The tetravalent bispecific NK-cell engaging antibody AFM13 (CD30/CD16A) engages and primes innate
immune cells for anti-cancer immunity
Martin Treder, PhD
Affimed GmbH
AACR Annual Meeting 2017
Forward-looking statements / safe harbor
This presentation and the accompanying oral commentary contain “forward-looking” statements that involve substantial risks and uncertainties. All statements other than statements of historical facts contained in this presentation and the accompanying oral commentary, including statements regarding our future financial condition, business strategy and plans and objectives ofmanagement for future operations, are forward-looking statements. In some cases, you can identify forward-looking statements by terminology such as “believe,” “will,” “may,” “estimate,” “continue,” “anticipate,” “intend,” “should,” “plan,”“might,” “approximately,” “expect,” “predict,” “could,” “potentially” or the negative of these terms or other similar expressions. Forward-looking statements appear in a number of places throughout this presentation and the accompanying oral commentary and include statements regarding our intentions, beliefs, projections, outlook, analyses and current expectations concerning, among other things, our ongoing and planned preclinical development and clinical trials, our collaborations and development of our products in combination with other therapies, the timing of and our ability to make regulatory filings and obtain and maintain regulatory approvals for our product candidates our intellectual property position, our collaboration activities, our ability to develop commercial functions, expectations regarding clinical trial data, our results of operations, cash needs, financial condition, liquidity, prospects, future transactions, growth and strategies, the industry in which we operate, the trends that may affect the industry or us and the risks uncertainties and other factors described underthe heading “Risk Factors” in Affimed’s filings with the Securities and Exchange Commission.
Forward-looking statements involve known and unknown risks, uncertainties, assumptions and other factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements.
Forward-looking statements represent our management’s beliefs and assumptions only as of the date of this presentation. Except as required by law, we assume no obligation to update these forward-looking statements publicly, or to update the reasons why actual results could differ materially from those anticipated in the forward-looking statements, even if new information becomes available in the future.
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Disclosures
• I have the following financial relationship to disclose:
• Employee of Affimed (Nasdaq: AFMD)
• I will not discuss off label use and/or investigational use in my presentation
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Cancer: Dysregulated NK-cells need to be(re-)activated therapeutically
Pahl & Cerwenka, Immunobiology, 2017
CD16A-specific tetravalent,bispecific antibodies with
high affinity and specificity
Highly potent NK-cellactivation
and immune-cell crosstalk
Affimed technology: (re-)activation of NK-cell
anti-tumor responses
Tumor escape Immuno-surveillance
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Affimed develops bispecific NK- and T-cell engagers to treat hematologic and solid tumors
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AFM13: A first-in-class CD16A-targeting NK-cell engager
• Clinical/PD activity in heavily pretreated HL patients:
• In Phase 1, tumor shrinkage in 62% and PRs in 23% of patients treated
• Favorable safety profile, offering opportunities for combination with wide range of other drugs
• Phase 2 monotherapy trial (NCT02321592) and Phase 1b combination trial of AFM13 + pembrolizumab (NCT02665650) in patients with relapsed or refractory HL ongoing
• Well differentiated from regular IgG or Fc-enhanced IgG antibodies
• Synergy with checkpoint modulators, such as PD-1 (PDX model), further combination opportunities to enhance efficacy, such as with cytokines
• Achieving more potent and deeper response through CD16A-binding (enhances crosstalk with adaptive immune cells)
CD16A-binding addresses issues inherent in monoclonal antibody approaches
• Specificity: CD16A binding engages NK-cells or macrophages; no binding to CD16B on neutrophils
• Affinity: >1000x higher to CD16A as compared to monoclonal antibodies
• Potency and efficacy: improved as compared with anti-CD30 IgG1 and Fc-engineered anti-CD30 IgG1
• Overcomes factors influencing IgG efficacy
• Independent of 158 V/F polymorphisms
• Virtually no competition for NK-cell binding by circulating IgG
Efficacy of target cell lysis in vitro
AFM13
Fc-enh. CD30 IgG1
CD30 IgG
AFM13
CD30 IgG
Fc-enh. CD30 IgG
Mean
flo
ure
scen
ce
inte
nsit
y
IgG concentration (mg/ml)
Binding to primary human NK-cells
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NK-cell activation is mediated by AFM13
• AFM13 target cell binding results in an activated NK-cell phenotype with specificmarkers on NK-cells being upregulated in response to AFM13-induced CD30+
target cell lysis
• Modulation of NK-cells by AFM13 suggests potential synergy with check-point modulators and cytokines
CD25IL-2RCD137
CD132IL-2R NKp46
NK-cells + target + control antibody
NK-cells + target + AFM13NK-cells only
NK-cells + AFM13
DNAM-1CD69
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NK-cells show improved IL-2- and IL-15-mediated proliferation after exposure to AFM13.
Exposure
CFSE+ NK cells
coated AFM13or medium
replate residual NK
1d
Culture
IL-2 titrationIL-15 titration
6d0d
20h 5d
Analyze CFSE and count NK cells
medium
IL-2coated AFM13
IL-2
12.5 U/mL
25 U/mL
50 U/mL
100 U/mL
200 U/mL
400 U/mL
AFM13 sensitizes NK-cells to cytokine stimulation and proliferation
sensitization also achieved by IL-15
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Restimulation: AFM13-opsonized targets
Lysis Intracell. IFN-
coated AFM13medium coated AFM13 IL-2
rescue also achieved by IL-15
Transient NK-cell dysfunction can be restored by cytokine recovery (enhanced by AFM13)
After recovery, NK-cells are potent for a new round of AFM13-mediated killing.
Exposure
NK cells
coated AFM13or medium
NK phenotype
replate residual NK
1d
Culture
IL-26d0d
20h 5d
NK phenotype
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Model: AFM13-mediated NK-cell activation and AFM13-supported cytokine recovery of NK-cell cytotoxicity after transient dysfunction
Conclusions
• NK-cells are potent cytotoxic effectors important for tumor immuno-surveillance
• Tumor targeting and activation of NK-cells via bispecific tetravalentCD16A-specific engagers provides high efficacy and potency independentof CD16A polymorphism and serum IgG competition
• AFM13 immunomodulates and results in an activated NK-cell phenotype
• AFM13 sensitizes NK-cells to IL-2 and IL-15 stimulation
• Phase 2 monotherapy and Phase 1b combination trials of AFM13 + pembrolizumab in r/r HL patients are ongoing
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Acknowledgments
Frank MalischewskyClaudia LinhardMelanie KuhseSonja RichtJessica KientzSarah FlößerPhillip FiegerUte Schniegler-MattoxThomas MüllerJürgen WeikCarolin BöhmAndre MüllerStefanie WolffAlexandra StolarekRaphael BleilerTatjana KosbarTorsten HanekeCarmen Herbrecht
Martin Treder Erich RajkovicIvica FucekKristina EllwangerMichael WeichelUwe ReuschStefan KnackmussThorsten GantkeMichael TesarMichael KlugeJoachim Koch
Vera MolkenthinVolker Lang
Adelheid CerwenkaJens Pahl