 on vascular endothelial cells:
  • Fibrinogen binding during wound healing (Cell, 1989)
  • Angiogenesis (Science, 1994)
  • Ocular neovasculor disease (PNAS, 1996)
  • Targeting vasculor avβ3 induces tumor regression (Cell, 1994)
Driver of invasive cancer cell phenotype:
  • Melanoma (Cancer Metastasis Rev, 1991)
  • Glioblastoma (JCI, 1991)
  • Breast cancer (Clin Can Res. 1998)
Role of avβ3 In tissue remodeling:
  • Osteoclasts (JBC, 1991)
  • Wound repair (AJP, 1996)
  • Ischemio (MP. 1996)
  • Atherosclerosis (Cell Adhes Commun, 1998)
  • Rheumatoid arthritis (JCI 1999)
Role in adenovirus infection (Cell, 1993)

2000’s (anti-avβ3 for cancer therapy)

Provided consultation to generate a fully humanized and affinity matured form of LW°, Vitaxin/Abegrin was tested in hundreds of cancer patients

Recent work (Role of avβ3 In cancer cells)

Integrin avβ3 promotes a more aggressive and dangerous cancer cell phenotype:

  • Mesenchymal cell invasion (Moi Biol Cell, 2008)
  • Anchorage independence & metastasis (Nat Med, 2009)
  • Cancer stemness & drug resistance (Nat Cell Biol, 2014)
  • KRAS addiction in lung/pancreas cancer (Can Disc, 2017)
  • GLUT3 addiction in GBM (Cancer Cell, 2017)

2019 (Basis for ABT-l01 development)

  • Co-enrichment of avβ3 with tumor-associated macrophages (TAMs) (Cancer Res, 2019)
  • LM609 recruits TAMs tor tumor killing (Cancer Res, 2019)

Scientific rationale for targeting integrin avβ3

avβ3 is a driver of cancer progression, drug resistance, & sternness

Integrin avβ3 is linked to progression and metastasis across multiple cancer types

Melanoma

Vertical growth phase and lymph node adhesion (Albelda et al, Cancer Res, 1990; Nip et al, J Clin Invest, 1992)

Prostate

Bone metastasis (McCabe et al, Oncogene, 2007)

Breast

Bone metastasis (Takayama et al, Anticancer Res, 2005; Sloan et al, Breast Cancer Res, 2006; Felding-Habermann et al, PNAS, 2001)

GBM

Expressed at the tumor margin; role in invasion (Bello et al, Neurosurgery, 2001)

Lung

Poor outcome (Dingenanis et al, Molecular Cancer, 2010)

Pancreas

Lymph node metastasis, poor outcome (Hosotani et al, Pancreas, 2002; Desgrosellier et al, Nature Medicine, 2009)

Integrin avβ3 is enriched on drug-resistant and stem-like EGFR mutant lung cancer cells

Seguin et al, Nat Cell Biol 16(5): 457-468, 2014

KEY HIGHLIGHTS: Abegrin/etaracizumab/ MEDI-522

Clinical Track Record

  • Good safety with no dose-limiting toxicity
  • Some clinical activity in a range of cancers
    • Patients were not selected for avβ3 expression on tumor cells
    • Some trials combined with immunosuppressive agents
      • Melanoma trial: Longer survival for [Abegrin] vs. [Abegrin + dacarbazine]
    • Optimized for NK cell engagement, but not macrophages

Room for Improvement

  • Re-engineer to promote macrophage engagement
  • Do not combine with immunosuppressive agents
  • Select patient populations with high avβ3 expression on tumor cells
    • Cancers that are metastatic, drug-resistant, late-stage, KRAS addicted

Scientific rationale for engaging macrophages

avβ3+ tumor cells recruit macrophages, but not NK cells

Integrin avβ3 expression is sufficient to enrich for macrophages

Analysis of human cancer (TCGA datasets) shows co-enrichment of avβ3 with macrophages, but not NK cells

Anfi-avβ3 eliminates cancer drug resistance and circulating tumor cells (CTC) in mice

avβ3+ tumor cells recruit macrophages, but not NK cells

LM609 prevents acquired drug resistance in vivo

LM609 prevents the enrichment of β3 expression

LM609 prevents the emergence of circulating tumor cells

Anti-tumor activity of anti-avβ3 in mice depends on tumor associated macrophages (TAMs)

Mice treated with clodronate liposomes to deplete macrophages