The tetravalent bispecific NK-cell engaging antibody AFM13 (CD30/CD16A) engages and primes innate immune cells for anti-cancer immunity

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1 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

2 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 of management 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 under the 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. 2

3 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 3

4 Cancer: Dysregulated NK-cells need to be (re-)activated therapeutically Affimed technology: (re-)activation of NK-cell anti-tumor responses Tumor escape Immuno-surveillance CD16A-specific tetravalent, bispecific antibodies with high affinity and specificity Highly potent NK-cell activation and immune-cell crosstalk Pahl & Cerwenka, Immunobiology,

5 Affimed develops bispecific NK- and T-cell engagers to treat hematologic and solid tumors 5

6 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 (NCT ) and Phase 1b combination trial of AFM13 + pembrolizumab (NCT ) 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) 6

7 Mean flourescence intensity 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 IgG 1 and Fc-engineered anti-cd30 IgG 1 Overcomes factors influencing IgG efficacy Independent of 158 V/F polymorphisms Virtually no competition for NK-cell binding by circulating IgG Binding to primary human NK-cells IgG concentration (mg/ml) Efficacy of target cell lysis in vitro AFM13 Fc-enh. CD30 IgG 1 CD30 IgG AFM13 CD30 IgG Fc-enh. CD30 IgG 7

8 NK-cell activation is mediated by AFM13 AFM13 target cell binding results in an activated NK-cell phenotype with specific markers 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 CD69 CD137 CD25 IL-2R CD132 IL-2R NKp46 DNAM-1 NK-cells only NK-cells + AFM13 NK-cells + target + AFM13 NK-cells + target + control antibody 8

9 AFM13 sensitizes NK-cells to cytokine stimulation and proliferation medium IL U/mL coated AFM13 IL-2 Exposure coated AFM13 0d or medium CFSE+ NK cells 20h 1d replate residual NK Culture IL-2 titration IL-15 titration 5d 6d Analyze CFSE and count NK cells 25 U/mL 50 U/mL 100 U/mL 200 U/mL 400 U/mL NK-cells show improved IL-2- and IL-15-mediated proliferation after exposure to AFM13. sensitization also achieved by IL-15 9

10 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 coated AFM13 0d or medium 20h 1d Culture IL-2 5d 6d Restimulation: AFM13-opsonized targets NK cells NK phenotype replate residual NK NK phenotype Lysis Intracell. IFN- rescue also achieved by IL-15 medium coated AFM13 coated AFM13 IL-2 10

11 Model: AFM13-mediated NK-cell activation and AFM13- supported cytokine recovery of NK-cell cytotoxicity after transient dysfunction 11

12 Conclusions NK-cells are potent cytotoxic effectors important for tumor immunosurveillance Tumor targeting and activation of NK-cells via bispecific tetravalent CD16A-specific engagers provides high efficacy and potency independent of 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 12

13 Acknowledgments Martin Treder Erich Rajkovic Ivica Fucek Kristina Ellwanger Michael Weichel Uwe Reusch Stefan Knackmuss Thorsten Gantke Michael Tesar Michael Kluge Joachim Koch Frank Malischewsky Claudia Linhard Melanie Kuhse Sonja Richt Jessica Kientz Sarah Flößer Phillip Fieger Ute Schniegler-Mattox Thomas Müller Jürgen Weik Carolin Böhm Andre Müller Stefanie Wolff Alexandra Stolarek Raphael Bleiler Tatjana Kosbar Torsten Haneke Carmen Herbrecht Vera Molkenthin Volker Lang Adelheid Cerwenka Jens Pahl 13